title: Tearing down to build up: Metalloenzymes in the biosynthesis lincomycin, hormaomycin and the pyrrolo [1,4]benzodiazepines.
abstract: The metabolic pathways for the production of lincomycin, hormaomycin and the antitumor pyrrolo [1,4] benzodiazepines share a vinyl substituted pyrroline carboxylic acid (3-vinyl-2,3-pyrroline-5-carboxylic acid, VPCA) as a common intermediate. Biosynthesis of this vinyl substituted pyrroline carboxylic acid intermediate requires a short, three-enzyme pathway containing two metalloenzymes: a heme-dependent l-tyrosine hydroxylase and a non-heme Fe(2+) dependent l-DOPA dioxygenase. The l-tyrosine hydroxylase is an unprecedented type of peroxidase that specifically monohydroxylates tyrosine, while the l-DOPA extradiol cleaving enzyme is a single-domain vicinal-oxygen-chelate (VOC) dioxygenase. The dioxygenase product subsequently undergoes an, as yet uncharacterized, C-C bond cleavage reaction. This mini-pathway demonstrates the use of metal-dependent chemistry typically associated with natural product degradation in order to build a compact, functionalized building block for larger, bioactive molecules.
authors.affiliation: Department of Chemistry, Muhlenberg College, Allentown, PA 18104, United States. Electronic address: colabroy@muhlenberg.edu.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Colabroy
mesh_terms: D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000378:metabolism*; D047630:Depsipeptides / Q000096:biosynthesis*; D004798:Enzymes / Q000737:chemistry / Q000378:metabolism*; D008034:Lincomycin / Q000096:biosynthesis*; D008667:Metalloproteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D010456:Peptides, Cyclic
chemical_list: D001569:Benzodiazepines; D047630:Depsipeptides; D004798:Enzymes; D008034:Lincomycin; D008667:Metalloproteins; C510371:hormaomycin; D010456:Peptides, Cyclic
keywords: Biosynthesis; Dioxygenase; Heme; Hormaomycin; Lincomycin; Metalloenzymes; Pyrrolo [1,4]benzodiazepines