7-Carboxy-7-deazaguanine synthase: A radical S-adenosyl-L-methionine enzyme with polar tendencies

Nathan A. Bruender, Tsehai A J Grell, Daniel P. Dowling, Reid M. McCarty, Catherine L. Drennan, Vahe Bandarian

Research output: Research - peer-reviewArticle

  • 3 Citations

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.

LanguageEnglish (US)
Pages1912-1920
Number of pages9
JournalJournal of the American Chemical Society
Volume139
Issue number5
DOIs
StatePublished - Feb 8 2017
Externally publishedYes

Fingerprint

S-Adenosylmethionine
Enzymes
6-carboxypterin
7-deazaguanine
Esters
Substrates
Biosynthesis
Carrier concentration
Iron
Atoms
Decarboxylation
Dithionite
Reducing Agents
Biological Products
7-deazapurine
tetrahydropterin
5'-deoxyadenosine
Catalytic Domain
Electrons

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Bruender, N. A., Grell, T. A. J., Dowling, D. P., McCarty, R. M., Drennan, C. L., & Bandarian, V. (2017). 7-Carboxy-7-deazaguanine synthase: A radical S-adenosyl-L-methionine enzyme with polar tendencies. Journal of the American Chemical Society, 139(5), 1912-1920. DOI: 10.1021/jacs.6b11381

7-Carboxy-7-deazaguanine synthase : A radical S-adenosyl-L-methionine enzyme with polar tendencies. / Bruender, Nathan A.; Grell, Tsehai A J; Dowling, Daniel P.; McCarty, Reid M.; Drennan, Catherine L.; Bandarian, Vahe.

In: Journal of the American Chemical Society, Vol. 139, No. 5, 08.02.2017, p. 1912-1920.

Research output: Research - peer-reviewArticle

Bruender NA, Grell TAJ, Dowling DP, McCarty RM, Drennan CL, Bandarian V. 7-Carboxy-7-deazaguanine synthase: A radical S-adenosyl-L-methionine enzyme with polar tendencies. Journal of the American Chemical Society. 2017 Feb 8;139(5):1912-1920. Available from, 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. In: Journal of the American Chemical Society. 2017 ; Vol. 139, No. 5. pp. 1912-1920
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