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  • Free radical‐initiated peptide sequencing (FRIPS)‐based cross‐linkers for improved peptide and protein structure analysis
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-04-16
    Claudio Iacobucci; Mathias Schäfer; Andrea Sinz

    Free radical‐initiated peptide sequencing (FRIPS) has recently been introduced as an analytical strategy to create peptide radical ions in a predictable and effective way by collisional activation of specifically modified peptides ions. FRIPS is based on the unimolecular dissociation of open‐shell ions and yields fragments that resemble those obtained by electron capture dissociation (ECD) or electron transfer dissociation (ETD). In this review article, we describe the fundamentals of FRIPS and highlight its fruitful combination with chemical cross‐linking/mass spectrometry (MS) as a highly promising option to derive complementary structural information of peptides and proteins. FRIPS does not only yield exhaustive sequence information of cross‐linked peptides, but also defines the exact cross‐linking sites of the connected peptides. The development of more advanced FRIPS cross‐linkers that extend the FRIPS‐based cross‐linking/MS approach to the study of large protein assemblies and protein interaction networks can be eagerly anticipated.

  • Electron‐ion reaction‐based dissociation: A powerful ion activation method for the elucidation of natural product structures
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-03-30
    Xiangfeng Chen; Ze Wang; Y.‐L. Elaine Wong; Ri Wu; Feng Zhang; T.‐W. Dominic Chan

    The structural elucidation of natural products (NPs) remains a challenge due to their structurally diversities and unpredictable functionalities, motifs, and scaffolds. Tandem mass spectrometry (MS/MS) is an effective method that assists the full elucidation of complicated NP structures. Ion activation methods play a key role in determining the fragmentation pathways and the structural information obtained from MS/MS. Electron‐ion reaction‐based dissociation (ExD) methods, including electron capture dissociation (ECD), electron transfer dissociation (ETD), electron‐induced dissociation (EID), and electron detachment dissociation (EDD), can induce the breakage of specific chemical bonds and the generation of distinct fragment ions. This review article provides an overview of the mechanisms, instrumentation, and typical applications related to ExD MS/MS in the structural elucidation of NPs, primarly including lipids, oligosaccharides, glycoconjugates, metabolites, and pharmaceutical drugs. This work aims to reveal the capacity and potential of ExD mass spectrometry in analyzing NPs and consequently helping the NP communities to utilize the modern capabilities of MS/MS in the discovery and evaluation of novel NPs.

  • Hydrogen/deuterium exchange in mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-03-30
    Yury Kostyukevich; Thamina Acter; Alexander Zherebker; Arif Ahmed; Sunghwan Kim; Eugene Nikolaev

    The isotopic exchange approach is in use since the first observation of such reactions in 1933 by Lewis. This approach allows the investigation of the pathways of chemical and biochemical reactions, determination of structure, composition, and conformation of molecules. Mass spectrometry has now become one of the most important analytical tools for the monitoring of the isotopic exchange reactions. Investigation of conformational dynamics of proteins, quantitative measurements, obtaining chemical, and structural information about individual compounds of the complex natural mixtures are mainly based on the use of isotope exchange in combination with high resolution mass spectrometry. The most important reaction is the Hydrogen/Deuterium exchange, which is mainly performed in the solution. Recently we have developed the approach allowing performing of the Hydrogen/Deuterium reaction on‐line directly in the ionization source under atmospheric pressure. Such approach simplifies the sample preparation and can accelerate the exchange reaction so that certain hydrogens that are considered as non‐labile will also participate in the exchange. The use of in‐ionization source H/D exchange in modern mass spectrometry for structural elucidation of molecules serves as the basic theme in this review. We will focus on the mechanisms of the isotopic exchange reactions and on the application of in‐ESI, in‐APCI, and in‐APPI source Hydrogen/Deuterium exchange for the investigation of petroleum, natural organic matter, oligosaccharides, and proteins including protein‐protein complexes. The simple scenario for adaptation of H/D exchange reactions into mass spectrometric method is also highlighted along with a couple of examples collected from previous studies.

  • Molecules and elements for quantitative bioanalysis: The allure of using electrospray, MALDI, and ICP mass spectrometry side‐by‐side
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-03-30
    Michael W. Linscheid

    To understand biological processes, not only reliable identification, but quantification of constituents in biological processes play a pivotal role. This is especially true for the proteome: protein quantification must follow protein identification, since sometimes minute changes in abundance tell the real tale. To obtain quantitative data, many sophisticated strategies using electrospray and MALDI mass spectrometry (MS) have been developed in recent years. All of them have advantages and limitations. Several years ago, we started to work on strategies, which are principally capable to overcome some of these limits. The fundamental idea is to use elemental signals as a measure for quantities. We began by replacing the radioactive 32P with the “cold” natural 31P to quantify modified nucleotides and phosphorylated peptides and proteins and later used tagging strategies for quantification of proteins more generally. To do this, we introduced Inductively Coupled Plasma Mass Spectrometry (ICP‐MS) into the bioanalytical workflows, allowing not only reliable and sensitive detection but also quantification based on isotope dilution absolute measurements using poly‐isotopic elements. The detection capability of ICP‐MS becomes particularly attractive with heavy metals. The covalently bound proteins tags developed in our group are based on the well‐known DOTA chelate complex (1,4,7,10‐tetraazacyclododecane‐N,N′,N″,N‴‐tetraacetic acid) carrying ions of lanthanoides as metal core. In this review, I will outline the development of this mutual assistance between molecular and elemental mass spectrometry and discuss the scope and limitations particularly of peptide and protein quantification. The lanthanoide tags provide low detection limits, but offer multiplexing capabilities due to the number of very similar lanthanoides and their isotopes. With isotope dilution comes previously unknown accuracy. Separation techniques such as electrophoresis and HPLC were used and just slightly adapted workflows, already in use for quantification in bioanalysis. Imaging mass spectrometry (MSI) with MALDI and laser ablation ICP‐MS complemented the range of application in recent years.

  • Mass spectrometry for protein sialoglycosylation
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 11 Decembe
    Qiwei Zhang; Zack Li; Yawei Wang; Qi Zheng; Jianjun Li

    Sialic acids are a family of structurally unique and negatively charged nine‐carbon sugars, normally found at the terminal positions of glycan chains on glycoproteins and glycolipids. The glycosylation of proteins is a universal post‐translational modification in eukaryotic species and regulates essential biological functions, in which the most common sialic acid is N‐acetyl‐neuraminic acid (2‐keto‐5‐acetamido‐3,5‐dideoxy‐D‐glycero‐D‐galactononulopyranos‐1‐onic acid) (Neu5NAc). Because of the properties of sialic acids under general mass spectrometry (MS) conditions, such as instability, ionization discrimination, and mixed adducts, the use of MS in the analysis of protein sialoglycosylation is still challenging. The present review is focused on the application of MS related methodologies to the study of both N‐ and O‐linked sialoglycans. We reviewed MS‐based strategies for characterizing sialylation by analyzing intact glycoproteins, proteolytic digested glycopeptides, and released glycans. The review concludes with future perspectives in the field.

  • Mass spectrometry of aerosol particle analogues in molecular beam experiments
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 27 Novembe
    Michal Fárník; Jozef Lengyel

    Nanometer‐size particles such as ultrafine aerosol particles, ice nanoparticles, water nanodroplets, etc, play an important, however, not yet fully understood role in the atmospheric chemistry and physics. These species are often composed of water with admixture of other atmospherically relevant molecules. To mimic and investigate such particles in laboratory experiments, mixed water clusters with atmospherically relevant molecules can be generated in molecular beams and studied by various mass spectrometric methods. The present review demonstrates that such experiments can provide unprecedented details of reaction mechanisms, and detailed insight into the photon‐, electron‐, and ion‐induced processes relevant to the atmospheric chemistry. After a brief outline of the molecular beam preparation, cluster properties, and ionization methods, we focus on the mixed clusters with various atmospheric molecules, such as hydrated sulfuric acid and nitric acid clusters, NxOy and halogen‐containing molecules with water. A special attention is paid to their reactivity and solvent effects of water molecules on the observed processes.

  • Mass spectrometry‐based metabolomics: Targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 12 Novembe
    Hemi Luan; Xian Wang; Zongwei Cai

    Metabolomics seeks to take a “snapshot” in a time of the levels, activities, regulation and interactions of all small molecule metabolites in response to a biological system with genetic or environmental changes. The emerging development in mass spectrometry technologies has shown promise in the discovery and quantitation of neuroactive small molecule metabolites associated with gut microbiota and brain. Significant progress has been made recently in the characterization of intermediate role of small molecule metabolites linked to neural development and neurodegenerative disorder, showing its potential in understanding the crosstalk between gut microbiota and the host brain. More evidence reveals that small molecule metabolites may play a critical role in mediating microbial effects on neurotransmission and disease development. Mass spectrometry‐based metabolomics is uniquely suitable for obtaining the metabolic signals in bidirectional communication between gut microbiota and brain. In this review, we summarized major mass spectrometry technologies including liquid chromatography‐mass spectrometry, gas chromatography‐mass spectrometry, and imaging mass spectrometry for metabolomics studies of neurodegenerative disorders. We also reviewed the recent advances in the identification of new metabolites by mass spectrometry and metabolic pathways involved in the connection of intestinal microbiota and brain. These metabolic pathways allowed the microbiota to impact the regular function of the brain, which can in turn affect the composition of microbiota via the neurotransmitter substances. The dysfunctional interaction of this crosstalk connects neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. The mass spectrometry‐based metabolomics analysis provides information for targeting dysfunctional pathways of small molecule metabolites in the development of the neurodegenerative diseases, which may be valuable for the investigation of underlying mechanism of therapeutic strategies.

