Journal
NATURE CHEMICAL BIOLOGY
Volume 7, Issue 3, Pages 154-160Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.512
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Funding
- US National Institutes of Health [CA094426]
- Chinese National Natural Science Foundation [20832009, 30525001, 90713012, 20921091]
- Chinese Ministry of Science and Technology [2009ZX09501-008]
- Chinese National Basic Research Program (973 program) [2010CB833200]
- Chinese Academy of Sciences [KJCX2-YW-H08, KSCX2-YW-G-06]
- Science and Technology Commission of Shanghai Municipality of China [09QH1402700]
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The radical S-adenosylmethionine (S-AdoMet) superfamily contains thousands of proteins that catalyze highly diverse conversions, most of which are poorly understood, owing to a lack of information regarding chemical products and radical-dependent transformations. We here report that NosL, involved in forming the indole side ring of the thiopeptide nosiheptide (NOS), is a radical S-AdoMet 3-methyl-2-indolic acid (MIA) synthase. NosL catalyzed an unprecedented carbon chain reconstitution of L-tryptophan to give MIA, showing removal of the C alpha-N unit and shift of the carboxylate to the indole ring. Dissection of the enzymatic process upon the identification of products and a putative glycyl intermediate uncovered a radical-mediated, unusual fragmentation-recombination reaction. This finding unveiled a key step in radical S-AdoMet enzyme-catalyzed structural rearrangements during complex biotransformations. Additionally, NosL tolerated fluorinated L-tryptophan as the substrate, allowing for production of a regiospecifically halogenated thiopeptide that has not been found among the more than 80 members of the naturally occurring thiopeptide family.
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