Abstract
Filamentous fungi produce a very wide range of complex and often bioactive metabolites, demonstrating their inherent ability as hosts of complex biosynthetic pathways. Recent advances in molecular sciences related to fungi have afforded the development of new tools that allow the rational total biosynthesis of highly complex specialized metabolites in a single process. Increasingly, these pathways can also be engineered to produce new metabolites. Engineering can be at the level of gene deletion, gene addition, formation of mixed pathways, engineering of scaffold synthases and engineering of tailoring enzymes. Combination of these approaches with hosts that can metabolize low-value waste streams opens the prospect of one-step syntheses from garbage.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hyde, K. D. et al. The amazing potential of fungi: 50 ways we can exploit fungi industrially. Fungal Divers. 97, 1–136 (2019).
de Mattos-Shipley, K. M. et al. The good, the bad and the tasty: the many roles of mushrooms. Stud. Mycol. 85, 125–157 (2016).
Hamed, R. B. et al. The enzymes of β-lactam biosynthesis. Nat. Prod. Rep. 30, 21–107 (2013).
Covvey, J. R. & Guarascio, A. J. Clinical use of lefamulin: a first-in-class semisynthetic pleuromutilin antibiotic. J. Intern. Med. 291, 51–63 (2022).
Chooi, Y.-H., Cacho, R. & Tang, Y. Identification of the viridicatumtoxin and griseofulvin gene clusters from Penicillium aethiopicum. Chem. Biol. 17, 483–494 (2010).
Sauter, H., Steglich, W. & Anke, T. Strobilurins: evolution of a new class of active substances. Angew. Chem. Int. Ed. 38, 1328–1349 (1999).
Wang, J. et al. Structural basis for the biosynthesis of lovastatin. Nat. Commun. 12, 867 (2021).
Kuhnert, E. et al. Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases. Environ. Microbiol. 20, 3325–3342 (2018).
Wring, S. A. et al. Preclinical pharmacokinetics and pharmacodynamic target of SCY-078, a first-in-class orally active antifungal glucan synthesis inhibitor, in murine models of disseminated candidiasis. Antimicrob. Agents Chemother. 61, e02068-16 (2017).
Lebe, K. E. & Cox, R. J. Oxidative steps during the biosynthesis of squalestatin S1. Chem. Sci. 10, 1227–1231 (2019).
Luo, H. et al. Genes and evolutionary fates of the amanitin biosynthesis pathway in poisonous mushrooms. Proc. Natl Acad. Sci. USA 119, e2201113119 (2022).
Minto, R. E. & Townsend, C. A. Enzymology and molecular biology of aflatoxin biosynthesis. Chem. Rev. 97, 2537–2556 (1997).
Matsuda, Y., Wakimoto, T., Mori, T., Awakawa, T. & Abe, I. Complete biosynthetic pathway of anditomin: nature’s sophisticated synthetic route to a complex fungal meroterpenoid. J. Am. Chem. Soc. 136, 15326–15336 (2014).
Wang, C. et al. Diversely functionalised cytochalasins through mutasynthesis and semi-synthesis. Chem. Eur. J. 26, 13578–13583 (2020).
Nett, R. S. et al. Elucidation of gibberellin biosynthesis in bacteria reveals convergent evolution. Nat. Chem. Biol. 13, 69–74 (2016).
Chaverra-Muñoz, L., Briem, T. & Hüttel, S. Optimization of the production process for the anticancer lead compound illudin M: improving titers in shake-flasks. Microb. Cell Fact. 21, 98 (2022).
Hsiao, C.-J. et al. Pycnidione, a fungus-derived agent, induces cell cycle arrest and apoptosis in A549 human lung cancer cells. Chem. Biol. Interact. 197, 23–30 (2012).
Zhang, W. et al. Compartmentalized biosynthesis of mycophenolic acid. Proc. Natl Acad. Sci. USA 116, 13305–13310 (2019).
Yang, X. et al. Cyclosporine biosynthesis in Tolypocladium inflatum benefits fungal adaptation to the environment. mBio 9, e01211-18 (2018).
Fricke, J., Blei, F. & Hoffmeister, D. Enzymatic synthesis of psilocybin. Angew. Chem. Int. Ed. 56, 12352–12355 (2017).
Wong, G. et al. Reconstituting the complete biosynthesis of D-lysergic acid in yeast. Nat. Commun. 13, 712 (2022).
