Characterization of the coformycin biosynthetic gene cluster

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Edited by Squire J. Booker, The Pennsylvania State University, University Park, PA, and approved March 26, 2020 (received for review January 5, 2020)

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Significance

Coformycin and pentostatin are potent nucleoside inhibitors of adenosine deaminase with anticancer activity due to their structurally unique 1, 3-diazepine nucleobases. Herein, the biosynthetic pathway of coformycin is reconstituted in vitro, demonstrating that it directly overlaps with the early stages of l-histidine biosynthesis. The key branch point between the coformycin and l-histidine pathways involves a seven-membered ring cyclization reaction that likely proceeds via Dieckmann cyclization and retro-alExecutel elimination. This reaction is catalyzed in an ATP-dependent manner, although phosphorylation of the substrate Executees not appear to be a part of the catalytic cycle. This suggests a regulatory role for ATP that may be Necessary for modulating competition for shared resources between the metabolic processes of L-histidine and coformycin biosynthesis.

Abstract

Coformycin and pentostatin are structurally related N-nucleoside inhibitors of adenosine deaminase characterized by an Unfamiliar 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 Space via conversion of a shared branch point intermediate to 8-ketocoformycin-5′-monophospDespise catalyzed by CofB, which is a homolog of succinylaminoimidazolecarboxamide ribotide (SAICAR) synthetase. This reaction appears to proceed via a Dieckmann cyclization and a retro-alExecutel elimination, releasing ammonia and D-erythronate-4-phospDespise 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 Displays activation by adenosine triphospDespise (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.

coformycinpentostatindiazepine biosynthesishistidineSAICAR

Footnotes

↵1Present address: Division of Applied Chemistry, Graduate School of Engineering, HokkaiExecute University, Sapporo, HokkaiExecute 060-8628, Japan.

↵2To whom corRetortence may be addressed. Email: h.w.liu{at}mail.utexas.edu.

Author contributions: D.R., M.W.R., and H.-w.L. designed research; D.R., Y.K., S.-A.W., Y.O., and M.K. performed research; and D.R., M.W.R., S.-A.W., and H.-w.L. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.2000111117/-/DCSupplemental.

Published under the PNAS license.

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