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.
Original language | English (US) |
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Pages (from-to) | 1912-1920 |
Number of pages | 9 |
Journal | Journal of the American Chemical Society |
Volume | 139 |
Issue number | 5 |
DOIs | |
State | Published - Feb 8 2017 |
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry
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Dive into the research topics of '7-Carboxy-7-deazaguanine synthase: A radical S-adenosyl-L-methionine enzyme with polar tendencies'. Together they form a unique fingerprint.Datasets
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Crystal Structure of QueE from Bacillus subtilis with methionine bound
Bruender, N. A. (Contributor), Grell, T. A. J. (Contributor), Dowling, D. P. (Contributor), McCarty, R. M. (Contributor), Drennan, C. L. (Contributor) & Bandarian, V. (Contributor), Protein Data Bank (PDB), Jan 18 2017
DOI: 10.2210/pdb5TGS/pdb, https://www.wwpdb.org/pdb?id=pdb_00005tgs
Dataset
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Crystal Structure of QueE from Bacillus subtilis with 6-carboxypterin-5'-deoxyadenosyl ester bound
Bruender, N. A. (Contributor), Grell, T. A. J. (Contributor), Dowling, D. P. (Contributor), McCarty, R. M. (Contributor), Drennan, C. L. (Contributor) & Bandarian, V. (Contributor), Protein Data Bank (PDB), Jan 18 2017
DOI: 10.2210/pdb5TH5/pdb, https://www.wwpdb.org/pdb?id=pdb_00005th5
Dataset