Pathak, A., Nowell, R. W., Wilson, C. G., Ryan, M. J. & Barraclough, T. G. Comparative genomics of Alexander Fleming’s original Penicillium isolate (IMI 15378) reveals sequence divergence of penicillin synthesis genes. Sci. Rep. 10, 15705 (2020).
Foy, N. J. & Pronin, S. V. Synthesis of pleuromutilin. J. Am. Chem. Soc. 144, 10174–10179 (2022).
Goethe, O., DiBello, M. & Herzon, S. B. Total synthesis of structurally diverse pleuromutilin antibiotics. Nat. Chem. 14, 1270–1277 (2022).
Roberts, A. A., Ryan, K. S., Moore, B. S. & Gulder, T. A. M. in Natural Products via Enzymatic Reactions (ed. Piel, J.) 149–203 (Springer, 2010).
Kahlert, L., Schotte, C. & Cox, R. J. Total mycosynthesis: rational bioconstruction and bioengineering of fungal natural products. Synthesis 53, 2381–2394 (2021).
Boecker, S., Zobel, S., Meyer, V. & Süssmuth, R. D. Rational biosynthetic approaches for the production of new-to-nature compounds in fungi. Fungal Genet. Biol. 89, 89–101 (2016).
Alberti, F., Foster, G. D. & Bailey, A. M. Natural products from filamentous fungi and production by heterologous expression. Appl. Microbiol. Biotechnol. 101, 493–500 (2017).
He, Y. et al. Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp. Biotechnol. Adv. 36, 739–783 (2018).
Bailey, A. M. et al. Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production. Sci. Rep. 6, 25202 (2016).
Shenouda, M. L., Ambilika, M., Skellam, E. & Cox, R. J. Heterologous expression of secondary metabolite genes in Trichoderma reesei for waste valorization. J. Fungi 8, 355 (2022).
Smith, D. J., Burnham, M. K. R., Edwards, J., Earl, A. J. & Turner, G. Cloning and heterologous expression of the penicillin biosynthetic gene cluster from Penicillium chrysogenum. Biotechnology 8, 39–41 (1990).
Houbraken, J., Frisvad, J. C. & Samson, R. A. Fleming’s penicillin producing strain is not Penicillium chrysogenum but P. rubens. IMA Fungus 2, 87–95 (2011).
Sakai, K., Kinoshita, H., Shimizu, T. & Nihira, T. Construction of a citrinin gene cluster expression system in heterologous Aspergillus oryzae. J. Biosci. Bioeng. 106, 466–472 (2008).
Song, Z. et al. Heterologous expression of the avirulence gene ACE1 from the fungal rice pathogen Magnaporthe oryzae. Chem. Sci. 6, 4837–4845 (2015).
Pahirulzaman, K. A. K., Williams, K. & Lazarus, C. M. A toolkit for heterologous expression of metabolic pathways in Aspergillus oryzae. Methods Enzymol. 517, 241–60 (2012).
Nofiani, R. et al. Strobilurin biosynthesis in Basidiomycete fungi. Nat. Commun. 9, 3940 (2018).
Blin, K. et al. antiSMASH 6.0: improving cluster detection and comparison capabilities. Nucleic Acids Res. 49, W29–W35 (2021).
Terlouw, B. R. et al. MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters. Nucleic Acids Res. 51, D603–D610 (2022).
Gilchrist, C. L. M. et al. cblaster: a remote search tool for rapid identification and visualization of homologous gene clusters. Bioinform. Adv. 1, vbab016 (2021).
Alberti, F. et al. Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform. Chem. Sci. 14, 3826–3833 (2022).
Tagami, K. et al. Reconstitution of biosynthetic machinery for indole-diterpene paxilline in Aspergillus oryzae. J. Am. Chem. Soc. 135, 1260–1263 (2013).
Tagami, K. et al. Rapid reconstitution of biosynthetic machinery for fungal metabolites in Aspergillus oryzae: total biosynthesis of aflatrem. ChemBioChem 15, 2076–2080 (2014).
Robinson, S. L. & Panaccione, D. G. Heterologous expression of lysergic acid and novel ergot alkaloids in Aspergillus fumigatus. Appl. Environ. Microbiol. 80, 6465–6472 (2014).
Hoefgen, S. et al. Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi. Metab. Eng. 48, 44–51 (2018).
Yamamoto, S. et al. Elucidation of late-stage biosynthesis of phomoidride: proposal of cyclization mechanism affording characteristic nine-membered ring of fungal dimeric anhydride. J. Am. Chem. Soc. 144, 20998–21004 (2022).
