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Cited by 5Microbial Natural Products and BiosynthesisMicrobial Metabolism and ApplicationsBioactive Natural Diterpenoids Research

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Insights into the biosynthesis of icumazole, unveiling a distinctive family of crotonyl-CoA carboxylase/reductase

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Xie, Feng, Kiefer, Alexander F., Hirsch, Anna K.H., Kalinina, Olga V., Fu, Chengzhang, Müller, Rolf·2023·Cell Reports Physical Science
DOI 10.1016/j.xcrp.2023.101394

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Abstract

Icumazoles are potent antifungal polyketides with intriguing structural features. Here, we present the polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) hybrid biosynthetic gene cluster of icumazoles. Surprisingly, an unusual nonterminal thioesterase domain divides the PKS/NRPS assembly line. The succeeding PKS modules potentially form a rare precursor 4-methyl-2-hexenoyl-ACP, thus deviating from the previously proposed polyoxypeptin pathway. The 4-methyl-2-hexenoyl-ACP is further reductively carboxylated to 2-methylbutylmalonyl-ACP, essential for icumazole biosynthesis by IcuL. We characterize IcuL and its homologs TgaD and Leu10 in vitro, suggesting a stricter substrate specificity of this new family of crotonyl carboxylases/reductases (CCRs) than found in canonical ones. Intriguingly, we also find that TgaD unprecedently utilizes both nicotinamide adenine dinucleotide phosphate (NADPH) and NADH as cofactors with similar efficiency, diverging from the NADPH-specific characteristic of canonical CCRs. Furthermore, a sequence similarity network-based and phylogenetic bioinformatic survey reveals that the IcuL-like CCRs are evolutionarily separated from canonical CCRs.

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Research works printed but not linked: 51