  • Analysis of the plasma proteome using iTRAQ and TMT‐based Isobaric labeling
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 09 Novembe
    Robert Moulder; Santosh D. Bhosale; David R. Goodlett; Riitta Lahesmaa

    Over the past decade, chemical labeling with isobaric tandem mass tags, such as isobaric tags for relative and absolute quantification reagents (iTRAQ) and tandem mass tag (TMT) reagents, has been employed in a wide range of different clinically orientated serum and plasma proteomics studies. In this review the scope of these works is presented with attention to the areas of research, methods employed and performance limitations. These applications have covered a wide range of diseases, disorders and infections, and have implemented a variety of different preparative and mass spectrometric approaches. In contrast to earlier works, which struggled to quantify more than a few hundred proteins, increasingly these studies have provided deeper insight into the plasma proteome extending the numbers of quantified proteins to over a thousand.

  • A tutorial in small molecule identification via electrospray ionization‐mass spectrometry: The practical art of structural elucidation
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 09 Novembe
    Thomas De Vijlder; Dirk Valkenborg; Filip Lemière; Edwin P. Romijn; Kris Laukens; Filip Cuyckens

    The identification of unknown molecules has been one of the cornerstone applications of mass spectrometry for decades. This tutorial reviews the basics of the interpretation of electrospray ionization‐based MS and MS/MS spectra in order to identify small‐molecule analytes (typically below 2000 Da). Most of what is discussed in this tutorial also applies to other atmospheric pressure ionization methods like atmospheric pressure chemical/photoionization. We focus primarily on the fundamental steps of MS‐based structural elucidation of individual unknown compounds, rather than describing strategies for large‐scale identification in complex samples. We critically discuss topics like the detection of protonated and deprotonated ions ([M + H]+ and [M − H]−) as well as other adduct ions, the determination of the molecular formula, and provide some basic rules on the interpretation of product ion spectra. Our tutorial focuses primarily on the fundamental steps of MS‐based structural elucidation of individual unknown compounds (eg, contaminants in chemical production, pharmacological alteration of drugs), rather than describing strategies for large‐scale identification in complex samples. This tutorial also discusses strategies to obtain useful orthogonal information (UV/Vis, H/D exchange, chemical derivatization, etc) and offers an overview of the different informatics tools and approaches that can be used for structural elucidation of small molecules. It is primarily intended for beginning mass spectrometrists and researchers from other mass spectrometry sub‐disciplines that want to get acquainted with structural elucidation are interested in some practical tips and tricks.

  • Ion traps in modern mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 30 October
    Dirk Nolting; Robert Malek; Alexander Makarov

    This review is devoted to trapping mass spectrometry wherein ions are confined by electromagnetic fields for prolonged periods of time within limited volume, with mass measurement taking place within the same volume. Three major types of trapping mass spectrometers are discussed, specifically radiofrequency ion trap, Fourier transform ion cyclotron resonance and Orbitrap. While these three branches are intricately interwoven with each other over their recent history, they also differ greatly in their fundamentals, roots and historical origin. This diversity is reflected also in the difference of viewpoints from which each of these directions is addressed in this review. Following the theme of the issue, we focus on developments mainly associated with the country of Germany but, at the same time, we use this review as an illustration of the rapidly increasing globalization of science and expanding multi‐national collaborations.

  • Metabolomics toward personalized medicine
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 26 October
    Minnie Jacob; Andreas L. Lopata; Majed Dasouki; Anas M. Abdel Rahman

    Metabolomics, which is the metabolites profiling in biological matrices, is a key tool for biomarker discovery and personalized medicine and has great potential to elucidate the ultimate product of the genomic processes. Over the last decade, metabolomics studies have identified several relevant biomarkers involved in complex clinical phenotypes using diverse biological systems. Most diseases result in signature metabolic profiles that reflect the sums of external and internal cellular activities. Metabolomics has a major role in clinical practice as it represents >95% of the workload in clinical laboratories worldwide. Many of these metabolites require different analytical platforms, such as Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), and Ultra Performance Liquid Chromatography (UPLC), while many clinically relevant metabolites are still not routinely amenable to detection using currently available assays. Combining metabolomics with genomics, transcriptomics, and proteomics studies will result in a significantly improved understanding of the disease mechanisms and the pathophysiology of the target clinical phenotype. This comprehensive approach will represent a major step forward toward providing precision medical care, in which individual is accounted for variability in genes, environment, and personal lifestyle. In this review, we compare and evaluate the metabolomics strategies and studies that focus on the discovery of biomarkers that have “personalized” diagnostic, prognostic, and therapeutic value, validated for monitoring disease progression and responses to various management regimens.

  • Laser desorption ionization mass spectrometry: Recent progress in matrix‐free and label‐assisted techniques
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 13 October
    Arundhoti Mandal; Monisha Singha; Partha Sarathi Addy; Amit Basak

    The MALDI‐based mass spectrometry, over the last three decades, has become an important analytical tool. It is a gentle ionization technique, usually applicable to detect and characterize analytes with high molecular weights like proteins and other macromolecules. The earlier difficulty of detection of analytes with low molecular weights like small organic molecules and metal ion complexes with this technique arose due to the cluster of peaks in the low molecular weight region generated from the matrix. To detect such molecules and metal ion complexes, a four‐prong strategy has been developed. These include use of alternate matrix materials, employment of new surface materials that require no matrix, use of metabolites that directly absorb the laser light, and the laser‐absorbing label‐assisted LDI‐MS (popularly known as LALDI‐MS). This review will highlight the developments with all these strategies with a special emphasis on LALDI‐MS.

  • Anatomy and evolution of database search engines—a central component of mass spectrometry based proteomic workflows
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 13 Septemb
    Kenneth Verheggen; Helge Ræder; Frode S. Berven; Lennart Martens; Harald Barsnes; Marc Vaudel

    Sequence database search engines are bioinformatics algorithms that identify peptides from tandem mass spectra using a reference protein sequence database. Two decades of development, notably driven by advances in mass spectrometry, have provided scientists with more than 30 published search engines, each with its own properties. In this review, we present the common paradigm behind the different implementations, and its limitations for modern mass spectrometry datasets. We also detail how the search engines attempt to alleviate these limitations, and provide an overview of the different software frameworks available to the researcher. Finally, we highlight alternative approaches for the identification of proteomic mass spectrometry datasets, either as a replacement for, or as a complement to, sequence database search engines.

  • Quality control in mass spectrometry‐based proteomics
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 07 Septemb
    Wout Bittremieux; David L. Tabb; Francis Impens; An Staes; Evy Timmerman; Lennart Martens; Kris Laukens

    Mass spectrometry is a highly complex analytical technique and mass spectrometry‐based proteomics experiments can be subject to a large variability, which forms an obstacle to obtaining accurate and reproducible results. Therefore, a comprehensive and systematic approach to quality control is an essential requirement to inspire confidence in the generated results. A typical mass spectrometry experiment consists of multiple different phases including the sample preparation, liquid chromatography, mass spectrometry, and bioinformatics stages. We review potential sources of variability that can impact the results of a mass spectrometry experiment occurring in all of these steps, and we discuss how to monitor and remedy the negative influences on the experimental results. Furthermore, we describe how specialized quality control samples of varying sample complexity can be incorporated into the experimental workflow and how they can be used to rigorously assess detailed aspects of the instrument performance.

  • Standardization approaches in absolute quantitative proteomics with mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 31 July 20
    Francisco Calderón‐Celis; Jorge Ruiz Encinar; Alfredo Sanz‐Medel

    Mass spectrometry‐based approaches have enabled important breakthroughs in quantitative proteomics in the last decades. This development is reflected in the better quantitative assessment of protein levels as well as to understand post‐translational modifications and protein complexes and networks. Nowadays, the focus of quantitative proteomics shifted from the relative determination of proteins (ie, differential expression between two or more cellular states) to absolute quantity determination, required for a more‐thorough characterization of biological models and comprehension of the proteome dynamism, as well as for the search and validation of novel protein biomarkers. However, the physico‐chemical environment of the analyte species affects strongly the ionization efficiency in most mass spectrometry (MS) types, which thereby require the use of specially designed standardization approaches to provide absolute quantifications. Most common of such approaches nowadays include (i) the use of stable isotope‐labeled peptide standards, isotopologues to the target proteotypic peptides expected after tryptic digestion of the target protein; (ii) use of stable isotope‐labeled protein standards to compensate for sample preparation, sample loss, and proteolysis steps; (iii) isobaric reagents, which after fragmentation in the MS/MS analysis provide a final detectable mass shift, can be used to tag both analyte and standard samples; (iv) label‐free approaches in which the absolute quantitative data are not obtained through the use of any kind of labeling, but from computational normalization of the raw data and adequate standards; (v) elemental mass spectrometry‐based workflows able to provide directly absolute quantification of peptides/proteins that contain an ICP‐detectable element. A critical insight from the Analytical Chemistry perspective of the different standardization approaches and their combinations used so far for absolute quantitative MS‐based (molecular and elemental) proteomics is provided in this review.

