ArticleJournal of the American Chemical Society2013
Analysis and refactoring of the A-74528 biosynthetic pathway.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed, 11 citations in OpenAlex.
- StreptoCAD: An Open-Source Software Toolbox Automating Genome Engineering Workflows in Streptomycetes.ACS synthetic biology · 2025Article
- An unusual aromatase/cyclase programs the formation of the phenyldimethylanthrone framework in anthrabenzoxocinones and fasamycin.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Assembling the carbon skeleton of A-74528.Chemical science · 2022Article
- Biosynthesis of aromatic polyketides in microorganisms using type II polyketide synthases.Microbial cell factories · 2020Review
- New insights into bacterial type II polyketide biosynthesis.F1000Research · 2017Review
- A systematic computational analysis of biosynthetic gene cluster evolution: lessons for engineering biosynthesis.PLoS computational biology · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
A-74528 is a C30 polyketide natural product that functions as an inhibitor of 2',5'-oligoadenylate phosphodiesterase (2'-PDE), a key regulatory enzyme of the interferon pathway. Modulation of 2'-PDE represents a unique therapeutic approach for regulating viral infections. The gene cluster responsible for biosynthesis of A-74528 yields minute amounts of this natural product together with considerably larger quantities of a structurally dissimilar C30 cytotoxic agent, fredericamycin. Through construction and analysis of a series of knockout mutants, we identified the genes necessary for A-74528 biosynthesis. Remarkably, the formation of six stereocenters and the regiospecific formation of six rings in A-74528 appear to be catalyzed by only two tailoring enzymes, a cyclase and an oxygenase, in addition to the core polyketide synthase. The inferred pathway was genetically refactored in a heterologous host, Streptomyces coelicolor CH999, to produce 3 mg/L A-74528 in the absence of fredericamycin.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.