Williams, K. et al. Heterologous production of fungal maleidrides reveals the cryptic cyclization involved in their biosynthesis. Angew. Chem. Int. Ed. 55, 6784–6788 (2016).
Fukaya, M. et al. Total biosynthesis of melleolides from basidiomycota fungi: mechanistic analysis of the multi-functional GMC oxidase Mld7. Angew. Chem. Int. Ed. 62, e202308881 (2023).
Tazawa, A. et al. Total biosynthesis of brassicicenes: identification of a key enzyme for skeletal diversification. Org. Lett. 20, 6178–6182 (2018).
Liu, C. et al. Efficient reconstitution of basidiomycota diterpene erinacine gene cluster in ascomycota host Aspergillus oryzae based on genomic DNA sequences. J. Am. Chem. Soc. 141, 15519–15523 (2019).
Narita, K. et al. Total biosynthesis of antiangiogenic agent (−)-terpestacin by artificial reconstitution of the biosynthetic machinery in Aspergillus oryzae. J. Org. Chem. 83, 7042–7048 (2018).
Fujii, R. et al. Total biosynthesis of diterpene aphidicolin, a specific inhibitor of DNA polymerase α: heterologous expression of four biosynthetic genes in Aspergillus oryzae. Biosci. Biotechnol. Biochem. 75, 1813–1817 (2014).
Halo, L. M. et al. Late stage oxidations during the biosynthesis of the 2-pyridone tenellin in the entomopathogenic fungus Beauveria bassiana. J. Am. Chem. Soc. 130, 17988–17996 (2008).
Zhang, Z. et al. Enzyme-catalyzed inverse-electron demand Diels–Alder reaction in the biosynthesis of antifungal ilicicolin H. J. Am. Chem. Soc. 141, 5659–5663 (2019).
Kahlert, L., Bassiony, E. F., Cox, R. J. & Skellam, E. J. Diels–Alder reactions during the biosynthesis of sorbicillinoids. Angew. Chem. Int. Ed. 59, 5816–5822 (2020).
He, Y. & Cox, R. J. The molecular steps of citrinin biosynthesis in fungi. Chem. Sci. 7, 2119–2127 (2015).
Nielsen, M. et al. Heterologous reconstitution of the intact geodin gene cluster in Aspergillus nidulans through a simple and versatile PCR based approach. PLoS ONE 8, e72871 (2013).
Sakai, K., Kinoshita, H. & Nihira, T. Heterologous expression system in Aspergillus oryzae for fungal biosynthetic gene clusters of secondary metabolites. Appl. Microbiol. Biotechnol. 93, 2011–2022 (2012).
Kasahara, K. et al. Solanapyrone synthase, a possible Diels–Alderase and iterative type I polyketide synthase encoded in a biosynthetic gene cluster from Alternaria solani. ChemBioChem 11, 1245–1252 (2010).
Zhong, Y.-J. et al. Complex interplay and catalytic versatility of tailoring enzymes for efficient and selective biosynthesis of fungal mycotoxins. J. Agric. Food Chem. 71, 311–319 (2023).
Schor, R., Schotte, C., Wibberg, D., Kalinowski, J. & Cox, R. J. Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A. Nat. Commun. 9, 1963 (2018).
Leete, E. et al. The use of carbon-13 nuclear magnetic resonance to establish that the biosynthesis of tenellin involves an intramolecular rearrangement of phenylalanine. Tetrahedron Lett. 16, 4103–4106 (1975).
Heneghan, M. N. et al. First heterologous reconstruction of a complete functional fungal biosynthetic multigene cluster. ChemBioChem 11, 1508–1512 (2010).
Rigby, J. H. & Qabar, M. Convergent total synthesis of (±)-tenellin. J. Org. Chem. 54, 5852–5853 (1989).
Bai, T. et al. Structural diversification of andiconin-derived natural products by α-ketoglutarate-dependent dioxygenases. Org. Lett. 22, 4311–4315 (2020).
Li, L. & Cox, R. J. Stereochemical and biosynthetic rationalisation of the tropolone sesquiterpenoids. J. Fungi 8, 929 (2022).
Ainsworth, A. M. et al. Xenovulene A, a novel GABA-benzodiazepine receptor binding compound produced by Acremonium strictum. J. Antibiot. 48, 568–573 (1995).
