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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