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Cited by 9Microbial Natural Products and BiosynthesisMicrobial Metabolism and ApplicationsEnzyme Structure and Function

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The Streptomyces viridochromogenes product template domain represents an evolutionary intermediate between dehydratase and aldol cyclase of type I polyketide synthases

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Feng, Yuanyuan, Yang, Xu, Ji, Huining, Deng, Zixin, Lin, Shuangjun, Zheng, Jianting·2022·Communications Biology
DOI 10.1038/s42003-022-03477-8PMC PMC9135731

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Abstract

The product template (PT) domains act as an aldol cyclase to control the regiospecific aldol cyclization of the extremely reactive poly-β-ketone intermediate assembled by an iterative type I polyketide synthases (PKSs). Up to now, only the structure of fungal PksA PT that mediates the first-ring cyclization via C4–C9 aldol cyclization is available. We describe here the structural and computational characterization of a bacteria PT domain that controls C2–C7 cyclization in orsellinic acid (OSA) synthesis. Mutating the catalytic H949 of the PT abolishes production of OSA and results in a tetraacetic acid lactone (TTL) generated by spontaneous O-C cyclization of the acyl carrier protein (ACP)-bound tetraketide intermediate. Crystal structure of the bacterial PT domain closely resembles dehydrase (DH) domains of modular type I PKSs in the overall fold, dimerization interface and His-Asp catalytic dyad organization, but is significantly different from PTs of fungal iterative type I PKSs. QM/MM calculation suggests that the catalytic H949 abstracts a proton from C2 and transfers it to C7 carbonyl to mediate the cyclization reaction. According to structural similarity to DHs and functional similarity to fungal PTs, we propose that the bacterial PT represents an evolutionary intermediate between the two tailoring domains of type I PKSs.

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Metadata

Authors
Feng, Y., Yang, X., Ji, H., Deng, Z., Lin, S., & Zheng, J.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
Zheng, Jianting
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-05-26
Volume
5
Issue
1
Pages
508-508
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-022-03477-8
PMC
PMC9135731
OpenAlex
W4281558284
Cited by
9
References
1
Citations by year
2026: 2 · 2024: 4 · 2023: 2 · 2022: 1
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (32070040)
  • National key R&D Program of China
Topics
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Metabolism and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
type I polyketide synthase, aldol cyclization, dehydratase domain, Streptomyces viridochromogenes, regiospecific cyclization, catalytic histidine, evolutionary intermediates, QM/MM calculations, crystal structure
MeSH terms
Aldehydes, Hydro-Lyases, Streptomyces, Polyketide Synthases

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