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cell‐specific immunosuppressive compound with novel mode of pharmacological action both in vivo and in vitro, whose chemical structure was shown to be identical to a previously‐reported antifungal compound named tautomycetin (TMC). Inhibition of T cell proliferation with TMC was observed at concentrations 100‐fold lower than those needed to achieve maximal inhibition with cyclosporin A (CsA). TMC is classified as a type I polyketide derived metabolite based on its chemical structure, specifically the presence of a linear branched‐chain fatty acid‐like moiety.
The unique chemical structure of TMC that includes an ester bond linkage between a cyclic C8 dialkylmaleic anhydride at one terminus, and a linear polyketide chain bearing a terminal alkene at the other, indicated that the corresponding biosynthetic pathway features a number of unique biochemical steps with significant potential for generating novel TMC derivatives. Sequence information revealed two multi‐modular type I polyketide synthases (PKSs) and several additional gene products presumably involved in TMC biosynthesis. The deduced roles for most of the TMC PKS catalytic domains were consistent with the expected functions necessary for TMC chain elongation and processing. In addition, a tmcN with a deduced product of 1,029 amino acid residues, located on the 3’‐terminus of an approximately 70‐kb contiguous TMC biosynthetic gene cluster, was found to have amino acid sequence homology with a bacteria Large ATP‐binding regulators of the LuxR (LAL) protein family. Gene disruption of tmcN from the Streptomyces sp. CK4412 chromosome resulted in significantly reduced antifungal activity as well as the absence of TMC. In addition, overexpression of tmcN stimulated TMC biosynthesis, strongly suggesting that TmcN is a pathway‐specific positive‐regulator that activates transcription of the TMC biosynthetic pathway genes in Streptomyces sp. CK4412.