Harris, G. H. et al. Isolation and structure determination of pycnidione, A novel bistropolone stromelysin inhibitor from a Phoma sp. Tetrahedron 49, 2139–2144 (1993).
Mayerl, F. et al. Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum. J. Antibiot. 46, 1082–1088 (1993).
Zhai, Y. et al. Identification of the gene cluster for bistropolone-humulene meroterpenoid biosynthesis in Phoma sp. Fungal Genet. Biol. 129, 7–15 (2019).
Liu, J. et al. Tandem intermolecular [4 + 2] cycloadditions are catalysed by glycosylated enzymes for natural product biosynthesis. Nat. Chem. 15, 1083–1090 (2023).
Al Subeh, Z. Y. et al. Delivery of eupenifeldin via polymer-coated surgical buttresses prevents local lung cancer recurrence. J. Control. Release 331, 260–269 (2021).
Davison, J. et al. Genetic, molecular, and biochemical basis of fungal tropolone biosynthesis. Proc. Natl Acad. Sci. USA 109, 7642–7647 (2012).
Chen, Q. et al. Enzymatic intermolecular hetero-Diels–Alder reaction in the biosynthesis of tropolonic sesquiterpenes. J. Am. Chem. Soc. 141, 14052–14056 (2019).
Bergmann, T. C., Menssen, M., Schotte, C., Cox, R. J. & Lee-Thedieck, C. Bioactive effects of natural and novel unnatural tropolone sesquiterpenoids in a murine cell model of renal interstitial fibroblasts. Preprint at bioRxiv https://doi.org/10.1101/2023.07.19.549646 (2023).
Schotte, C., Li, L., Wibberg, D., Kalinowski, J. & Cox, R. J. Synthetic biology driven biosynthesis of unnatural tropolone sesquiterpenoids. Angew. Chem. Int. Ed. 59, 23870–23878 (2020).
Schotte, C., Lukat, P., Deuschmann, A., Blankenfeldt, W. & Cox, R. J. Understanding and engineering the stereoselectivity of humulene synthase. Angew. Chem. Int. Ed. 60, 20308–20312 (2021).
Xu, H., Schotte, C., Cox, R. J. & Dickschat, J. S. Stereochemical characterisation of the non-canonical α-humulene synthase from Acremonium strictum. Org. Biomol. Chem. 19, 8482–8486 (2021).
Bemis, C. Y. et al. Total synthesis and computational investigations of sesquiterpene-tropolones ameliorate stereochemical inconsistencies and resolve an ambiguous biosynthetic relationship. J. Am. Chem. Soc. 143, 6006–6017 (2021).
Patel, K. D., MacDonald, M. R., Ahmed, S. F., Singh, J. & Gulick, A. M. Structural advances toward understanding the catalytic activity and conformational dynamics of modular nonribosomal peptide synthetases. Nat. Prod. Rep. 40, 1550–1582 (2023).
Lou, T. et al. Structural insights into three sesquiterpene synthases for the biosynthesis of tricyclic sesquiterpenes and chemical space expansion by structure-based mutagenesis. J. Am. Chem. Soc. 145, 8474–8485 (2023).
Cox, R. J. & Skellam, E. J. in Comprehensive Natural Products III 3rd edn, Vol. 1 (eds Liu, H. & Begley, T.) 266–312 (Elsevier, 2020).
Cox, R. J. Curiouser and curiouser: progress in understanding the programming of iterative highly-reducing polyketide synthases. Nat. Prod. Rep. 40, 9–27 (2022).
Xu, Y. et al. Characterization of the biosynthetic genes for 10,11-dehydrocurvularin, a heat shock response-modulating anticancer fungal polyketide from Aspergillus terreus. Appl. Environ. Microbiol. 79, 2038–2047 (2013).
Xu, Y. et al. Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases. Proc. Natl Acad. Sci. USA 111, 12354–12359 (2014).
Bai, J. et al. Diversity-oriented combinatorial biosynthesis of hybrid polyketide scaffolds from azaphilone and benzenediol lactone biosynthons. Org. Lett. 18, 1262–1265 (2016).
Xu, Y. et al. Rational reprogramming of fungal polyketide first-ring cyclization. Proc. Natl Acad. Sci. USA 110, 5398–5403 (2013).
Fisch, K. M. Biosynthesis of natural products by microbial iterative hybrid PKS–NRPS. RSC Adv. 3, 18228–18247 (2013).