  • The Skyline ecosystem: Informatics for quantitative mass spectrometry proteomics
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 09 July 20
    Lindsay K. Pino; Brian C. Searle; James G. Bollinger; Brook Nunn; Brendan MacLean; Michael J. MacCoss

    Skyline is a freely available, open‐source Windows client application for accelerating targeted proteomics experimentation, with an emphasis on the proteomics and mass spectrometry community as users and as contributors. This review covers the informatics encompassed by the Skyline ecosystem, from computationally assisted targeted mass spectrometry method development, to raw acquisition file data processing, and quantitative analysis and results sharing.

  • Discovering cellular protein‐protein interactions: Technological strategies and opportunities
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-06-29
    Kevin Titeca; Irma Lemmens; Jan Tavernier; Sven Eyckerman

    The analysis of protein interaction networks is one of the key challenges in the study of biology. It connects genotypes to phenotypes, and disruption often leads to diseases. Hence, many technologies have been developed to study protein‐protein interactions (PPIs) in a cellular context. The expansion of the PPI technology toolbox however complicates the selection of optimal approaches for diverse biological questions. This review gives an overview of the binary and co‐complex technologies, with the former evaluating the interaction of two co‐expressed genetically tagged proteins, and the latter only needing the expression of a single tagged protein or no tagged proteins at all. Mass spectrometry is crucial for some binary and all co‐complex technologies. After the detailed description of the different technologies, the review compares their unique specifications, advantages, disadvantages, and applicability, while highlighting opportunities for further advancements.

  • Mass spectrometry is a multifaceted weapon to be used in the battle against Alzheimer's disease: Amyloid beta peptides and beyond
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-06-15
    Giuseppe Grasso

    Amyloid‐β peptide (Aβ) accumulation and aggregation have been considered for many years the main cause of Alzheimer's disease (AD), and therefore have been the principal target of investigation as well as of the proposed therapeutic approaches (Grasso [2011] Mass Spectrom Rev. 30: 347‐365). However, the amyloid cascade hypothesis, which considers Aβ accumulation the only causative agent of the disease, has proven to be incomplete if not wrong. In recent years, actors such as metal ions, oxidative stress, and other cofactors have been proposed as possible co‐agents or, in some cases, main causative factors of AD. In this scenario, MS investigation has proven to be fundamental to design possible diagnostic strategies of this elusive disease, as well as to understand the biomolecular mechanisms involved, in the attempt to find a possible therapeutic solution. We review the current applications of MS in the search for possible Aβ biomarkers of AD to help the diagnosis of the disease. Recent examples of the important contributions that MS has given to prove or build theories on the molecular pathways involved with such terrible disease are also reviewed.

  • DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-06-11
    Byeong Hwa Yun; Jingshu Guo; Medjda Bellamri; Robert J. Turesky

    Hazardous chemicals in the environment and diet or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. In addition, reactive intermediates can be generated in the body through oxidative stress and damage the genome. The identification and measurement of DNA adducts are required for understanding exposure and the causal role of a genotoxic chemical in cancer risk. Over the past three decades, 32P‐postlabeling, immunoassays, gas chromatography/mass spectrometry, and liquid chromatography/mass spectrometry (LC/MS) methods have been established to assess exposures to chemicals through measurements of DNA adducts. It is now possible to measure some DNA adducts in human biopsy samples, by LC/MS, with as little as several milligrams of tissue. In this review article, we highlight the formation and biological effects of DNA adducts, and highlight our advances in human biomonitoring by mass spectrometric analysis of formalin‐fixed paraffin‐embedded tissues, untapped biospecimens for carcinogen DNA adduct biomarker research.

  • Proteomics biomarkers for solid tumors: Current status and future prospects
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-06-11
    Iwona Belczacka; Agnieszka Latosinska; Jochen Metzger; David Marx; Antonia Vlahou; Harald Mischak; Maria Frantzi

    Cancer is a heterogeneous multifactorial disease, which continues to be one of the main causes of death worldwide. Despite the extensive efforts for establishing accurate diagnostic assays and efficient therapeutic schemes, disease prevalence is on the rise, in part, however, also due to improved early detection. For years, studies were focused on genomics and transcriptomics, aiming at the discovery of new tests with diagnostic or prognostic potential. However, cancer phenotypic characteristics seem most likely to be a direct reflection of changes in protein metabolism and function, which are also the targets of most drugs. Investigations at the protein level are therefore advantageous particularly in the case of in‐depth characterization of tumor progression and invasiveness. Innovative high‐throughput proteomic technologies are available to accurately evaluate cancer formation and progression and to investigate the functional role of key proteins in cancer. Employing these new highly sensitive proteomic technologies, cancer biomarkers may be detectable that contribute to diagnosis and guide curative treatment when still possible. In this review, the recent advances in proteomic biomarker research in cancer are outlined, with special emphasis placed on the identification of diagnostic and prognostic biomarkers for solid tumors. In view of the increasing number of screening programs and clinical trials investigating new treatment options, we discuss the molecular connections of the biomarkers as well as their potential as clinically useful tools for diagnosis, risk stratification and therapy monitoring of solid tumors.

  • Cross‐linked peptide identification: A computational forest of algorithms
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-03-12
    Şule Yılmaz; Genet A. Shiferaw; Josep Rayo; Anastassios Economou; Lennart Martens; Elien Vandermarliere

    Chemical cross‐linking analyzed by mass spectrometry (XL‐MS) has become an important tool in unravelling protein structure, dynamics, and complex formation. Because the analysis of cross‐linked proteins with mass spectrometry results in specific computational challenges, many computational tools have been developed to identify cross‐linked peptides from mass spectra and subsequently interpret the identified cross‐links within their structural context. In this review, we will provide an overview of the different tools that are currently available to tackle the computational part of an XL‐MS experiment. First, we give an introduction on the computational challenges encountered when processing data from a cross‐linking experiment. We then discuss available tools to identify peptides that are linked by intact or MS‐cleavable cross‐linkers, and we provide an overview of tools to interpret cross‐linked peptides in the context of protein structure. Finally, we give an outlook on data management and dissemination challenges and opportunities for cross‐linking experiments.

  • Negative ion laser desorption/ionization time‐of‐flight mass spectrometric analysis of small molecules by using nanostructured substrate as matrices
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-03-06
    Zian Lin; Zongwei Cai

    Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) is an excellent analytical technique for rapid and sensitive analysis of macromolecules such as polymers and proteins. However, the main drawback of MALDI‐TOF MS is its difficulty to detect small molecules with mass below 700 Da because of the intensive interference from MALDI matrix in the low mass region. In recent years there has been considerable interest in developing matrix‐free laser desorption/ionization by using nanostructured substrates to substitute the conventional organic matrices, which is often referred as surface‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (SALDI‐TOF MS). Despite these attractive features, most of the current SALDI‐TOF MS for the analysis of small molecules employ positive ion mode, which is subjected to produce multiple alkali metal adducts, and thus increases the complexity of the analysis. Different from the complicated adducts produced in positive ion mode, mass spectra obtained in negative ion mode are featured by deprotonated ion peaks without matrix interference, which simplifies the interpretation of mass spectra and detection of unknown. In this review, we critically survey recent advances in nanostructured substrates for negative ion LDI‐TOF MS analysis of small molecules in the last 5 years. Special emphasis is placed on the preparation of the nanostructured substrates and the results achieved in negative ion SALDI‐MS. In addition, a variety of promising applications including environmental, biological, and clinical analysis are introduced. The ionization mechanism of negative ionization is briefly discussed.

