Visualizing acyl carrier protein interactions within a crosslinked type I polyketide synthase

Ziran Jiang, Graham W. Heberlig, Jeffrey A. Chen, Jennifer Huynh, James J. Clair and Michael D. Burkart ()
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Ziran Jiang: University of California, San Diego
Graham W. Heberlig: University of California, San Diego
Jeffrey A. Chen: University of California, San Diego
Jennifer Huynh: University of California, San Diego
James J. Clair: University of California, San Diego
Michael D. Burkart: University of California, San Diego

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Using a combination of dual covalent crosslinking and cryo-EM analyses, we elucidate the structure of mycocerosic acid synthase from Mycobacterium tuberculosis trapped in two distinct catalytic states during its iterative cycle. These structures reveal domain architecture of the acyl carrier protein mediating condensation and dehydration through dual site-selective crosslinking of the acyl carrier protein with the ketosynthase and dehydratase domains. Map density was sufficient to visualize full domain architecture with active site-bound probes and elucidate key interactions of four distinct crosslinked species. Here, iterative vectorial polyketide biosynthesis arises through an overall twisting and tilting architecture, enabling positioning and entry of the cognate substrate at each enzymatic domain. These structures present valuable details for future therapeutic design against mycocerosic acid biosynthesis in M. tuberculosis.

Date: 2025
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DOI: 10.1038/s41467-025-63024-x

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