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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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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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