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

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...

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Bibliographic Details
Published in:Nature communications Vol. 16; no. 1; pp. 7798 - 14
Main Authors: Jiang, Ziran, Heberlig, Graham W., Chen, Jeffrey A., Huynh, Jennifer, La Clair, James J., Burkart, Michael D.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 21.08.2025
Nature Publishing Group
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Subjects:
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Acyl carrier protein
Acyl Carrier Protein - chemistry
Acyl Carrier Protein - metabolism
Acyl Carrier Protein - ultrastructure
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Biosynthesis
Catalytic Domain
Cross-Linking Reagents - chemistry
Crosslinking
Cryoelectron Microscopy
Dehydration
E coli
Enzymes
Humanities and Social Sciences
Models, Molecular
multidisciplinary
Multidrug resistant organisms
Mycobacterium tuberculosis
Mycobacterium tuberculosis - enzymology
Mycobacterium tuberculosis - metabolism
Polyketide synthase
Polyketide Synthases - chemistry
Polyketide Synthases - metabolism
Polyketide Synthases - ultrastructure
Protein interaction
Proteins
Science
Science (multidisciplinary)
Tuberculosis
Virulence factors
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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 . Bacterial Type I polyketide synthases are responsible for producing both lifesaving medicines and virulence factors, yet their stepwise mechanism remains elusive. Here, Burkart et al. characterize acyl carrier protein bound states of mycocerosic acid synthase from Mycobacterium tuberculosis through crosslinking and cryo-EM.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-63024-x