TitleFunctional Studies and Revision of the NFAT-133/TM-123 Biosynthetic Pathway in .
Publication TypeJournal Article
Year of Publication2022
AuthorsZhou W, Alharbi HA, Hummingbird E, Keatinge-Clay AT, Mahmud T
JournalACS Chem Biol
Volume17
Issue8
Pagination2039-2045
Date Published2022 Aug 19
ISSN1554-8937
KeywordsBiosynthetic Pathways, Multigene Family, Pentanols, Pentanones, Polyketide Synthases, Streptomyces
Abstract

The biosynthetic gene cluster of NFAT-133, an inhibitor of the nuclear factor of activated T cells, was recently identified in 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 KS 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 "" during the polyketide chain assembly processes.

DOI10.1021/acschembio.2c00454
Alternate JournalACS Chem Biol
PubMed ID35904416
PubMed Central IDPMC9391300
Grant ListR01 AI129957 / AI / NIAID NIH HHS / United States
R01 GM106112 / GM / NIGMS NIH HHS / United States
S10 OD018518 / OD / NIH HHS / United States