Papers

Peer-reviewed International journal
May 12, 2020

Characterization of the coformycin biosynthetic gene cluster in Streptomyces kaniharaensis.

Proceedings of the National Academy of Sciences of the United States of America
  • Daan Ren
  • ,
  • Mark W Ruszczycky
  • ,
  • Yeonjin Ko
  • ,
  • Shao-An Wang
  • ,
  • Yasushi Ogasawara
  • ,
  • Minje Kim
  • ,
  • Hung-Wen Liu

Volume
117
Number
19
First page
10265
Last page
10270
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1073/pnas.2000111117

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.

Link information
DOI
https://doi.org/10.1073/pnas.2000111117
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32350138
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229688
ID information
  • DOI : 10.1073/pnas.2000111117
  • Pubmed ID : 32350138
  • Pubmed Central ID : PMC7229688

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