Abstract:
:The catalytic versatility of cytochrome P450 monooxygenases is remarkable. Here, we present mechanistic and structural characterizations of TleB from Streptomyces blastmyceticus and its homolog HinD from Streptoalloteichus hindustanus, which catalyze unusual intramolecular C-N bond formation to generate indolactam V from the dipeptide N-methylvalyl-tryptophanol. In vitro analyses demonstrated that both P450s exhibit promiscuous substrate specificity, and modification of the N13-methyl group resulted in the formation of indole-fused 6/5/6 tricyclic products. Furthermore, X-ray crystal structures in complex with substrates and structure-based mutagenesis revealed the intimate structural details of the enzyme reactions. We propose that the generation of a diradical species is critical for the indolactam formation, and that the intramolecular C(sp2)-H amination is initiated by the abstraction of the N1 indole hydrogen. After indole radical repositioning and subsequent removal of the N13 hydrogen, the coupling of the properly-folded diradical leads to the formation of the C4-N13 bond of indolactam.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
He F,Mori T,Morita I,Nakamura H,Alblova M,Hoshino S,Awakawa T,Abe Idoi
10.1038/s41589-019-0380-9subject
Has Abstractpub_date
2019-12-01 00:00:00pages
1206-1213issue
12eissn
1552-4450issn
1552-4469pii
10.1038/s41589-019-0380-9journal_volume
15pub_type
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