Genetic basis for the biosynthesis of the pharmaceutically important class of epoxyketone proteasome inhibitors.
Genetic basis for the biosynthesis of the pharmaceutically important class of epoxyketone proteasome inhibitors.
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药学上重要的一类环氧酮蛋白酶体抑制剂生物合成的遗传基础。
DOI：
10.1021/cb400699p
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发表时间：
2014-01-17
影响因子：
4
通讯作者：
Kaysser, Leonard
中科院分区：
文献类型：
--
作者：
Schorn, Michelle;Zettler, Judith;Noel, Joseph P.;Dorrestein, Pieter C.;Moore, Bradley S.;Kaysser, Leonard
环氧酮蛋白酶体抑制剂是用于治疗癌症的已确立的一类治疗剂。其独特的α′，β′-环氧酮药效团允许以非凡的特异性结合蛋白酶体的催化β亚基。在这里，我们报告的第一个基因簇的生物合成天然肽基环氧酮的表征。使用用于Ion Torrent PGM基因组测序的修改的方案，分别在放线菌生产菌株ATCC 53904和吸水链霉菌ATCC 53709中鉴定了环氧霉素（抗癌药物Kyprolis™的先导化合物）和eponemycin的簇。这两个基因簇编码一个杂合非核糖体肽合成酶/聚酮合酶多功能酶复合物和同源氧化还原酶。在白色链霉菌J1046中通过全途径表达异源产生环氧霉素和环氧霉素。此外，我们采用质谱分子网络的一个新的比较代谢组学方法在异源系统中，并发现了一些推定的环氧酮衍生物。通过这项研究，我们第一次在任何生物体中明确地将环氧酮蛋白酶体抑制剂及其生物合成基因联系起来，现在可以对其进行详细的生化研究。
The epoxyketone proteasome inhibitors are an established class of therapeutic agents for the treatment of cancer. Their unique α′,β′-epoxyketone pharmacophore allows binding to the catalytic β-subunits of the proteasome with extraordinary specificity. Here we report the characterization of the first gene clusters for the biosynthesis of natural peptidyl-epoxyketones. The clusters for epoxomicin, the lead compound for the anti-cancer drug Kyprolis™, and for eponemycin were identified in the actinobacterial producer strains ATCC 53904 and Streptomyces hygroscopicus ATCC 53709, respectively, using a modified protocol for Ion Torrent PGM genome sequencing. Both gene clusters code for a hybrid non-ribosomal peptide synthetase/polyketide synthase multifunctional enzyme complex and homologous redox enzymes. Epoxomicin and eponemycin were heterologously produced in Streptomyces albus J1046 via whole pathway expression. Moreover, we employed mass spectral molecular networking for a new comparative metabolomics approach in a heterologous system and discovered a number of putative epoxyketone derivatives. With this study we have definitively linked epoxyketone proteasome inhibitors and their biosynthesis genes for the first time in any organism, which will now allow for their detailed biochemical investigation.
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影响因子：
--
作者：
Guthals A;Watrous JD;Dorrestein PC;Bandeira N
通讯作者：
Bandeira N
影响因子：
2.1
作者：
Flett, F;Mersinias, V;Smith, CP
通讯作者：
Smith, CP
DOI：
10.1016/j.ijantimicag.2004.02.023
发表时间：
2004-09-01
影响因子：
10.8
作者：
Glenn, RJ;Pemberton, AJ;Steverding, D
通讯作者：
Steverding, D
影响因子：
15
作者：
Kaysser L;Bernhardt P;Nam SJ;Loesgen S;Ruby JG;Skewes-Cox P;Jensen PR;Fenical W;Moore BS
通讯作者：
Moore BS
影响因子：
3.3
作者：
HANADA, M;SUGAWARA, K;OKI, T
通讯作者：
OKI, T