TitleBiosynthesis of the Nuclear Factor of Activated T Cells Inhibitor NFAT-133 in .
Publication TypeJournal Article
Year of Publication2020
AuthorsZhou W, Posri P, Abugrain ME, Weisberg AJ, Chang JH, Mahmud T
JournalACS Chem Biol
Volume15
Issue12
Pagination3217-3226
Date Published2020 12 18
ISSN1554-8937
KeywordsComputational Biology, Genes, Bacterial, Genome, Bacterial, Magnetic Resonance Spectroscopy, Multigene Family, Pentanols, Pentanones, Polyketide Synthases, Streptomyces
Abstract

NFAT-133 is a -derived aromatic polyketide compound with immunosuppressive, antidiabetic, and antitrypanosomal activities. It inhibits transcription mediated by nuclear factor of activated T cells (NFAT), leading to the suppression of interleukin-2 expression and T cell proliferation. It also activates the AMPK pathway in L6 myotubes and increases glucose uptake. In addition to NFAT-133, a number of its congeners, e.g., panowamycins and benwamycins, have been identified. However, little is known about their modes of formation in the producing organisms. Through genome sequencing of ATCC 27456, gene inactivation, and genetic complementation experiments, the biosynthetic gene cluster of NFAT-133 and its congeners has been identified. The cluster contains a highly disordered genetic organization of type I modular polyketide synthase genes with several genes that are necessary for the formation of the aromatic core unit and tailoring processes. In addition, a number of new analogs of NFAT-133 were isolated and their chemical structures elucidated. It is suggested that the heptaketide NFAT-133 is derived from an octaketide intermediate, TM-123. The current study shows yet another unusual biosynthetic pathway involving a noncanonical polyketide synthase assembly line to produce a group of small molecules with valuable bioactivities.

DOI10.1021/acschembio.0c00775
Alternate JournalACS Chem Biol
PubMed ID33284588
PubMed Central IDPMC7891853
Grant ListR01 AI129957 / AI / NIAID NIH HHS / United States
S10 OD018518 / OD / NIH HHS / United States