Opposed effects of enzymatic gliotoxin N- and S-methylations.

摘要: Gliotoxin (1), a virulence factor of the human pathogenic fungus Aspergillus fumigatus, is prototype epipoly(thiodioxopiperazine) (ETP) toxins. Here we report discovery and functional analysis two methyl transferases (MTs) that play crucial roles for ETP toxicity. Genome comparisons, knockouts, in vitro enzyme studies identified new S-adenosyl-l-methionine-dependent S-MT (TmtA) is, surprisingly, encoded outside gli gene cluster. We found TmtA irreversibly inactivates by S-alkylation this detoxification strategy appears to be not only limited producers. Furthermore, unveiled GliN functions as freestanding amide N-MT. GliN-mediated methylation confers stability ETP, damping spontaneous formation tri- tetrasulfides. In addition, enzymatic N-alkylation constitutes last step gliotoxin biosynthesis prerequisite cytotoxicity molecule. Thus, these specialized alkylating enzymes have dramatic full...