Minami, A., Ugai, T., Ozaki, T. & Oikawa, H. Predicting the chemical space of fungal polyketides by phylogeny-based bioinformatics analysis of polyketide synthase-nonribosomal peptide synthetase and its modification enzymes. Sci. Rep. 10, 13556 (2020).
Nielsen, M. L. et al. Linker flexibility facilitates module exchange in fungal hybrid PKS-NRPS engineering. PLoS ONE 11, e0161199 (2016).
Xu, W., Cai, X., Jung, M. E. & Tang, Y. Analysis of intact and dissected fungal polyketide synthase-nonribosomal peptide synthetase in vitro and in Saccharomyces cerevisiae. J. Am. Chem. Soc. 132, 13604–13607 (2010).
Fisch, K. M. et al. Rational domain swaps decipher programming in fungal highly reducing polyketide synthases and resurrect an extinct metabolite. J. Am. Chem. Soc. 133, 16635–16641 (2011).
Yang, X.-L. et al. Molecular basis of methylation and chain-length programming in a fungal iterative highly reducing polyketide synthase. Chem. Sci. 10, 8478–8489 (2019).
Cox, R. Oxidative rearrangements during fungal biosynthesis. Nat. Prod. Rep. 31, 1405–1424 (2014).
Zwick, C. R. & Renata, H. Harnessing the biocatalytic potential of iron- and α-ketoglutarate-dependent dioxygenases in natural product total synthesis. Nat. Prod. Rep. 37, 1065–1079 (2020).
Chakrabarty, S., Romero, E. O., Pyser, J. B., Yazarians, J. A. & Narayan, A. R. H. Chemoenzymatic total synthesis of natural products. Acc. Chem. Res. 54, 1374–1384 (2021).
Pyser, J. B. et al. Stereodivergent, chemoenzymatic synthesis of azaphilone natural products. J. Am. Chem. Soc. 141, 18551–18559 (2019).
Renata, H., Wang, Z. J. & Arnold, F. H. Expanding the enzyme universe: accessing non-natural reactions by mechanism-guided directed evolution. Angew. Chem. Int. Ed. 54, 3351–3367 (2015).
Awakawa, T., Mori, T., Ushimaru, R. & Abe, I. Structure-based engineering of α-ketoglutarate dependent oxygenases in fungal meroterpenoid biosynthesis. Nat. Prod. Rep. 40, 46–61 (2022).
Tao, H. et al. Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF. Nat. Commun. 13, 95 (2022).
Nakashima, Y. et al. Structure function and engineering of multifunctional non-heme iron dependent oxygenases in fungal meroterpenoid biosynthesis. Nat. Commun. 9, 104 (2018).
Baker Dockrey, S. A., Lukowski, A. L., Becker, M. R. & Narayan, A. R. H. Biocatalytic site- and enantioselective oxidative dearomatization of phenols. Nat. Chem. 10, 119–125 (2018).
al Fahad, A. et al. Oxidative dearomatisation: the key step of sorbicillinoid biosynthesis. Chem. Sci. 5, 523–527 (2013).
Abood, A. et al. Kinetic characterisation of the FAD dependent monooxygenase TropB and investigation of its biotransformation potential. RSC Adv. 5, 49987–49995 (2015).
Chiang, Y.-M. et al. A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J. Am. Chem. Soc. 131, 2965–2970 (2009).
Zabala, A. O., Xu, W., Chooi, Y.-H. & Tang, Y. Characterization of a silent azaphilone gene cluster from Aspergillus niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation. Chem. Biol. 19, 1049–1059 (2012).
Benítez, A. R. et al. Structural basis for selectivity in flavin-dependent monooxygenase-catalyzed oxidative dearomatization. ACS Catal. 9, 3633–3640 (2019).
Chiang, C.-H. et al. Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction. Proc. Natl Acad. Sci. USA 120, e2218248120 (2023).
Schor, R. & Cox, R. Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick. Nat. Prod. Rep. 35, 230–256 (2018).
Cox, R. J. & Gulder, T. A. M. Introduction to engineering the biosynthesis of fungal natural products. Nat. Prod. Rep. 40, 7–8 (2023).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Zhu, X. et al. Synthetic biology of plant natural products: from pathway elucidation to engineered biosynthesis in plant cells. Plant Commun. 2, 100229 (2021).
Skellam, E. Subcellular localization of fungal specialized metabolites. Fungal Biol. Biotechnol. 9, 11 (2022).
