研究领域
Chemical Biology and Analytical Chemistry: Developing and applying chemoproteomic and metabolomic platforms to map metabolic drivers of human diseases; using chemoproteomic approaches to map proteome-wide hyper-reactivity and functionality to expand the druggable proteome; investigating toxicological mechanisms of environmental chemicals and pharmaceutical drugs.
The Nomura Research Group is focused on developing and applying chemical proteomic and metabolomic platforms to identify and pharmacologically target metabolic drivers of human disease. Our laboratory currently has three major research areas. Our first research area focuses on developing and applying chemoproteomic and metabolomic platforms to map metabolic drivers of complex human diseases, including cancer, neurodegenerative diseases, and inflammatory disorders, towards developing novel therapeutic strategies to cure these complex human pathologies. Our second research areafocuses on developing chemoproteomic tools and technologies to map proteome-wide hyper-reactive and ligandable hotspots towards massively expanding our capability of developing pharmacological tools and eventually therapeutics against the entirety of the proteome. Our third research area is around developing innovative chemoproteomic and metabolomic strategies for comprehensive assessment of chemical toxicology ranging from small-molecule target identification, target characterization, and predictive and mechanistic toxicological assessment.
Mapping Metabolic Drivers of Cancer. Cancer cells possess fundamentally altered cellular metabolism that not only leads to a re-wiring of cellular biochemistry, but also drives nearly every aspect of cancer pathogenicity. While targeting dysregulated metabolism is a promising strategy for cancer treatment, much of research in cancer metabolism has focused on well-understood metabolic pathways in central carbon metabolism underlying cellular transformation and early-stages of cancer, and has largely ignored the majority of cellular metabolic pathways or those networks involved in cancer progression, despite clear genetic or metabolic evidence of their involvement in cancer. This is in-part because our efforts are hindered by our largely incomplete understanding of metabolic networks in normal physiology, let alone in human cancers. This includes the large number of uncharacterized or misannotated metabolic enzymes, undiscovered metabolites, and orphan metabolic networks. Historically, scientists have shied away from uncovering the oncological roles of these uncharacterized enzymes and metabolic pathways, leaving untapped the large therapeutic potential that remains in the majority of the unexplored metabolic genome. A major focus of our research group is to massively expand the arsenal of targets, mechanisms, and drugs to combat cancer by mapping the unexplored and untapped novel metabolic drivers of cancer using chemoproteomic and functional metabolomic platforms.We have already made substantial progress towards this goal by using integrated platforms that incorporate: 1) activity-based protein profiling (ABPP) platform, which uses active-site directed chemical probes coupled to proteomics to enrich, detect, and quantify dysregulated metabolic enzyme activities en masse in cancer; 2) functional targeted and discovery-based metabolomic platforms to identify novel dysregulated metabolic pathways and functionally annotate the metabolic and pathophysiological roles of cancer-relevant enzymes; and 3) a competitive ABPP inhibitor/drug-discovery platform based on competing small-molecule inhibitors against activity-based probe binding to enzyme active sites to discover potent, selective, and in vivo active compounds for further biological validation.
Using Reactivity-Based Chemoproteomic Platforms to Expand the Druggable Proteome through High-Throughput Pharmacological Mapping of Ligandable Sites. Despite the completion of human genome sequencing efforts nearly 15 years ago and the promise of genome-based discoveries that would cure human diseases, more than 75% of all protein research still focuses on the same 10% of proteins characterized before the sequencing of the human genome. Even with the identification of many novel protein targets that control disease, these potential drug targets have remained largely untranslated, in-part because most protein targets are “undruggable,” and the majority of the proteome is devoid of pharmacological tools, hindering and oftentimes paralyzing translational research efforts in drug discovery. Development of high-quality chemical tools for proteins catalyzes research into the function and therapeutic exploitation of those proteins, thus correlating the development of chemical tools for specific proteins with their associated research activity. Thus, developing pharmacological tools for every protein in the proteome would radically expand our ability to understand protein function, mine the entirety of the proteome for drug targets, and accelerate the drug discovery process to cure complex diseases. However, “drugging” all proteins simultaneously, has remained practically impossible. Furthermore, assessing the quality and selectivity of small-molecule modulators of protein function has remained challenging. We have been using the reactivity-based chemoproteomic platforms to enable simultaneous high-throughput discovery of small-molecule leads for drug discovery across the entire proteome by globally profiling and pharmacologically interrogating proteome-wide hyper-reactive hotspots.We have been combining the screening of reactive small-molecule fragment libraries against the profiling of proteome-wide hyper-reactive hotspots with reactivity-based probes directly in complex proteomesto enable: 1) the identification of proteome-wide hyper-reactive and functional hotspots with reactivity-based probes, which in-turn serve as sites that can be pharmacologically interrogated; 2) accelerated and massively parallel development of small-molecule modulators of large numbers of protein targets and the assessment of their proteome-wide selectivity; and 3) chemical genomics coupled with facile target identification to identify novel therapeutic targets.
