string(19) "en/achievements/746" Evolutionary repurposing of a metabolic thiolase complex enables antibiotic biosynthesis-Shenzhen Medical Academy of Research and Translation
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Evolutionary repurposing of a metabolic thiolase complex enables antibiotic biosynthesis

Date：2022/02/09

Source：深圳医学科学院

This Nature Communications paper reports the evolutionary neofunctionalization of a conserved tripartite enzyme complex (HMGS–ACAT–DUF35) into a Friedel–Crafts C-acylase that produces antibiotics in oral Streptococcus. The streptococcal complex SmaATase catalyzes regioselective acetylation of preRTC-A to form the antibiotic reutericyclin A, using acetyl-CoA as the physiological donor.


Cryo-EM structures reveal a dodecamer/octamer architecture highly similar to archaeal mevalonate-pathway complexes, but with key catalytic mutations (loss of HMGS E–C–H–N tetrad and ACAT HDxF motif) that abolish ancestral HMG-CoA synthesis and redirect function toward small-molecule acylation.


Genome mining identifies over 1,000 similar bacterial clusters, with some representing evolutionary intermediates. Acetylation by SmaATase is essential for potent antimicrobial activity against Gram-positive pathogens.


This work reveals a new paradigm of enzyme evolution: multimeric enzyme complexes can be repurposed via minimal mutations to drive specialized natural product biosynthesis, offering new templates for synthetic biocatalysts.


This study used the Orbitrap 480 highresolution LCMS in the Multi-omics Mass Spectrometry Core Facility of SMART Bio-Tech Center for protein modification analysis, enabling the identification of acetylation modifications.


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