ArticleProceedings of the National Academy of Sciences of the United States of America2016
Anatomy of the β-branching enzyme of polyketide biosynthesis and its interaction with an acyl-ACP substrate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 39 citations in OpenAlex.
- β-Branching in the biosynthesis of bongkrekic acid: a complex affair.RSC advances · 2025Article
- Divergent Tandem Acyl Carrier Proteins Necessitate In-Series Polyketide Processing in the Leinamycin Family.Angewandte Chemie (International ed. in English) · 2025Article
- Article
- An optimized reverse β-oxidation pathway to produce selected medium-chain fatty acids in Saccharomyces cerevisiae.Biotechnology for biofuels and bioproducts · 2023Article
- Decrypting the programming of β-methylation in virginiamycin M biosynthesis.Nature communications · 2023Article
- Initiating polyketide biosynthesis by on-line methyl esterification.Nature communications · 2021Article
- The Sandarazols are Cryptic and Structurally Unique Plasmid-Encoded Toxins from a Rare Myxobacterium*.Angewandte Chemie (International ed. in English) · 2021Article
- Development of a Pantetheine Force Field Library for Molecular Modeling.Journal of chemical information and modeling · 2021Article
- Membrane fluidity adjusts the insertion of the transacylase PlsX to regulate phospholipid biosynthesis in Gram-positive bacteria.The Journal of biological chemistry · 2020Article
- The Mitochondrial Acyl-carrier Protein Interaction Network Highlights Important Roles for LYRM Family Members in Complex I and Mitoribosome Assembly.Molecular & cellular proteomics : MCP · 2020Article
- Insights into Thiotemplated Pyrrole Biosynthesis Gained from the Crystal Structure of Flavin-Dependent Oxidase in Complex with Carrier Protein.Biochemistry · 2019Article
- Protein-protein interactions in "cis-AT" polyketide synthases.Natural product reports · 2018Review
- Chemoenzymatic Dissection of Polyketide β-Branching in the Bryostatin Pathway.Methods in enzymology · 2018Article
- PKS-NRPS Enzymology and Structural Biology: Considerations in Protein Production.Methods in enzymology · 2018Article
- The Uncommon Enzymology of Cis-Acyltransferase Assembly Lines.Chemical reviews · 2017Review
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5 authors at 3 institutions in 1 country.
Funding
Abstract
Alkyl branching at the β position of a polyketide intermediate is an important variation on canonical polyketide natural product biosynthesis. The branching enzyme, 3-hydroxy-3-methylglutaryl synthase (HMGS), catalyzes the aldol addition of an acyl donor to a β-keto-polyketide intermediate acceptor. HMGS is highly selective for two specialized acyl carrier proteins (ACPs) that deliver the donor and acceptor substrates. The HMGS from the curacin A biosynthetic pathway (CurD) was examined to establish the basis for ACP selectivity. The donor ACP (CurB) had high affinity for the enzyme (Kd = 0.5 μM) and could not be substituted by the acceptor ACP. High-resolution crystal structures of HMGS alone and in complex with its donor ACP reveal a tight interaction that depends on exquisite surface shape and charge complementarity between the proteins. Selectivity is explained by HMGS binding to an unusual surface cleft on the donor ACP, in a manner that would exclude the acceptor ACP. Within the active site, HMGS discriminates between pre- and postreaction states of the donor ACP. The free phosphopantetheine (Ppant) cofactor of ACP occupies a conserved pocket that excludes the acetyl-Ppant substrate. In comparison with HMG-CoA (CoA) synthase, the homologous enzyme from primary metabolism, HMGS has several differences at the active site entrance, including a flexible-loop insertion, which may account for the specificity of one enzyme for substrates delivered by ACP and the other by CoA.
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