Tearing down to build up: Metalloenzymes in the biosynthesis lincomycin, hormaomycin and the pyrrolo [1,4]benzodiazepines

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• 作者：Keri L. Colabroy ^{colabroy@muhlenberg.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Metalloenzymes ; Lincomycin ; Hormaomycin ; Pyrrolo [1 ; 4]benzodiazepines ; Dioxygenase ; Heme ; Biosynthesis
• 刊名：Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：1864
• 期：6
• 页码：724-737
• 全文大小：2441 K

文摘

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.