  1. Newman, 2020, Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019, J. Nat. Prod., 83, 770, 10.1021/acs.jnatprod.9b01285 · DOI
  2. Herrmann, 2017, Natural products from myxobacteria: novel metabolites and bioactivities, Nat. Prod. Rep., 34, 135, 10.1039/C6NP00106H · DOI
  3. Weissman, 2010, Myxobacterial secondary metabolites: bioactivities and modes-of-action, Nat. Prod. Rep., 27, 1276, 10.1039/c001260m · DOI
  4. Bollag, 1995, Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action, Cancer Res., 55, 2325
  5. Gerth, 1996, Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties, J. Antibiot., 49, 560, 10.7164/antibiotics.49.560 · DOI
  6. Baumann, 2014, Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity, Angew. Chem. Int. Ed. Engl., 53, 14605, 10.1002/anie.201409964 · DOI
  7. Hüttel, 2017, Discovery and total synthesis of natural cystobactamid derivatives with superior activity against Gram-negative pathogens, Angew. Chem. Int. Ed. Engl., 56, 12760, 10.1002/anie.201705913 · DOI
  8. Plaza, 2012, Aetheramides A and B, potent HIV-inhibitory depsipeptides from a myxobacterium of the new genus "Aetherobacter, Org. Lett., 14, 2854, 10.1021/ol3011002 · DOI
  9. Fu, 2017, The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD, Nat. Commun., 8, 1529, 10.1038/s41467-017-01671-5 · DOI
  10. Jansen, 2010, Carolacton - a macrolide ketocarbonic acid that reduces biofilm formation by the Caries- and Endocarditis-associated bacterium Streptococcus mutans, Eur. J. Org. Chem., 2010, 1284, 10.1002/ejoc.200901126 · DOI
  11. Barbier, 2012, Isolation and total synthesis of icumazoles and noricumazoles--antifungal antibiotics and cation-channel blockers from Sorangium cellulosum, Angew. Chem. Int. Ed. Engl., 51, 1256, 10.1002/anie.201106435 · DOI
  12. Fischbach, 2006, Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms, Chem. Rev., 106, 3468, 10.1021/cr0503097 · DOI
  13. Wilson, 2012, Beyond ethylmalonyl-CoA: the functional role of crotonyl-CoA carboxylase/reductase homologs in expanding polyketide diversity, Nat. Prod. Rep., 29, 72, 10.1039/C1NP00082A · DOI
  14. Liu, 1999, Role of crotonyl coenzyme A reductase in determining the ratio of polyketides monensin A and monensin B produced by Streptomyces cinnamonensis, J. Bacteriol., 181, 6806, 10.1128/JB.181.21.6806-6813.1999 · DOI
  15. Erb, 2007, Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway, Proc. Natl. Acad. Sci. USA, 104, 10631, 10.1073/pnas.0702791104 · DOI
  16. Erb, 2009, Carboxylation mechanism and stereochemistry of crotonyl-CoA carboxylase/reductase, a carboxylating enoyl-thioester reductase, Proc. Natl. Acad. Sci. USA, 106, 8871, 10.1073/pnas.0903939106 · DOI
  17. Zhang, 2015, Rational control of polyketide extender units by structure-based engineering of a crotonyl-CoA carboxylase/reductase in antimycin biosynthesis, Angew. Chem. Int. Ed. Engl., 54, 13462, 10.1002/anie.201506899 · DOI
  18. Quade, 2011, Unusual carbon fixation gives rise to diverse polyketide extender units, Nat. Chem. Biol., 8, 117, 10.1038/nchembio.734 · DOI
  19. Ray, 2016, A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units, Nat. Commun., 7, 10.1038/ncomms13609 · DOI
  20. Pohl, 2001, Remarkably broad substrate tolerance of malonyl-CoA synthetase, an enzyme capable of intracellular synthesis of polyketide precursors, J. Am. Chem. Soc., 123, 5822, 10.1021/ja0028368 · DOI
  21. Kopp, 2011, Insights into the complex biosynthesis of the leupyrrins in Sorangium cellulosum So ce690, Mol. Biosyst., 7, 1549, 10.1039/c0mb00240b · DOI
  22. Buntin, 2010, Biosynthesis of thuggacins in myxobacteria: comparative cluster analysis reveals basis for natural product structural diversity, Chem. Biol., 17, 342, 10.1016/j.chembiol.2010.02.013 · DOI
  23. Buntin, 2010, An unusual thioesterase promotes isochromanone ring formation in ajudazol biosynthesis, Chembiochem, 11, 1137, 10.1002/cbic.200900712 · DOI
  24. Boldt, 2023, Bursts in biosynthetic gene cluster transcription are accompanied by surges of natural compound production in the myxobacterium Sorangium sp, Microb. Biotechnol., 00, 1
  25. Chisuga, 2022, Structural Insight into the reaction mechanism of ketosynthase-like decarboxylase in a loading module of modular polyketide synthases, ACS Chem. Biol., 17, 198, 10.1021/acschembio.1c00856 · DOI
  26. Gaitatzis, 2002, The biosynthesis of the aromatic myxobacterial electron transport inhibitor stigmatellin is directed by a novel type of modular polyketide synthase, J. Biol. Chem., 277, 13082, 10.1074/jbc.M111738200 · DOI
  27. Liou, 2003, Quantitative analysis of loading and extender acyltransferases of modular polyketide synthases, Biochemistry, 42, 200, 10.1021/bi0268100 · DOI
  28. Long, 2002, Engineering specificity of starter unit selection by the erythromycin-producing polyketide synthase, Mol. Microbiol., 43, 1215, 10.1046/j.1365-2958.2002.02815.x · DOI