Mapping Proteome-Wide Interactions of Environmental Chemicals to Uncover Novel Toxicological Mechanisms. We are environmentally exposed to countless synthetic chemicals on a daily basis, with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Understanding the direct protein targets of chemicals provides critical information on the types of biochemical and (patho)physiological effects that may be expected from exposure to the chemical. Our lab has been using the activity-based and reactivity-based chemoproteomic strategies to comprehensively identify chemical-protein interactions in complex biological systems, which has in-turn allowed us to identify unique and novel toxicological mechanisms for many widely used chemicals in our environment.
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Ward CC, Kleinman J, Nomura DK. (2017) NHS-esters as versatile reactivity-based probes for mapping proteome-wide ligandable hotspots. ACS Chemical Biology doi:10.1021/acschembio.7b00125. PMID 28445029 PDF
Bateman LA#, Nguyen TB#, Roberts AM#, Miyamoto DK, Ku W-M, Huffman TR, Heslin MJ, Contreras CM, Skibola CF, Olzmann JA*, Nomura DK*. (2017) Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in Reticulon 4 that impairs ER morphology and cancer pathogenicity. Chemical Communications doi: 10.1039/C7CC01480E. PMID 28352901 (#co-first authors; *co-corresponding author) PDF
Castellano, B.M., Thelen, A.M., Moldavski O, Feltes M, van der Welle R, Mydock-McGrane L, Jiang X, van Eijkeren RJ, Davis OB, Louie SM, Perera RM, Covey D, Nomura DK, Ory DS, Zoncu R. (2017) Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann Pick C1 signaling complex. Science 355, 1306-1311. PMID 28336668 PDF
Roberts LS, Yan P, Bateman LA, Nomura DK. (2017) Mapping novel metabolic nodes targeted by anti-cancer drugs that impair triple-negative breast cancer pathogenicity. ACS Chemical Biology 12, 1133-1140. PMID 28248089 PDF
Bateman LA, Ku W-M, Heslin MJ, Contrearas CM, Skibola CF, Nomura DK. (2017) ASS1 is an important metabolic regulator of colorectal cancer. ACS Chemical Biology 12, 905-911. PMID 28229591 PDF
Roberts AM, Miyamoto DK, Huffman TR, Bateman LA, Ives AN, Akopian D, Heslin MJ, Contreras CM, Rape M, Skibola CF, Nomura DK. (2017) Chemoproteomic screening of covalent ligands reveals UBA5 as a novel pancreatic cancer target. ACS Chemical Biology 12, 899-904. PMID 28186401 PDF
Counihan JL, Duckering M, Dalvie E, Ku W-m, Bateman LA, Fisher KJ, Nomura DK. (2017) Mapping proteome-wide reactivity of the widely used herbicide acetochlor in mice. ACS Chemical Biology 12, 635-642. PMID 28094496 PDF
Whang MI, Taveras RM, Benjamin DI, Kattah MG, Advincula R, Nomura DK, Debnath J, Malynn BA, Ma A. (2017) The ubiquitin binding protein TAX1BP mediates autophagasome induction and the metabolic transition of activated T cells. Immunity 46, 405-420. PMID 28314591 PDF
Anderton B, Camarda R, Balkrishnan S, Balakrishnan A, Kohnz RA, Lim L, Evason KJ, Momcilovic O, Kruttwig K, Huang Q, Xu G, Nomura DK, Goga A. (2017) MYC-driven inhibition of the glumate-cysteine ligase promotes glutathione depletion in liver cancer. EMBO Report 18, 569-585. PMID 28219903 PDF
Ford B, Bateman LA, Gutierrez-Palominos L, Park R, Nomura DK. (2017) Mapping proteome-wide targets of glyphosate in mice. Cell Chemical Biology 24, 133-140. PMID 28132892 PDF
