Characterization of the coformycin biosynthetic gene cluster in Streptomyces kaniharaensis .

Autor:	Ren D; Department of Chemistry, University of Texas at Austin, Austin, TX 78712., Ruszczycky MW; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712., Ko Y; Department of Chemistry, University of Texas at Austin, Austin, TX 78712., Wang SA; Department of Chemistry, University of Texas at Austin, Austin, TX 78712., Ogasawara Y; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712., Kim M; Department of Chemistry, University of Texas at Austin, Austin, TX 78712., Liu HW; Department of Chemistry, University of Texas at Austin, Austin, TX 78712; h.w.liu@mail.utexas.edu.; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 May 12; Vol. 117 (19), pp. 10265-10270. Date of Electronic Publication: 2020 Apr 29.
DOI:	10.1073/pnas.2000111117
Abstrakt:	Coformycin and pentostatin are structurally related N-nucleoside inhibitors of adenosine deaminase characterized by an unusual 1,3-diazepine nucleobase. Herein, the cof gene cluster responsible for coformycin biosynthesis is identified. Reconstitution of the coformycin biosynthetic pathway in vitro demonstrates that it overlaps significantly with the early stages of l-histidine biosynthesis. Committed entry into the coformycin pathway takes place via conversion of a shared branch point intermediate to 8-ketocoformycin-[Formula: see text]-monophosphate catalyzed by CofB, which is a homolog of succinylaminoimidazolecarboxamide ribotide (SAICAR) synthetase. This reaction appears to proceed via a Dieckmann cyclization and a retro-aldol elimination, releasing ammonia and D-erythronate-4-phosphate as coproducts. Completion of coformycin biosynthesis involves reduction and dephosphorylation of the CofB product, with the former reaction being catalyzed by the NADPH-dependent dehydrogenase CofA. CofB also shows activation by adenosine triphosphate (ATP) despite the reaction requiring neither a phosphorylated nor an adenylated intermediate. This may serve to help regulate metabolic partitioning between the l-histidine and coformycin pathways. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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