  29. Rangan, 1997, Alteration of the substrate specificity of the malonyl-CoA/acetyl-CoA:acyl carrier protein S-acyltransferase domain of the multifunctional fatty acid synthase by mutation of a single arginine residue, J. Biol. Chem., 272, 11975, 10.1074/jbc.272.18.11975 · DOI
  30. Zhai, 2020, Cross-module enoylreduction in the azalomycin F polyketide synthase, Angew. Chem. Int. Ed. Engl., 59, 22738, 10.1002/anie.202011357 · DOI
  31. Dowling, 2016, Structural elements of an NRPS cyclization domain and its intermodule docking domain, Proc. Natl. Acad. Sci. USA, 113, 12432, 10.1073/pnas.1608615113 · DOI
  32. Little, 2022, Chain release mechanisms in polyketide and non-ribosomal peptide biosynthesis, Nat. Prod. Rep., 39, 163, 10.1039/D1NP00035G · DOI
  33. He, 2014, Cis-double bond formation by thioesterase and transfer by ketosynthase in FR901464 biosynthesis, J. Am. Chem. Soc., 136, 4488, 10.1021/ja500942y · DOI
  34. Little, 2022, An intramodular thioesterase domain catalyses chain release in the biosynthesis of a cytotoxic virulence factor, RSC Chem. Biol., 3, 1121, 10.1039/D2CB00121G · DOI
  35. Umezawa, 2001, Biosynthesis of polyoxypeptin A: novel amino acid 3-hydroxy-3-methylproline derived from isoleucine, J. Chem. Soc. Perkin 1, 1, 1550, 10.1039/b101942m · DOI
  36. Du, 2014, Identification and characterization of the biosynthetic gene cluster of polyoxypeptin A, a potent apoptosis inducer, BMC Microbiol., 14, 30, 10.1186/1471-2180-14-30 · DOI
  37. Mo, 2011, Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues, J. Am. Chem. Soc., 133, 976, 10.1021/ja108399b · DOI
  38. Liu, 2019, Heterologous expression of a cryptic giant type I PKS gene cluster leads to the production of ansaseomycin, Org. Lett., 21, 3785, 10.1021/acs.orglett.9b01237 · DOI
  39. Keatinge-Clay, 2017, The uncommon enzymology of cis-Acyltransferase assembly lines, Chem. Rev., 117, 5334, 10.1021/acs.chemrev.6b00683 · DOI
  40. Yoo, 2011, Characterization of 2-octenoyl-CoA carboxylase/reductase utilizing pteB from Streptomyce avermitilis, Biosci. Biotechnol. Biochem., 75, 1191, 10.1271/bbb.110003 · DOI
  41. Rosenthal, 2014, Direct evidence for a covalent ene adduct intermediate in NAD(P)H-dependent enzymes, Nat. Chem. Biol., 10, 50, 10.1038/nchembio.1385 · DOI
  42. Spaans, 2015, NADPH-generating systems in bacteria and archaea, Front. Microbiol., 6, 742, 10.3389/fmicb.2015.00742 · DOI
  43. Schwander, 2016, A synthetic pathway for the fixation of carbon dioxide in vitro, Science, 354, 900, 10.1126/science.aah5237 · DOI
  44. 2021, UniProt: the universal protein knowledgebase in 2021, Nucleic Acids Res., 49, D480, 10.1093/nar/gkaa1100 · DOI · Paper page
  45. Yan, 2012, Biosynthetic pathway for high structural diversity of a common dilactone core in antimycin production, Org. Lett., 14, 4142, 10.1021/ol301785x · DOI
  46. Eustáquio, 2009, Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine, Proc. Natl. Acad. Sci. USA, 106, 12295, 10.1073/pnas.0901237106 · DOI
  47. Blažič, 2015, Roles of the crotonyl-CoA carboxylase/reductase homologues in acetate assimilation and biosynthesis of immunosuppressant FK506 in Streptomyces tsukubaensis, Microb. Cell Fact., 14, 164, 10.1186/s12934-015-0352-z · DOI
  48. Irschik, 2007, The thuggacins, novel antibacterial macrolides from Sorangium cellulosum acting against selected Gram-positive bacteria, J. Antibiot., 60, 733, 10.1038/ja.2007.95 · DOI
  49. Bode, 2003, The leupyrrins: a structurally unique family of secondary metabolites from the myxobacterium Sorangium cellulosum, J. Nat. Prod., 66, 1203, 10.1021/np030109v · DOI
  50. Steinmetz, 2007, Thuggacins, macrolide antibiotics active against Mycobacterium tuberculosis: isolation from myxobacteria, structure elucidation, conformation analysis and biosynthesis, Chemistry, 13, 5822, 10.1002/chem.200700269 · DOI
  51. Umezawa, 1998, Polyoxypeptin isolated from Streptomyces: a bioactive cyclic depsipeptide containing the novel amino acid 3-hydroxy-3-methylproline, Tetrahedron Lett., 39, 1389, 10.1016/S0040-4039(98)00031-8 · DOI

Metadata

Authors
Xie, F., Kiefer, A. F., Hirsch, A. K. H., Kalinina, O. V., Fu, C., & Müller, R.
Affiliations
  • Helmholtz Centre for Infection Research (DE)
  • German Center for Infection Research (DE)
Corresponding author
  • Fu, Chengzhang
  • Müller, Rolf
ORCID
Venue
Cell Reports Physical Science
Publisher
Elsevier BV
Published
2023-05
Volume
4
Issue
5
Pages
101394
ISSN
2666-3864 (ISSN-L)
DOI
10.1016/j.xcrp.2023.101394
OpenAlex
W4367627146
Cited by
5
References
1
Citations by year
2026: 2 · 2025: 1 · 2024: 1 · 2023: 1
FWCI
0.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports Physical Science (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Metabolism and Applications
  • Physical Sciences › Chemistry › Organic Chemistry › Bioactive Natural Diterpenoids Research
Keywords
polyketide biosynthesis, biosynthetic gene clusters, crotonyl-CoA carboxylase/reductase, substrate specificity, fungal secondary metabolites, sequence similarity networks, phylogenetic analysis

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