7-Carboxy-7-deazaguanine Synthase: A Radical
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Author(s)
Bruender, Nathan A.
McCarty, Reid M.
Bandarian, Vahe
Grell, Tsehai Ariane
Dowling, Daniel P.
Drennan, Catherine L
Date Issued
January 2017
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Bruender, Nathan A. et al. “7-Carboxy-7-Deazaguanine Synthase: A Radical S-Adenosyl-l-Methionine Enzyme with Polar Tendencies.” Journal of the American Chemical Society 139, 5 (January 2017): 1912–1920 © 2017 American Chemical Society
Version
Final published version
Abstract
Radical S-adenosyl-L-methionine (SAM) enzymes are widely distributed and catalyze diverse reactions. SAM binds to the unique iron atom of a site-differentiated [4Fe-4S] cluster and is reductively cleaved to generate a 5'-deoxyadenosyl radical, which initiates turnover. 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes a key step in the biosynthesis of 7-deazapurine containing natural products. 6-Carboxypterin (6-CP), an oxidized analogue of the natural substrate 6-carboxy-5,6,7,8-tetrahydropterin (CPH4), is shown to be an alternate substrate for CDG synthase. Under reducing conditions that would promote the reductive cleavage of SAM, 6-CP is turned over to 6-deoxyadenosylpterin (6-dAP), presumably by radical addition of the 5'-deoxyadenosine followed by oxidative decarboxylation to the product. By contrast, in the absence of the strong reductant, dithionite, the carboxylate of 6-CP is esterified to generate 6-carboxypterin-5'-deoxyadenosyl ester (6-CP-dAdo ester). Structural studies with 6-CP and SAM also reveal electron density consistent with the ester product being formed in crystallo. The differential reactivity of 6-CP under reducing and nonreducing conditions highlights the ability of radical SAM enzymes to carry out both polar and radical transformations in the same active site.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/JACS.6B11381