  • Challenges and emergent solutions for LC‐MS/MS based untargeted metabolomics in diseases
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-02-27
    Liang Cui; Haitao Lu; Yie Hou Lee

    In the past decade, advances in liquid chromatography‐mass spectrometry (LC‐MS) have revolutionized untargeted metabolomics analyses. By mining metabolomes more deeply, researchers are now primed to uncover key metabolites and their associations with diseases. The employment of untargeted metabolomics has led to new biomarker discoveries and a better mechanistic understanding of diseases with applications in precision medicine. However, many major pertinent challenges remain. First, compound identification has been poor, and left an overwhelming number of unidentified peaks. Second, partial, incomplete metabolomes persist due to factors such as limitations in mass spectrometry data acquisition speeds, wide‐range of metabolites concentrations, and cellular/tissue/temporal‐specific expression changes that confound our understanding of metabolite perturbations. Third, to contextualize metabolites in pathways and biology is difficult because many metabolites partake in multiple pathways, have yet to be described species specificity, or possess unannotated or more‐complex functions that are not easily characterized through metabolomics analyses. From a translational perspective, information related to novel metabolite biomarkers, metabolic pathways, and drug targets might be sparser than they should be. Thankfully, significant progress has been made and novel solutions are emerging, achieved through sustained academic and industrial community efforts in terms of hardware, computational, and experimental approaches. Given the rapidly growing utility of metabolomics, this review will offer new perspectives, increase awareness of the major challenges in LC‐MS metabolomics that will significantly benefit the metabolomics community and also the broader the biomedical community metabolomics aspire to serve.

  • Radical solutions: Principles and application of electron‐based dissociation in mass spectrometry‐based analysis of protein structure
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-02-09
    Frederik Lermyte; Dirk Valkenborg; Joseph A. Loo; Frank Sobott

    In recent years, electron capture (ECD) and electron transfer dissociation (ETD) have emerged as two of the most useful methods in mass spectrometry‐based protein analysis, evidenced by a considerable and growing body of literature. In large part, the interest in these methods is due to their ability to induce backbone fragmentation with very little disruption of noncovalent interactions which allows inference of information regarding higher order structure from the observed fragmentation behavior. Here, we review the evolution of electron‐based dissociation methods, and pay particular attention to their application in “native” mass spectrometry, their mechanism, determinants of fragmentation behavior, and recent developments in available instrumentation. Although we focus on the two most widely used methods—ECD and ETD—we also discuss the use of other ion/electron, ion/ion, and ion/neutral fragmentation methods, useful for interrogation of a range of classes of biomolecules in positive‐ and negative‐ion mode, and speculate about how this exciting field might evolve in the coming years.

  • The expanding role of mass spectrometry in the field of vaccine development
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-05-31
    Vaneet Kumar Sharma; Ity Sharma; James Glick

    Biological mass spectrometry has evolved as a core analytical technology in the last decade mainly because of its unparalleled ability to perform qualitative as well as quantitative profiling of enormously complex biological samples with high mass accuracy, sensitivity, selectivity and specificity. Mass spectrometry‐based techniques are also routinely used to assess glycosylation and other post‐translational modifications, disulfide bond linkage, and scrambling as well as for the detection of host cell protein contaminants in the field of biopharmaceuticals. The role of mass spectrometry in vaccine development has been very limited but is now expanding as the landscape of global vaccine development is shifting towards the development of recombinant vaccines. In this review, the role of mass spectrometry in vaccine development is presented, some of the ongoing efforts to develop vaccines for diseases with global unmet medical need are discussed and the regulatory challenges of implementing mass spectrometry techniques in a quality control laboratory setting are highlighted.

  • On‐line reaction monitoring by mass spectrometry, modern approaches for the analysis of chemical reactions
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-06-19

    The application of on‐line mass spectrometry for direct analysis of chemical and other types of process continues to grow in importance and impact. The ability of the technique to characterize many aspects of a chemical reaction such as product and impurity formation, along with reactant consumption in a single experiment is key to its adoption and development. Innovations in ionization techniques and mass spectrometry instrumentation are enabling this adoption. An increasing range of ambient ionization techniques make on‐line mass spectrometry applicable to a large range of chemistries. The academic development and commercialization of small footprint portable/transportable mass spectrometers is providing technology that can be positioned with any process under investigation. These developments, coupled with research into new ways of sampling representatively from both the condensed and gaseous phases, are positioning mass spectrometry as an essential technology for on‐line process optimization, understanding and intelligent control. It is recognized that quantitative capability of mass spectrometry in this application can cause some resistance to its adoption, but research activities to tackle this limitation are on‐going.

  • Gas phase basicities of polyfunctional molecules. Part 6: Cyanides and isocyanides
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-06-16
    Guy Bouchoux

    This paper gathers structural and thermochemical informations related to the gas‐phase basicity of molecules containing cyanides (nitriles) and isocyanides (isonitriles) functional groups. It constitutes the sixth part of a general review devoted to gas‐phase basicities of polyfunctional compounds. A large corpus of cyanides and isocyanides molecules is examined under seven major chapters. In the first one, a rapid overview of the definitions and methods leading to gas‐phase basicity, GB, proton affinity, PA, and protonation entropy, ΔpS°, is given. In the same chapter, several aspects of the gas phase chemistry of protonated cyanides and isocyanides are also presented. Chapters II‐VI detail the protonation energetics of aliphatic, unsaturated, and heteroatom substituted (halogens, O, S, N, P) cyanides. A seventh chapter is devoted to isocyanides. Experimental data available in the literature (120 references) were reevaluated according to the presently adopted basicity scale that is the NIST database anchored to PA(NH3) = 853.6 kJ/mol and GB (NH3) = 819 kJ/mol. In this latter source, however, several erroneous values have been identified which were corrected in the present review. Structural and energetic information given by G4MP2 quantum chemistry computations on ca. 60 typical systems are presented. The present review includes the GB, PA, and ΔpS° values of ca. 110 cyanides and isocyanides, and, for selected examples, is completed by a set of computed heats of formation (ΔfH°) at 0 and 298 K.

  • Identification of small molecules using accurate mass MS/MS search
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-04-24
    Tobias Kind; Hiroshi Tsugawa; Tomas Cajka; Yan Ma; Zijuan Lai; Sajjan S. Mehta; Gert Wohlgemuth; Dinesh Kumar Barupal; Megan R. Showalter; Masanori Arita; Oliver Fiehn

    Tandem mass spectral library search (MS/MS) is the fastest way to correctly annotate MS/MS spectra from screening small molecules in fields such as environmental analysis, drug screening, lipid analysis, and metabolomics. The confidence in MS/MS‐based annotation of chemical structures is impacted by instrumental settings and requirements, data acquisition modes including data‐dependent and data‐independent methods, library scoring algorithms, as well as post‐curation steps. We critically discuss parameters that influence search results, such as mass accuracy, precursor ion isolation width, intensity thresholds, centroiding algorithms, and acquisition speed. A range of publicly and commercially available MS/MS databases such as NIST, MassBank, MoNA, LipidBlast, Wiley MSforID, and METLIN are surveyed. In addition, software tools including NIST MS Search, MS‐DIAL, Mass Frontier, SmileMS, Mass++, and XCMS2 to perform fast MS/MS search are discussed. MS/MS scoring algorithms and challenges during compound annotation are reviewed. Advanced methods such as the in silico generation of tandem mass spectra using quantum chemistry and machine learning methods are covered. Community efforts for curation and sharing of tandem mass spectra that will allow for faster distribution of scientific discoveries are discussed.

  • Marine environment pollution: The contribution of mass spectrometry to the study of seawater
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-09-09
    Emanuele Magi; Marina Di Carro

    The study of marine pollution has been traditionally addressed to persistent chemicals, generally known as priority pollutants; a current trend in environmental analysis is a shift toward “emerging pollutants,” defined as newly identified or previously unrecognized contaminants. The present review is focused on the peculiar contribution of mass spectrometry (MS) to the study of pollutants in the seawater compartment. The work is organized in five paragraphs where the most relevant groups of pollutants, both “classical” and “emerging,” are presented and discussed, highlighting the relative data obtained by the means of different MS techniques. The hyphenation of MS and separative techniques, together with the development of different ion sources, makes MS and tandem MS the analytical tool of choice for the determination of trace organic contaminants in seawater. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2013–2014
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2018-04-17
    David J. Harvey

    This review is the eighth update of the original article published in 1999 on the application of Matrix‐assisted laser desorption/ionization mass spectrometry (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2014. Topics covered in the first part of the review include general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation, and arrays. The second part of the review is devoted to applications to various structural types such as oligo‐ and poly‐ saccharides, glycoproteins, glycolipids, glycosides, and biopharmaceuticals. Much of this material is presented in tabular form. The third part of the review covers medical and industrial applications of the technique, studies of enzyme reactions, and applications to chemical synthesis.

  • On-line reaction monitoring by mass spectrometry, modern approaches for the analysis of chemical reactions
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-06-19
    Andrew Ray, Tony Bristow, Chris Whitmore, Jackie Mosely

    The application of on-line mass spectrometry for direct analysis of chemical and other types of process continues to grow in importance and impact. The ability of the technique to characterize many aspects of a chemical reaction such as product and impurity formation, along with reactant consumption in a single experiment is key to its adoption and development. Innovations in ionization techniques and mass spectrometry instrumentation are enabling this adoption. An increasing range of ambient ionization techniques make on-line mass spectrometry applicable to a large range of chemistries. The academic development and commercialization of small footprint portable/transportable mass spectrometers is providing technology that can be positioned with any process under investigation. These developments, coupled with research into new ways of sampling representatively from both the condensed and gaseous phases, are positioning mass spectrometry as an essential technology for on-line process optimization, understanding and intelligent control. It is recognized that quantitative capability of mass spectrometry in this application can cause some resistance to its adoption, but research activities to tackle this limitation are on-going.

