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  • Title: Functional Studies and Revision of the NFAT-133/TM-123 Biosynthetic Pathway in Streptomyces pactum.
    Author: Zhou W, Alharbi HA, Hummingbird E, Keatinge-Clay AT, Mahmud T.
    Journal: ACS Chem Biol; 2022 Aug 19; 17(8):2039-2045. PubMed ID: 35904416.
    Abstract:
    The biosynthetic gene cluster of NFAT-133, an inhibitor of the nuclear factor of activated T cells, was recently identified in Streptomyces pactum ATCC 27456. This cluster is conspicuous by its highly disordered noncollinear type I modular polyketide synthase (PKS) genes that encode PKSs with one module more than those expected for the heptaketide NFAT-133 biosynthesis. Thus, the major metabolite NFAT-133 was proposed to derive from an octaketide analogue, TM-123. Here, we report that further bioinformatic analysis and gene inactivation studies suggest that NFAT-133 is not derived from TM-123 but rather a product of programmed KS7 extension skipping of a nascent heptaketide from the PKS assembly line that produces TM-123. Furthermore, identification of NFAT-133/TM-123 analogues from mutants of the ATCC 27456 strain suggests that NftN (a putative dehydrogenase), NftE (a cytochrome P450), and NftG (a putative hydrolase/decarboxylase) function "in trans" during the polyketide chain assembly processes.
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