title: Identification of Alp1U and Lom6 as epoxy hydrolases and implications for kinamycin and lomaiviticin biosynthesis.
abstract: The naturally occurring diazobenzofluorenes, kinamycins, fluostatins and lomaiviticins, possess highly oxygenated A-rings, via which the last forms a dimeric pharmacophore. However, neither the A-ring transformation nor the dimerization mechanisms have been explored thus far. Here we propose a unified biosynthetic logic for the three types of antibiotics and verify one key reaction via detailed genetic and enzymatic experiments. Alp1U and Lom6 from the kinamycin and lomaiviticin biosynthesis, respectively, are shown to catalyse epoxy hydrolysis on a substrate that is obtained by chemical deacetylation of a kinamycin-pathway-derived intermediate. Thus, our study provides the first evidence for the existence of an epoxy intermediate in lomaiviticin biosynthesis. Furthermore, our results suggest that the dimerization in the lomaiviticin biosynthesis proceeds after dehydration of a product generated by Lom6.
authors.affiliation: 1] State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China [2] College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: 1] State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China [2] College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guomin
authors.initials: G
authors.lastname: Ai
authors.affiliation: 1] Université de Lorraine, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandœuvre-lès-Nancy F-54506, France [2] INRA, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandœuvre-lès-Nancy F-54506, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Aigle
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Keqian
authors.initials: K
authors.lastname: Yang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000378:metabolism*; D053898:Biosynthetic Pathways; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004851:Epoxide Hydrolases / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D005449:Fluorenes / Q000378:metabolism; D013058:Mass Spectrometry; D011809:Quinones / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology; D000095602:Angucyclines and Angucyclinones
chemical_list: D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D004851:Epoxide Hydrolases; D004852:Epoxy Compounds; D005449:Fluorenes; D011809:Quinones; C433842:lomaiviticin A; D000095602:Angucyclines and Angucyclinones; C433843:lomaiviticin B; C059021:kinamycin F; C000606399:Alp1U protein, Streptomyces ambofaciens; C000606398:Lom6 protein, Streptomyces ambofaciens