title: The biosynthesis of thiol- and thioether-containing cofactors and secondary metabolites catalyzed by radical S-adenosylmethionine enzymes.
abstract: Sulfur atoms are present as thiol and thioether functional groups in amino acids, coenzymes, cofactors, and various products of secondary metabolic pathways. The biosynthetic pathways for several sulfur-containing biomolecules require the substitution of sulfur for hydrogen at unreactive aliphatic or electron-rich aromatic carbon atoms. Examples discussed in this review include biotin, lipoic acid, methylthioether modifications found in some nucleic acids and proteins, and thioether cross-links found in peptide natural products. Radical S-adenosyl-L-methionine (SAM) enzymes use an iron-sulfur cluster to catalyze the reduction of SAM to methionine and a highly reactive 5'-deoxyadenosyl radical; this radical can abstract hydrogen atoms at unreactive positions, facilitating the introduction of a variety of functional groups. Radical SAM enzymes that catalyze sulfur insertion reactions contain a second iron-sulfur cluster that facilitates the chemistry, either by donating the cluster's endogenous sulfide or by binding and activating exogenous sulfide or sulfur-containing substrates. The use of radical chemistry involving iron-sulfur clusters is an efficient anaerobic route to the generation of carbon-sulfur bonds in cofactors, secondary metabolites, and other natural products.
authors.affiliation: From the Department of Chemistry, University of Hawaii at Manoa, Honolulu, Hawaii 96822 jtj@hawaii.edu.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Jarrett
mesh_terms: D000818:Animals; D003067:Coenzymes / Q000378:metabolism*; D005609:Free Radicals / Q000737:chemistry*; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008745:Methylation; D011496:Protein Methyltransferases / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry*
chemical_list: D003067:Coenzymes; D005609:Free Radicals; D007506:Iron-Sulfur Proteins; D013438:Sulfhydryl Compounds; D013440:Sulfides; D012436:S-Adenosylmethionine; D011496:Protein Methyltransferases
keywords: Biotin, Lipoic Acid; Enzyme Catalysis; Enzyme Mechanism; Enzyme Structure; Iron-Sulfur Protein; Oxidation-Reduction (Redox); Radical; Radical Enzyme; S-Adenosylmethionine (SAM); Sulfhydryl; Sulfur; Thioether