  • Characterization of microbial mixtures by mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-05-16
    Todd R. Sandrin, Plamen A. Demirev

    MS applications in microbiology have increased significantly in the past 10 years, due in part to the proliferation of regulator-approved commercial MALDI MS platforms for rapid identification of clinical infections. In parallel, with the expansion of MS technologies in the “omics” fields, novel MS-based research efforts to characterize organismal as well as environmental microbiomes have emerged. Successful characterization of microorganisms found in complex mixtures of other organisms remains a major challenge for researchers and clinicians alike. Here, we review recent MS advances toward addressing that challenge. These include sample preparation methods and protocols, and established, for example, MALDI, as well as newer, for example, atmospheric pressure ionization (API) techniques. MALDI mass spectra of intact cells contain predominantly information on the highly expressed house-keeping proteins used as biomarkers. The API methods are applicable for small biomolecule analysis, for example, phospholipids and lipopeptides, and facilitate species differentiation. MS hardware and techniques, for example, tandem MS, including diverse ion source/mass analyzer combinations are discussed. Relevant examples for microbial mixture characterization utilizing these combinations are provided. Chemometrics and bioinformatics methods and algorithms, including those applied to large scale MS data acquisition in microbial metaproteomics and MS imaging of biofilms, are highlighted. Select MS applications for polymicrobial culture analysis in environmental and clinical microbiology are reviewed as well.

  • Mass spectrometry-driven drug discovery for development of herbal medicine
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-12-23
    Aihua Zhang, Hui Sun, Xijun Wang

    Herbal medicine (HM) has made a major contribution to the drug discovery process with regard to identifying products compounds. Currently, more attention has been focused on drug discovery from natural compounds of HM. Despite the rapid advancement of modern analytical techniques, drug discovery is still a difficult and lengthy process. Fortunately, mass spectrometry (MS) can provide us with useful structural information for drug discovery, has been recognized as a sensitive, rapid, and high-throughput technology for advancing drug discovery from HM in the post-genomic era. It is essential to develop an efficient, high-quality, high-throughput screening method integrated with an MS platform for early screening of candidate drug molecules from natural products. We have developed a new chinmedomics strategy reliant on MS that is capable of capturing the candidate molecules, facilitating their identification of novel chemical structures in the early phase; chinmedomics-guided natural product discovery based on MS may provide an effective tool that addresses challenges in early screening of effective constituents of herbs against disease. This critical review covers the use of MS with related techniques and methodologies for natural product discovery, biomarker identification, and determination of mechanisms of action. It also highlights high-throughput chinmedomics screening methods suitable for lead compound discovery illustrated by recent successes.

  • Signal preprocessing, multivariate analysis and software tools for MA(LDI)-TOF mass spectrometry imaging for biological applications
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-11-09
    Pere Ràfols, Dídac Vilalta, Jesús Brezmes, Nicolau Cañellas, Esteban del Castillo, Oscar Yanes, Noelia Ramírez, Xavier Correig

    Mass spectrometry imaging (MSI) is a label-free analytical technique capable of molecularly characterizing biological samples, including tissues and cell lines. The constant development of analytical instrumentation and strategies over the previous decade makes MSI a key tool in clinical research. Nevertheless, most MSI studies are limited to targeted analysis or the mere visualization of a few molecular species (proteins, peptides, metabolites, or lipids) in a region of interest without fully exploiting the possibilities inherent in the MSI technique, such as tissue classification and segmentation or the identification of relevant biomarkers from an untargeted approach. MSI data processing is challenging due to several factors. The large volume of mass spectra involved in a MSI experiment makes choosing the correct computational strategies critical. Furthermore, pixel to pixel variation inherent in the technique makes choosing the correct preprocessing steps critical. The primary aim of this review was to provide an overview of the data-processing steps and tools that can be applied to an MSI experiment, from preprocessing the raw data to the more advanced strategies for image visualization and segmentation. This review is particularly aimed at researchers performing MSI experiments and who are interested in incorporating new data-processing features, improving their computational strategy, and/or desire access to data-processing tools currently available. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX–XX, 2016.

  • Mass spectrometric strategies for the investigation of biomarkers of illicit drug use in wastewater
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-10-17
    Félix Hernández, Sara Castiglioni, Adrian Covaci, Pim de Voogt, Erik Emke, Barbara Kasprzyk-Hordern, Christoph Ort, Malcolm Reid, Juan V. Sancho, Kevin V. Thomas, Alexander L.N. van Nuijs, Ettore Zuccato, Lubertus Bijlsma

    The analysis of illicit drugs in urban wastewater is the basis of wastewater-based epidemiology (WBE), and has received much scientific attention because the concentrations measured can be used as a new non-intrusive tool to provide evidence-based and real-time estimates of community-wide drug consumption. Moreover, WBE allows monitoring patterns and spatial and temporal trends of drug use. Although information and expertise from other disciplines is required to refine and effectively apply WBE, analytical chemistry is the fundamental driver in this field. The use of advanced analytical techniques, commonly based on combined chromatography—mass spectrometry, is mandatory because the very low analyte concentration and the complexity of samples (raw wastewater) make quantification and identification/confirmation of illicit drug biomarkers (IDBs) troublesome. We review the most-recent literature available (mostly from the last 5 years) on the determination of IDBs in wastewater with particular emphasis on the different analytical strategies applied. The predominance of liquid chromatography coupled to tandem mass spectrometry to quantify target IDBs and the essence to produce reliable and comparable results is illustrated. Accordingly, the importance to perform inter-laboratory exercises and the need to analyze appropriate quality controls in each sample sequence is highlighted. Other crucial steps in WBE, such as sample collection and sample pre-treatment, are briefly and carefully discussed. The article further focuses on the potential of high-resolution mass spectrometry. Different approaches for target and non-target analysis are discussed, and the interest to perform experiments under laboratory-controlled conditions, as a complementary tool to investigate related compounds (e.g., minor metabolites and/or transformation products in wastewater) is treated. The article ends up with the trends and future perspectives in this field from the authors’ point of view. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Mass spectrometry-derived systems biology technologies delineate the system's biochemical applications of siderophores
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-08-31
    Qiao Su, Guang Xu, Tianbing Guan, Yumei Que, Haitao Lu

    Siderophores are chemically diverse secondary metabolites that primarily assist the host organisms to chelate iron. Siderophores are biosynthesized by many biological organisms, including bacteria, fungi, and plants and they are responsible for a variety of biological functions beyond capture iron. Thus, they could provide a novel understanding of host-pathogen interactions, plant physiology, disease pathogenesis, and drug development. However, knowledge gaps in analytical technologies, chemistry, and biology have severely impeded the applications of siderophores, and a new strategy is urgently needed to bridge these gaps. Mass spectrometry (MS) and associated technologies render unparalleled advantages in this niche in terms of high throughput, resolution, and sensitivity. Herein, this critical review briefly summarizes progress in the study of siderophores and specifically identifies MS-based novel strategies that attempt to mimic the complexity of siderophore systems in order to increase the applicability of these compounds in the scientific community. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX–XX, 2016.

  • Mass spectral fragmentation of trimethylsilylated small molecules
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-08-31
    Zijuan Lai, Oliver Fiehn

    Mass spectrometry-based untargeted metabolomics detects many peaks that cannot be identified. While advances have been made for automatic structure annotations in LC-electrospray-MS/MS, no open source solutions are available for hard electron ionization used in GC-MS. In metabolomics, most compounds bear moieties with acidic protons, for example, amino, hydroxyl, or carboxyl groups. Such functional groups increase the boiling points of metabolites too much for use in GC-MS. Hence, in GC-MS-focused metabolomics, derivatization of these groups is essential and has been employed since the 1960s. Specifically, trimethylsilylation is known as mild and universal method for GC-MS analysis. Here, we comprehensively compile accurate mass fragmentation rules and pathways of trimethylsilylated small molecules from 80 research articles over the past 5 decades, including diagnostic fragment ions, neutral losses, and typical ion ratios, for alcohols, carboxylic acids, amines, amino acids, sugars, steroids, thiols, and phosphates. These fragmentation rules were subsequently validated by specificity and sensitivity assessments using the NIST 14 nominal mass library and a new in-house GC-QTOF MS library containing 589 accurate mass spectra. From 556 tested fragmentation patterns, 228 rules yielded true positive hits within 4 mDa mass accuracy. These rules can be applied to assign substructures for mass spectra computation and unknown identification. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX–XX, 2016.