Ruby MA, Massart J, Hunerdosse DM, Schonke M, Correia JC, Louie SM, Ruas JL, Naslund E, Nomura DK, Zierath JR. (2017) Human carboxylesterase 2 reverses obesity-induced diacylglycerol accumulation and glucose intolerance. Cell Reports 18, 636-646. PMID 28099843 PDF
To M, Peterson CWH, Roberts MA, Counihan JL, Wu TT, Forster MS, Nomura DK, Olzmann JA. (2017) Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation. Molecular Biology of the Cell 28, 270-284. PMID 27881664 PDF
Roberts AM, Ward CC, Nomura DK. (2017) Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots. Current Opinion in Biotechnology 43, 25-33. PMID 27568596 PDF
Kim H-E, Grant AR, Simic MS, Kohnz RA, Nomura DK, Durieux J, Riera CE, Sanchez M, Kapernick E, Wolff Suzanne, Dillin A (2016) Lipid biosynthesis coordinates a mitochondrial-to-cytosolic stress response. Cell 166, 1539-1552. PMID 27568596 PDF
Sogi K, Holsclaw C, Fragiadakis G, Nomura DK, Leary J, Bertozzi C. (2016) Biosynthesis and regulation of sulfomenaquinone, a metabolite associated with virulence in Mycobacterium tuberculosis. ACS Infectious Diseases 2, 800-806. PMID 27933784 PDF
Braverman J, Sogi KM, Benjamin D, Nomura DK, Stanley SA. (2016) HIF-1alpha is an essential mediator of IFA-gamma-dependent immunity to Mycobacterium tuberculosis. Journal of Immunology doi: 10.4049/jimmunol.1600266. PMID 27430718 PDF
Kohnz RA, Roberts, LS, DeTomaso D, Badyopadhyay S, Yosef N, Nomura DK. (2016) Protein sialylation regulates a gene expression signature that promotes breast cancer cell pathogenicity. ACS Chemical Biology 11, 2131-2139. PMID 27380425 PDF
Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MT, Jedrychowski MP, Paolo J, Griffin PR, Nomura DK*, Spiegelman BM* (2016) PM20D1 secretion by thermogenic adipose cells regulates lipidated amino acid uncouplers of mitochondrial respiration. Cell 166, 424-435. PMID 27374330 (*co-corresponding authorship) PDF
Chomvong K, Bauer S, Benjamin DI, Li X, Nomura DK, Cate JHD. (2016) Bypassing the pentose phosphate pathway: Towards modular utilization of xylose. Plos One 11, e0158111. PMID 27336308 PDF
Louie SM, Grossman EA, Crawford LA, Ding L, Camarda R, Huffman TR, Miyamoto DK, Goga A, Weerapana E, Nomura DK. (2016) GSTP1 is a driver of triple-negative breast cancer cell metabolism and pathogenicity. Cell Chemical Biology 23, 1-12. PMID 27185638 PDF
Nomura DK, Casida JE (2016) Lipases and their inhibitors in health and disease. Chemico-Biological Interactions doi: 10.1016/j.cbi.2016.04.004. PMID 27067293 PDF
Zhang J, Medina-Cleghorn D, Bernal-Mizrachi L, Bracci PM, Hubbard A, Conde L, Riby J, Nomura DK, Skibola C (2016) The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma. Oncoscience 3, 31-41. PMID 26973858 PDF
Nikkanen J, Forsstrom S, Euro L, Paetau I, Kohnz RA, Wang L, Chilov D, Viinamaki J, Roivainen A, Marjamaki P, Liljenback H, Ahola S, Buzkova J, Terzioglu M, Khan NA, Pirnes-Karhu S, Paetau A, Lonnqvist T, Sajantila A, Isohanni P, Tyynaismaa H, Nomura DK, Battersby B, Velagapudi V, Carroll CJ, Suomalainen A (2016) Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism. Cell Metabolism 23, 635-648. PMID 26924217 PDF
Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, Eyob H, Kajimura S, Tward A, Krings G, Nomura DK, Goga A. (2016) Inhibition of fatty-acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nature Medicine 22, 427-432. PMID 26950360. PDF
Saghatelian A, Nomura DK, Weerapana E (2016) Omics: The maturation of chemical biology. Current Opinions in Chemical Biology 30: v-vi. PMID 26739665 PDF
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