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Title: 7-Carboxy-7-deazaguanine Synthase: A Radical S -Adenosyl- l -methionine Enzyme with Polar Tendencies

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.

Authors:
ORCiD logo; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFNIGMS
OSTI Identifier:
1373762
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of the American Chemical Society; Journal Volume: 139; Journal Issue: 5
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Bruender, Nathan A., Grell, Tsehai A. J., Dowling, Daniel P., McCarty, Reid M., Drennan, Catherine L., and Bandarian, Vahe. 7-Carboxy-7-deazaguanine Synthase: A Radical S -Adenosyl- l -methionine Enzyme with Polar Tendencies. United States: N. p., 2017. Web. doi:10.1021/jacs.6b11381.
Bruender, Nathan A., Grell, Tsehai A. J., Dowling, Daniel P., McCarty, Reid M., Drennan, Catherine L., & Bandarian, Vahe. 7-Carboxy-7-deazaguanine Synthase: A Radical S -Adenosyl- l -methionine Enzyme with Polar Tendencies. United States. doi:10.1021/jacs.6b11381.
Bruender, Nathan A., Grell, Tsehai A. J., Dowling, Daniel P., McCarty, Reid M., Drennan, Catherine L., and Bandarian, Vahe. Wed . "7-Carboxy-7-deazaguanine Synthase: A Radical S -Adenosyl- l -methionine Enzyme with Polar Tendencies". United States. doi:10.1021/jacs.6b11381.
@article{osti_1373762,
title = {7-Carboxy-7-deazaguanine Synthase: A Radical S -Adenosyl- l -methionine Enzyme with Polar Tendencies},
author = {Bruender, Nathan A. and Grell, Tsehai A. J. and Dowling, Daniel P. and McCarty, Reid M. and Drennan, Catherine L. and Bandarian, Vahe},
abstractNote = {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.},
doi = {10.1021/jacs.6b11381},
journal = {Journal of the American Chemical Society},
number = 5,
volume = 139,
place = {United States},
year = {Wed Jan 25 00:00:00 EST 2017},
month = {Wed Jan 25 00:00:00 EST 2017}
}
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