  • The quest for improved reproducibility in MALDI mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-07-15
    Matthew B. O'Rourke, Steven P. Djordjevic, Matthew P. Padula

    Reproducibility has been one of the biggest hurdles faced when attempting to develop quantitative protocols for MALDI mass spectrometry. The heterogeneous nature of sample recrystallization has made automated sample acquisition somewhat “hit and miss” with manual intervention needed to ensure that all sample spots have been analyzed. In this review, we explore the last 30 years of literature and anecdotal evidence that has attempted to address and improve reproducibility in MALDI MS. Though many methods have been attempted, we have discovered a significant publication history surrounding the use of nitrocellulose as a substrate to improve homogeneity of crystal formation and therefore reproducibility. We therefore propose that this is the most promising avenue of research for developing a comprehensive and universal preparation protocol for quantitative MALDI MS analysis. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Mass spectrometric epitope mapping
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-07-12
    Kwabena F.M. Opuni, Mahmoud Al-Majdoub, Yelena Yefremova, Reham F. El-Kased, Cornelia Koy, Michael O. Glocker

    Mass spectrometric epitope mapping has become a versatile method to precisely determine a soluble antigen's partial structure that directly interacts with an antibody in solution. Typical lengths of investigated antigens have increased up to several 100 amino acids while experimentally determined epitope peptides have decreased in length to on average 10–15 amino acids. Since the early 1990s more and more sophisticated methods have been developed and have forwarded a bouquet of suitable approaches for epitope mapping with immobilized, temporarily immobilized, and free-floating antibodies. While up to now monoclonal antibodies have been mostly used in epitope mapping experiments, the applicability of polyclonal antibodies has been proven. The antibody's resistance towards enzymatic proteolysis has been of key importance for the two mostly applied methods: epitope excision and epitope extraction. Sample consumption has dropped to low pmol amounts on both, the antigen and the antibody. While adequate in-solution sample handling has been most important for successful epitope mapping, mass spectrometric analysis has been found the most suitable read-out method from early on. The rapidity by which mass spectrometric epitope mapping nowadays is executed outperforms all alternative methods. Thus, it can be asserted that mass spectrometric epitope mapping has reached a state of maturity, which allows it to be used in any mass spectrometry laboratory. After 25 years of constant and steady improvements, its application to clinical samples, for example, for patient characterization and stratification, is anticipated in the near future. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Recent (2000–2015) developments in the analysis of minor unknown natural products based on characteristic fragment information using LC–MS
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-06-24
    Tian Cai, Ze-Qin Guo, Xiao-Ying Xu, Zhi-Jun Wu

    Liquid chromatography–Mass Spectrometry (LC–MS) has been widely used in natural product analysis. Global detection and identification of nontargeted components are desirable in natural product research, for example, in quality control of Chinese herbal medicine. Nontargeted components analysis continues to expand to exciting life science application domains such as metabonomics. With this background, the present review summarizes recent developments in the analysis of minor unknown natural products using LC–MS and mainly focuses on the determination of the molecular formulae, selection of precursor ions, and characteristic fragmentation patterns of the known compounds. This review consists of three parts. Firstly, the methods used to determine unique molecular formula of unknown compounds such as accurate mass measurements, MSn spectra, or relative isotopic abundance information, are introduced. Secondly, the methods improving signal-to-noise ratio of MS/MS spectra by manual-MS/MS or workflow targeting-only signals were elucidated; pure precursor ions can be selected by changing the precursor ion isolated window. Lastly, characteristic fragmentation patterns such as Retro-Diels–Alder (RDA), McLafferty rearrangements, “internal residue loss,” and so on, occurring in the molecular ions of natural products are summarized. Classical application of characteristic fragmentation patterns in identifying unknown compounds in extracts and relevant fragmentation mechanisms are presented (RDA reactions occurring readily in the molecular ions of flavanones or isoflavanones, McLafferty-type fragmentation reactions of some natural products such as epipolythiodioxopiperazines; fragmentation by “internal residue loss” possibly involving ion–neutral complex intermediates). © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Phospholipids as cancer biomarkers: Mass spectrometry-based analysis
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-06-08
    Raju Bandu, Hyuck Jun Mok, Kwang Pyo Kim

    Lipids, particularly phospholipids (PLs), are key components of cellular membrane. PLs play important and diverse roles in cells such as chemical-energy storage, cellular signaling, cell membranes, and cell–cell interactions in tissues. All these cellular processes are pertinent to cells that undergo transformation, cancer progression, and metastasis. Thus, there is a strong possibility that some classes of PLs are expected to present in cancer cells and tissues in cellular physiology. The mass spectrometric soft-ionization techniques, electrospray ionization (ESI), and matrix-assisted laser desorption/ionization (MALDI) are well-established in the proteomics field, have been used for lipidomic analysis in cancer research. This review focused on the applications of mass spectrometry (MS) mainly on ESI-MS and MALDI-MS in the structural characterization, molecular composition and key roles of various PLs present in cancer cells, tissues, blood, and urine, and on their importance for cancer-related problems as well as challenges for development of novel PL-based biomarkers. The profiling of PLs helps to rationalize their functions in biological systems, and will also provide diagnostic information to elucidate mechanisms behind the control of cancer, diabetes, and neurodegenerative diseases. The investigation of cellular PLs with MS methods suggests new insights on various cancer diseases and clinical applications in the drug discovery and development of biomarkers for various PL-related different cancer diseases. PL profiling in tissues, cells and body fluids also reflect the general condition of the whole organism and can indicate the existence of cancer and other diseases. PL profiling with MS opens new prospects to assess alterations of PLs in cancer, screening specific biomarkers and provide a basis for the development of novel therapeutic strategies. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Gas phase basicities of polyfunctional molecules. Part 5: Non-aromatic sp2 nitrogen containing compounds
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-06-08
    Guy Bouchoux, Mirjana Eckert-Maksic

    This paper constitutes the fifth part of a general review of the gas-phase protonation thermochemistry of polyfunctional molecules (Part 1: Theory and methods, Mass Spectrom Rev 2007, 26:775–835, Part 2: Saturated basic sites, Mass Spectrom Rev 2012, 31:353–390, Part 3: Amino acids, Mass Spectrom Rev 2012, 31:391–435, Part 4: Carbonyl as basic site, Mass Spectrom Rev 2015, 34:493–534). This part is devoted to non-aromatic molecules characterized by a lone pair located on a sp2 nitrogen atom, it embraces functional groups such as imines, amidines, guanidines, diazenes, hydrazines, oximes, and phosphazenes. Specific examples are examined under five major chapters. In the first one, aliphatic and unsaturated (conjugated and cyclic) imines, hydrazones, and oximes are considered. A second chapter describes the protonation energetic of aliphatic, conjugated, or cyclic amidines. Guanidines, polyguanides, and biomolecules containing guanidine were examined in the third chapter. A fourth chapter describes the particular case of the phosphazene molecules. Finally, diazenes and azides were considered in the last chapter. Experimental data were re-evaluated according to the presently adopted basicity scale, i.e., PA(NH3) = 853.6 kJ/mol, GB (NH3) = 819 kJ/mol. Structural and energetic information given by G4MP2 quantum chemistry computations on typical systems are presented. © 2016 Wiley Periodicals, Inc. Mass Spec Rev.

  • Direct analysis in real time—Mass spectrometry (DART-MS) in forensic and security applications
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-06-06
    Matthew J. Pavlovich, Brian Musselman, Adam B. Hall

    Over the last decade, direct analysis in real time (DART) has emerged as a viable method for fast, easy, and reliable “ambient ionization” for forensic analysis. The ability of DART to generate ions from chemicals that might be present at the scene of a criminal activity, whether they are in the gas, liquid, or solid phase, with limited sample preparation has made the technology a useful analytical tool in numerous forensic applications. This review paper summarizes many of those applications, ranging from the analysis of trace evidence to security applications, with a focus on providing the forensic scientist with a resource for developing their own applications. The most common uses for DART in forensics are in studying seized drugs, drugs of abuse and their metabolites, bulk and detonated explosives, toxic chemicals, chemical warfare agents, inks and dyes, and commercial plant and animal products that have been adulterated for economic gain. This review is meant to complement recent reviews that have described the fundamentals of the ionization mechanism and the general use of DART. We describe a wide range of forensic applications beyond the field of analyzing drugs of abuse, which dominates the literature, including common experimental and data analysis methods. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX–XX, 2016.

