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Cited by 41Microbial Natural Products and BiosynthesisTuberculosis Research and EpidemiologyEnzyme Structure and Function

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Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13

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Kim, Sun Kyung, Dickinson, Miles Sasha, Finer-Moore, Janet, Guan, Ziqiang, Kaake, Robyn M., Echeverria, Ignacia, Chen, Jen, Pulido, Ernst H., Sali, Andrej, Krogan, Nevan J., Rosenberg, Oren S., Stroud, Robert M.·2023·Nature Structural & Molecular Biology
DOI 10.1038/s41594-022-00918-0PMC PMC10312659

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Abstract

The mycolic acid layer of the Mycobacterium tuberculosis cell wall is essential for viability and virulence, and the enzymes responsible for its synthesis are targets for antimycobacterial drug development. Polyketide synthase 13 (Pks13) is a module encoding several enzymatic and transport functions that carries out the condensation of two different long-chain fatty acids to produce mycolic acids. We determined structures by cryogenic-electron microscopy of dimeric multi-enzyme Pks13 purified from mycobacteria under normal growth conditions, captured with native substrates. Structures define the ketosynthase (KS), linker and acyl transferase (AT) domains at 1.8 Å resolution and two alternative locations of the N-terminal acyl carrier protein. These structures suggest intermediate states on the pathway for substrate delivery to the KS domain. Other domains, visible at lower resolution, are flexible relative to the KS-AT core. The chemical structures of three bound endogenous long-chain fatty acid substrates were determined by electrospray ionization mass spectrometry.

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Metadata

Authors
Kim, S. K., Dickinson, M. S., Finer-Moore, J., Guan, Z., Kaake, R. M., Echeverria, I., Chen, J., Pulido, E. H., Sali, A., Krogan, N. J., Rosenberg, O. S., & Stroud, R. M.
Affiliations
  • University of California, San Francisco (US)
  • Duke Medical Center (US)
  • Gladstone Institutes (US)
Corresponding author
  • Rosenberg, Oren S.
  • Stroud, Robert M.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2023-02-13
Volume
30
Issue
3
Pages
296-308
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-022-00918-0
PMC
PMC10312659
OpenAlex
W4320486050
Cited by
41
References
76
Citations by year
2026: 7 · 2025: 11 · 2024: 16 · 2023: 7
FWCI
6.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • University of California, San Francisco
  • National Institute of General Medical Sciences (R01GM083960, R37GM024485, P41GM109824, R01GM024485, T32GM136568)
  • National Institute of Allergy and Infectious Diseases (R01AI128214, R01AI148366, P01AI095208, U19AI135990)
Topics
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
Pks13, polyketide synthase, Mycobacterium tuberculosis, mycolic acid biosynthesis, mycobacterial cell wall, ketosynthase domain, acyl carrier protein, enzyme dimer structure, substrate supply, antimycobacterial drug targets

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