Work

Insights into the Biosynthesis of Icumazole Unveiling a Distinctive Family of Crotonyl-CoA Carboxylase/Reductase

Year: 2022

Type: article

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.

Source: Cell Reports Physical Science

DOI: 10.1016/j.xcrp.2023.101394

Authors: Feng Xie, Alexander F. Kiefer, Anna K.H. Hirsch, Olga V. Kalinina, Chengzhang Fu, Rolf Müller

Institutions: Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, German Center for Infection Research

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Applied Microbiology and Biotechnology

Field: Immunology and Microbiology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $5,200

Funder: Deutsche Forschungsgemeinschaft