  • Negative ion cleavages of (M–H)− anions of peptides. Part 3. Post-translational modifications
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-03-28
    Tianfang Wang, T.T. Nha Tran, Hayley J. Andreazza, Daniel Bilusich, Craig S. Brinkworth, John H. Bowie

    It is now 25 years since we commenced the study of the negative-ion fragmentations of peptides and we have recently concluded this research with investigations of the negative-ion chemistry of most post-translational functional groups. Our first negative-ion peptide review (Bowie, Brinkworth, & Dua, 2002) dealt with the characteristic backbone fragmentations and side-chain cleavages from (M–H)− ions of underivatized peptides, while the second (Bilusich & Bowie, 2009) included negative-ion backbone cleavages for Ser and Cys and some initial data on some post-translational groups including disulfides. This third and final review provides a brief summary of the major backbone and side chain cleavages outlined before (Bowie, Brinkworth, & Dua, 2002) and describes the quantum mechanical hydrogen tunneling associated with some proton transfers in enolate anion/enolate systems. The review then describes, in more depth, the negative-ion cleavages of the post-translational groups Kyn, isoAsp, pyroglu, disulfides, phosphates, and sulfates. Particular emphasis is devoted to disulfides (both intra- and intermolecular) and phosphates because of the extensive and spectacular anion chemistry shown by these groups. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Mass spectrometry in the characterization of reactive metal alkoxides
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-04-04
    Valentina Peruzzo, Matteo Andrea Chiurato, Monica Favaro, Patrizia Tomasin

    Metal alkoxides are metal-organic compounds characterized by the presence of MOC bonds (M = metal). Their chemistry seems to be, in principle, relatively simple but the number of possible reactant species arising as a consequence of their behavior is very remarkable. The physico-chemical properties of metal alkoxides are determined by many different parameters, the most important ones being the electronegativity of the metal, the ramification of the ligand, and the acidity of the corresponding alcohol. Their reactivity makes them suitable and versatile candidates for many applications, including homogeneous catalysis, synthesis of new ceramic materials through the sol-gel process and, recently, also for Cultural Heritage. Metal alkoxides are characterized by a strong tendency to give clusters and/or oligomers through oxo-bridges. Mass spectrometry has been successfully employed for the characterization of metal alkoxides in the gas-phase. Electron ionization (EI) allowed the assessment of the molecular weight and of the most relevant decomposition pathways giving information on the relative bond strength of differently substituted molecules. On the other hand, information on the reactivity in solution of these molecules have been obtained by electrospray ionization (ESI)-matrix assisted laser desorption ionization (MALDI) experiments performed on their reaction products. These data were relevant to investigate the sol-gel process. In this review, these aspects are described and the results obtained are critically evaluated. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • A review on the mass spectrometric studies of americium: Present status and future perspective
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-05-06
    Suresh Kumar Aggarwal

    The manuscript reviews the various mass spectrometric techniques for analysis and chemical studies of Americium. These methods include thermal ionization mass spectrometry (TIMS), and inductively coupled plasma source mass spectrometry (ICPMS) for the determination of Am isotope ratios and concentration in nuclear fuel samples of interest in nuclear technology, and in complex biological and environmental samples. Ultra-sensitive mass spectrometric techniques of resonance-ionization mass spectrometry (RIMS), and accelerator-based mass spectrometry (AMS) are also discussed. The novel applications of electrospray ionization mass spectrometry (ESIMS) to understand the solution chemistry of Am and other actinides are presented. These studies are important in view of the world-wide efforts to develop novel complexing agents to separate lanthanides and minor actinides (Am, Np, and Cm) for partitioning and transmutation of minor actinides from the point of view of nuclear waste management. These mass spectrometry experiments are also of great interest to examine the covalent character of actinides with increasing atomic number. Studies on gas-phase chemistry of Am and its oxides with Knudsen effusion mass spectrometry (KEMS), Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS), and laser-based experiments with reflectron time-of-flight mass spectrometer (R-ToF) are highlighted. These studies are important to understand the fundamental chemistry of 5f electrons in actinides. Requirement of certified isotopic reference materials of Am to improve the accuracy of experimental nuclear data (e.g., the half-life of 243Am) is emphasized. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Historical and contemporary stable isotope tracer approaches to studying mammalian protein metabolism
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-05-16
    Daniel James Wilkinson

    Over a century ago, Frederick Soddy provided the first evidence for the existence of isotopes; elements that occupy the same position in the periodic table are essentially chemically identical but differ in mass due to a different number of neutrons within the atomic nucleus. Allied to the discovery of isotopes was the development of some of the first forms of mass spectrometers, driven forward by the Nobel laureates JJ Thomson and FW Aston, enabling the accurate separation, identification, and quantification of the relative abundance of these isotopes. As a result, within a few years, the number of known isotopes both stable and radioactive had greatly increased and there are now over 300 stable or radioisotopes presently known. Unknown at the time, however, was the potential utility of these isotopes within biological disciplines, it was soon discovered that these stable isotopes, particularly those of carbon (13C), nitrogen (15N), oxygen (18O), and hydrogen (2H) could be chemically introduced into organic compounds, such as fatty acids, amino acids, and sugars, and used to “trace” the metabolic fate of these compounds within biological systems. From this important breakthrough, the age of the isotope tracer was born. Over the following 80 yrs, stable isotopes would become a vital tool in not only the biological sciences, but also areas as diverse as forensics, geology, and art. This progress has been almost exclusively driven through the development of new and innovative mass spectrometry equipment from IRMS to GC-MS to LC-MS, which has allowed for the accurate quantitation of isotopic abundance within samples of complex matrices. This historical review details the development of stable isotope tracers as metabolic tools, with particular reference to their use in monitoring protein metabolism, highlighting the unique array of tools that are now available for the investigation of protein metabolism in vivo at a whole body down to a single protein level. Importantly, it will detail how this development has been closely aligned to the technological development within the area of mass spectrometry. Without the dedicated development provided by these mass spectrometrists over the past century, the use of stable isotope tracers within the field of protein metabolism would not be as widely applied as it is today, this relationship will no doubt continue to flourish in the future and stable isotope tracers will maintain their importance as a tool within the biological sciences for many years to come. © 2016 The Authors. Mass Spectrometry Reviews Published by Wiley Periodicals, Inc. Mass Spec Rev

  • Spatial perspectives in the redox code—Mass spectrometric proteomics studies of moonlighting proteins
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-05-17
    Gabriella Pinto, Marko Radulovic, Jasminka Godovac-Zimmermann

    The Redox Code involves specific, reversible oxidative changes in proteins that modulate protein tertiary structure, interactions, trafficking, and activity, and hence couple the proteome to the metabolic/oxidative state of cells. It is currently a major focus of study in cell biology. Recent studies of dynamic cellular spatial reorganization with MS-based subcellular-spatial-razor proteomics reveal that protein constituents of many subcellular structures, including mitochondria, the endoplasmic reticulum, the plasma membrane, and the extracellular matrix, undergo changes in their subcellular abundance/distribution in response to oxidative stress. These proteins are components of a diverse variety of functional processes spatially distributed across cells. Many of the same proteins are involved in response to suppression of DNA replication indicate that oxidative stress is strongly intertwined with DNA replication/proliferation. Both are replete with networks of moonlighting proteins that show coordinated changes in subcellular location and that include primary protein actuators of the redox code involved in the processing of NAD+/NADH, NADP+/NADPH, Cys/CySS, and GSH/GSSG redox couples. Small groups of key proteins such as {KPNA2, KPNB1, PCNA, PTMA, SET} constitute “spatial switches” that modulate many nuclear processes. Much of the functional response involves subcellular protein trafficking, including nuclear import/export processes, vesicle-mediated trafficking, the endoplasmic reticulum/Golgi pathway, chaperone-assisted processes, and other transport systems. This is not visible to measurements of total protein abundance by transcriptomics or proteomics. Comprehensive pictures of cellular function will require collection of data on the subcellular transport and local functions of many moonlighting proteins, especially of those with critical roles in spatial coordination across cells. The proteome-wide analysis of coordinated changes in abundance and trafficking of proteins offered by MS-based proteomics has a unique, crucial role to play in deciphering the complex adaptive systems that underlie cellular function. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Qualitative and quantitative characterization of protein biotherapeutics with liquid chromatography mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-04-20
    Miao Qu, Bo An, Shichen Shen, Ming Zhang, Xiaomeng Shen, Xiaotao Duan, Joseph P. Balthasar, Jun Qu

    In the last decade, the advancement of liquid chromatography mass spectrometry (LC/MS) techniques has enabled their broad application in protein characterization, both quantitatively and qualitatively. Owing to certain important merits of LC/MS techniques (e.g., high selectivity, flexibility, and rapid method development), LC/MS assays are often deemed as preferable alternatives to conventional methods (e.g., ligand-binding assays) for the analysis of protein biotherapeutics. At the discovery and development stages, LC/MS is generally employed for two purposes absolute quantification of protein biotherapeutics in biological samples and qualitative characterization of proteins. For absolute quantification of a target protein in bio-matrices, recent work has led to improvements in the efficiency of LC/MS method development, sample treatment, enrichment and digestion, and high-performance low-flow-LC separation. These advances have enhanced analytical sensitivity, specificity, and robustness. As to qualitative analysis, a range of techniques have been developed to characterize intramolecular disulfide bonds, glycosylation, charge variants, primary sequence heterogeneity, and the drug-to-antibody ratio of antibody drug conjugate (ADC), which has enabled a refined ability to assess product quality. In this review, we will focus on the discussion of technical challenges and strategies of LC/MS-based quantification and characterization of biotherapeutics, with the emphasis on the analysis of antibody-based biotherapeutics such as monoclonal antibodies (mAbs) and ADCs. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Single-molecule mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-02-12
    David Z. Keifer, Martin F. Jarrold