Chiang, C.-Y., Ohashi, M. & Tang, Y. Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining. Nat. Prod. Rep. 40, 89–127 (2022).
Barreiro, C. & García-Estrada, C. Proteomics and Penicillium chrysogenum: unveiling the secrets behind penicillin production. J. Proteom. 198, 119–131 (2019).
Feng, J., Hauser, M., Cox, R. J. & Skellam, E. Engineering Aspergillus oryzae for the heterologous expression of a bacterial modular polyketide synthase. J. Fungi 7, 1085 (2021).
Chiang, Y.-M. et al. Development of genetic dereplication strains in Aspergillus nidulans results in the discovery of aspercryptin. Angew. Chem. Int. Ed. 55, 1662–1665 (2015).
Gressler, M., Hortschansky, P., Geib, E. & Brock, M. A new high-performance heterologous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front. Microbiol. 6, 184 (2015).
Tomico-Cuenca, I., Mach, R. L., Mach-Aigner, A. R. & Derntl, C. An overview on current molecular tools for heterologous gene expression in Trichoderma. Fungal Biol. Biotechnol. 8, 11 (2021).
Floudas, D. et al. The paleozoic origin of enzymatic lignin decomposition reconstructed from 31 fungal genomes. Science 336, 1715–1719 (2012).
Porter, R. et al. Degradation of polypropylene by fungi Coniochaeta hoffmannii and Pleurostoma richardsiae. Microbiol. Res. 277, 127507 (2023).
Temporiti, M. E. E., Nicola, L., Nielsen, E. & Tosi, S. Fungal enzymes involved in plastics biodegradation. Microorganisms 10, 1180 (2022).
Lee, H. & Romero, J. Climate change 2023: synthesis report. Contribution of Working Groups I, II and III to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change (Intergovernmental Panel on Climate Change, 2023).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Biosynthetic gene cluster (BGC)
-
A co-located group of genes that encode the biosynthesis and transport of a particular specialized metabolite.
- Gene expression
-
The process by which a gene is transcribed into messenger RNA and translated by the ribosome into protein.
- Gene knockout
-
The precise deletion or disruption of a gene to ensure that its encoded protein cannot be produced.
- Heterologous expression
-
Gene expression that is performed in a non-native host organism.
- Host organism
-
An engineered organism in which BGCs of interest are expressed. Host organisms often have properties beneficial for fermentation or genetic engineering.
- Intron
-
A short sequence of non-coding nucleotides that must be removed (spliced) from messenger RNA to create the correct coding sequence for translation.
- Mutasynthesis
-
A process in which a mutation (usually a gene knockout) is chemically complemented by addition of a synthetic precursor or pathway intermediate to produce a new metabolite.
- Off-loading domain
-
Many synth(et)ases process substrates that are covalently attached via a thiolester or ester linkage. Off-loading domains hydrolyse or transesterify completed metabolites and free-up the synth(et)ase for another round of synthesis.
- Precursor-directed synthesis
-
Addition of a chemical precursor to a fermentation so that it is incorporated into the biosynthetic pathway, usually to produce a new specialized metabolite.
- Promoter sequence
-
A sequence of DNA upstream of biosynthetic genes that is bound by a transcription factor.
- Refactoring
-
The process of moving genes to a heterologous host while simultaneously replacing their native promoters with new promoters with desired properties suitable for use in the heterologous host.
- Synthase
-
A biosynthetic protein that builds the skeleton of a specialized metabolite without using adenosine triphosphate (ATP).
- Synthetase
-
A biosynthetic protein that builds the skeleton of a specialized metabolite that requires the use of adenosine triphosphate (ATP).
- Tailoring
-
Biosynthetic processes that occur after the action of a synth(et)ase. Tailoring often incudes redox processes, cyclization, alkylation and rearrangements.
- Titre
-
A measure of the productivity of a fermentation usually expressed in (m)g L−1 or (m)g Kg−1 of the desired product.
- Total biosynthesis
-
The biological equivalent of total chemical synthesis — the rational production of organic materials by the manipulation of the biosynthetic machinery.
- Wild-type organism
-
Also referred to as the donor organism, this is the organism in which BGCs of interest are found. Wild-type or donor organisms are often unsuitable for metabolite production, scale-up or genetic engineering.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cox, R.J. Engineered and total biosynthesis of fungal specialized metabolites. Nat Rev Chem 8, 61–78 (2024). https://doi.org/10.1038/s41570-023-00564-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41570-023-00564-0