title: Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase.
abstract: Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds-ikarugamycin (1), capsimycin (2) and capsimycin B (3)-two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method. The post-modification mechanism of the carbocyclic ring at C-14/C-13 of compound 1 in the biosynthesis of an important intermediate 3 was investigated. A putative cytochrome P450 superfamily gene, SXIM_40690 (ikaD), which was proximally localized to the ikarugamycin biosynthetic pathway, was characterized. In vivo gene inactivation and complementation experiment confirmed that IkaD catalysed the epoxide-ring formation reaction and further hydroxylation of ethyl side chain to form capsimycin G (3'). Binding affinities and kinetic parameters for the interactions between ikarugamycin (1) and capsimycin B (3) with IkaD were measured with Surface Plasmon Resonance. The intermediate compound 3' was isolated and identified as 30-hydroxyl-capsimycin B. The caspimycins 2 and 3, were transferred to methoxyl derivatives, 6 and 7, under acidic and heating conditions. Compounds 1-3 exhibited anti-proliferative activities against pancreatic carcinoma with IC50values of 1.30-3.37 μM.
authors.affiliation: Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: He-Lin
authors.initials: HL
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Shu-Heng
authors.initials: SH
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Institute of Oceanology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xu-Liang
authors.initials: XL
authors.lastname: Bu
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Institute of Oceanology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Weng
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Yang
authors.affiliation: Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Kun-Yan
authors.initials: KY
authors.lastname: He
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ao
authors.affiliation: State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Institute of Oceanology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Min-Juan
authors.initials: MJ
authors.lastname: Xu
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D006801:Humans; D006900:Hydroxylation; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D010802:Phylogeny; D066244:Proton Magnetic Resonance Spectroscopy; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013302:Streptomyces / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D009930:Organic Chemicals; C019287:capsimycin; D003577:Cytochrome P-450 Enzyme System