    In single-molecule mass spectrometry, the mass of each ion is measured individually; making it suitable for the analysis of very large, heterogeneous objects that cannot be analyzed by conventional means. A range of single-molecule mass spectrometry techniques has been developed, including time-of-flight with cryogenic detectors, a quadrupole ion trap with optical detection, single-molecule Fourier transform ion cyclotron resonance, charge detection mass spectrometry, quadrupole ion traps coupled to charge detector plates, and nanomechanical oscillators. In addition to providing information on mass and heterogeneity, these techniques have been used to study impact craters from cosmic dust, monitor the assembly of viruses, elucidate the fluorescence dynamics of quantum dots, and much more. This review focuses on the merits of each of these technologies, their limitations, and their applications. © 2016 Wiley Periodicals, Inc. Mass Spec Rev

  • Selection of internal standards for accurate quantification of complex lipid species in biological extracts by electrospray ionization mass spectrometry—What, how and why?
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-01-15
    Miao Wang, Chunyan Wang, Xianlin Han

    Lipidomics is rapidly expanding because of the great facilitation of recent advances in, and novel applications of, electrospray ionization mass spectrometry techniques. The greatest demands have been for successful quantification of lipid classes, subclasses, and individual molecular species in biological samples at acceptable accuracy. This review addresses the selection of internal standards in different methods for accurate quantification of individual lipid species. The principles of quantification with electrospray ionization mass spectrometry are first discussed to recognize the essentials for quantification. The basics of different lipidomics approaches are overviewed to understand the variables that need to be considered for accurate quantification. The factors that affect accurate quantification are extensively discussed, and the solutions to resolve these factors are proposed-largely through addition of internal standards. Finally, selection of internal standards for different methods is discussed in detail to address the issues of what, how, and why related to internal standards. We believe that thorough discussion of the topics related to internal standards should aid in quantitative analysis of lipid classes, subclasses, and individual molecular species and should have big impacts on advances in lipidomics. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX–XX, 2016.

  • Recent advances in mass spectrometric analysis of protein deamidation
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-01-13
    Piliang Hao, Sunil S. Adav, Xavier Gallart-Palau, Siu Kwan Sze

    Protein deamidation has been proposed to represent a “molecular clock” that progressively disrupts protein structure and function in human degenerative diseases and natural aging. Importantly, this spontaneous process can also modify therapeutic proteins by altering their purity, stability, bioactivity, and antigenicity during drug synthesis and storage. Deamidation occurs non-enzymatically in vivo, but can also take place spontaneously in vitro, hence artificial deamidation during proteomic sample preparation can hamper efforts to identify and quantify endogenous deamidation of complex proteomes. To overcome this, mass spectrometry (MS) can be used to conduct rigorous site-specific characterization of protein deamidation due to the high sensitivity, speed, and specificity offered by this technique. This article reviews recent progress in MS analysis of protein deamidation and discusses the strengths and limitations of common “top-down” and “bottom-up” approaches. Recent advances in sample preparation methods, chromatographic separation, MS technology, and data processing have for the first time enabled the accurate and reliable characterization of protein modifications in complex biological samples, yielding important new data on how deamidation occurs across the entire proteome of human cells and tissues. These technological advances will lead to a better understanding of how deamidation contributes to the pathology of biological aging and major degenerative diseases. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX–XX, 2016.

  • Issue Information - ToC
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-09-11


  • Computers in mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2017-04-28


  • Proteogenomics from a bioinformatics angle: A growing field
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2015-12-15
    Gerben Menschaert, David Fenyö

    Proteogenomics is a research area that combines areas as proteomics and genomics in a multi-omics setup using both mass spectrometry and high-throughput sequencing technologies. Currently, the main goals of the field are to aid genome annotation or to unravel the proteome complexity. Mass spectrometry based identifications of matching or homologues peptides can further refine gene models. Also, the identification of novel proteoforms is also made possible based on detection of novel translation initiation sites (cognate or near-cognate), novel transcript isoforms, sequence variation or novel (small) open reading frames in intergenic or un-translated genic regions by analyzing high-throughput sequencing data from RNAseq or ribosome profiling experiments. Other proteogenomics studies using a combination of proteomics and genomics techniques focus on antibody sequencing, the identification of immunogenic peptides or venom peptides. Over the years, a growing amount of bioinformatics tools and databases became available to help streamlining these cross-omics studies. Some of these solutions only help in specific steps of the proteogenomics studies, e.g. building custom sequence databases (based on next generation sequencing output) for mass spectrometry fragmentation spectrum matching. Over the last few years a handful integrative tools also became available that can execute complete proteogenomics analyses. Some of these are presented as stand-alone solutions, whereas others are implemented in a web-based framework such as Galaxy. In this review we aimed at sketching a comprehensive overview of all the bioinformatics solutions that are available for this growing research area. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:584–599, 2017

  • Protein complex analysis: From raw protein lists to protein interaction networks
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2015-12-28
    Pieter Meysman, Kevin Titeca, Sven Eyckerman, Jan Tavernier, Bart Goethals, Lennart Martens, Dirk Valkenborg, Kris Laukens

    The elucidation of molecular interaction networks is one of the pivotal challenges in the study of biology. Affinity purification—mass spectrometry and other co-complex methods have become widely employed experimental techniques to identify protein complexes. These techniques typically suffer from a high number of false negatives and false positive contaminants due to technical shortcomings and purification biases. To support a diverse range of experimental designs and approaches, a large number of computational methods have been proposed to filter, infer and validate protein interaction networks from experimental pull-down MS data. Nevertheless, this expansion of available methods complicates the selection of the most optimal ones to support systems biology-driven knowledge extraction. In this review, we give an overview of the most commonly used computational methods to process and interpret co-complex results, and we discuss the issues and unsolved problems that still exist within the field. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:600–614, 2017

  • Peptide retention time prediction
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-01-22
    Luminita Moruz, Lukas Käll

    Most methods for interpreting data from shotgun proteomics experiments are to large degree dependent on being able to predict properties of peptide-ions. Often such predicted properties are limited to molecular mass and fragment spectra, but here we put focus on a perhaps underutilized property, a peptide's chromatographic retention time. We review a couple of different principles of retention time prediction,and their applications within computational proteomics. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:615–623, 2017

  • Mining molecular structure databases: Identification of small molecules based on fragmentation mass spectrometry data
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-01-13
    Franziska Hufsky, Sebastian Böcker

    Mass spectrometry (MS) is a key technology for the analysis of small molecules. For the identification and structural elucidation of novel molecules, new approaches beyond straightforward spectral comparison are required. In this review, we will cover computational methods that help with the identification of small molecules by analyzing fragmentation MS data. We focus on the four main approaches to mine a database of metabolite structures, that is rule-based fragmentation spectrum prediction, combinatorial fragmentation, competitive fragmentation modeling, and molecular fingerprint prediction. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:624–633, 2017

  • Tandem mass spectral libraries of peptides and their roles in proteomics research
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-07-12
    Wenguang Shao, Henry Lam

    Proteomics is a rapidly maturing field aimed at the high-throughput identification and quantification of all proteins in a biological system. The cornerstone of proteomic technology is tandem mass spectrometry of peptides resulting from the digestion of protein mixtures. The fragmentation pattern of each peptide ion is captured in its tandem mass spectrum, which enables its identification and acts as a fingerprint for the peptide. Spectral libraries are simply searchable collections of these fingerprints, which have taken on an increasingly prominent role in proteomic data analysis. This review describes the historical development of spectral libraries in proteomics, details the computational procedures behind library building and searching, surveys the current applications of spectral libraries, and discusses the outstanding challenges. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:634–648, 2017.

  • Computational methods and challenges in hydrogen/deuterium exchange mass spectrometry
    Mass Spectrom. Rev. (IF 9.526) Pub Date : 2016-09-07
    Jürgen Claesen, Tomasz Burzykowski

    Hydrogen/Deuterium exchange (HDX) has been applied, since the 1930s, as an analytical tool to study the structure and dynamics of (small) biomolecules. The popularity of using HDX to study proteins increased drastically in the last two decades due to the successful combination with mass spectrometry (MS). Together with this growth in popularity, several technological advances have been made, such as improved quenching and fragmentation. As a consequence of these experimental improvements and the increased use of protein-HDXMS, large amounts of complex data are generated, which require appropriate analysis. Computational analysis of HDXMS requires several steps. A typical workflow for proteins consists of identification of (non-)deuterated peptides or fragments of the protein under study (local analysis), or identification of the deuterated protein as a whole (global analysis); determination of the deuteration level; estimation of the protection extent or exchange rates of the labile backbone amide hydrogen atoms; and a statistically sound interpretation of the estimated protection extent or exchange rates. Several algorithms, specifically designed for HDX analysis, have been proposed. They range from procedures that focus on one specific step in the analysis of HDX data to complete HDX workflow analysis tools. In this review, we provide an overview of the computational methods and discuss outstanding challenges. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:649–667, 2017

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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