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.affiliation: Department of Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Nathan A
authors.identifier: 0000-0002-6129-8897
authors.initials: NA
authors.lastname: Bruender
authors.forename: Tsehai A J
authors.initials: TA
authors.lastname: Grell
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Dowling
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Reid M
authors.initials: RM
authors.lastname: McCarty
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Drennan
authors.affiliation: Department of Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Vahe
authors.identifier: 0000-0003-2302-0277
authors.initials: V
authors.lastname: Bandarian
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism*; D019759:Carbon-Nitrogen Lyases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000096:biosynthesis* / Q000737:chemistry; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism*
chemical_list: C512929:7-deazapurine; D001426:Bacterial Proteins; D001688:Biological Products; D005609:Free Radicals; D011687:Purines; D012436:S-Adenosylmethionine; D019759:Carbon-Nitrogen Lyases; C000627324:7-carboxy-7-deazaguanine synthase, Burkholderia multivorans