Characterization of the bafilomycin biosynthetic gene cluster from Streptomyces lohii.
Characterization of the bafilomycin biosynthetic gene cluster from Streptomyces lohii.
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DOI：
10.1002/cbic.201200743
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发表时间：
2013-02-11
期刊：
影响因子：
3.2
通讯作者：
Li, Shengying
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Fortman, Jeffrey L.;Carlson, Jacob C.;Yan, Jinyong;Liu, Yi;Bai, Fali;Guan, Wenna;Jia, Junyong;Matainaho, Teatulohi;Sherman, David H.;Li, Shengying
巴filomycin B1是plecomacrolide家族天然产物的原型化合物，包括concanamycin， viranamycin, hygrolidin， elaiophylin及其相关代谢物。1该化合物于1984年首次从Streptomyces griseus sp. sulphurus （TÜ 1922）中分离得到。后来引入了多环内酯这一术语来描述具有16元或18元大内酯（含两个共轭二烯单元）和半缩醛侧链的聚酮亚群。这些化合物现已作为液泡atp酶（v - atp酶）抑制剂进行了广泛的研究，并因此显示出抗骨质疏松的一些希望。3,4此外，还报道了巴菲霉素A1与钙调磷酸酶抑制剂FK506对危及生命的真菌病原体新型隐球菌的协同抗真菌活性，5巴菲霉素A1抑制β-淀粉样蛋白的释放，6与其他巴菲霉素的抗肿瘤，7抗寄生虫，8和免疫抑制活性。尽管不断努力，但普遍的毒性使这些化合物无法临床应用。半合成衍生物已经提供了一些迹象，表明可以增强靶特异性。10然而，由于全合成的复杂性，对核心结构的广泛操作仍然阻碍了构效关系研究。在聚酮生物合成领域几十年的工作已经产生了通过基因操作对核心大环内酯产生细微变化的工具。13,14为了利用这些知识来产生新的类似物，必须阐明天然生物合成基因簇序列。当一种产生巴非霉素的生物，lohistreptomyces，在我们实验室正在进行的药物发现项目中被分离出来时，开始了巴非霉素生物合成途径的表征。
Bafilomycin B1 is the archetypal compound of the plecomacrolide family of natural products, which include concanamycins, viranamycins, hygrolidin, elaiophylin, and allied metabolites. 1 This compound was first isolated from Streptomyces griseus sp. sulphurus (TÜ 1922) in 1984. 2 The term plecomacrolide was later introduced to describe a subgroup of polyketides featured with a 16-or 18-membered macrolactone containing two conjugated diene units, and a hemiacetal side chain. 1 These compounds have now been studied extensively as vacuolar ATPase (V-ATPase) inhibitors and, as such, have shown some promise as anti-osteoporetics. 3, 4 In addition, synergistic antifungal activity of bafilomycin A1 with the calcineurin inhibitor FK506 against the life-threatening fungal pathogen Cryptococcus neoformans, 5 inhibition of the release of β-amyloid by bafilomycin A1, 6 together with antitumor, 7 antiparasitic, 8 and immunosuppressant9 activities of other bafilomycins were reported. Despite continued efforts, generalized toxicity has kept these compounds from clinical application. Semi-synthetic derivatives have provided some indication that target specificity can be enhanced. 10 However, extensive manipulation of the core structure for structure-activity relationship studies remains hampered by the complexity of total synthesis. 11, 12 Decades of work in the field of polyketide biosynthesis have yielded tools to generate subtle changes to the core macrolide via genetic manipulation. 13, 14 In order to utilize this knowledge to generate novel analogues, the native biosynthetic gene cluster sequence must be elucidated. When a bafilomycin-producing organism, Streptomyces lohii, was isolated during an ongoing drug discovery program in our laboratories, the characterization of the bafilomycin biosynthetic pathway was initiated.
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影响因子：
14.9
作者：
Ansari, MZ;Yadav, G;Mohanty, D
通讯作者：
Mohanty, D
DOI：
10.1073/pnas.0337542100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Gust, B;Challis, GL;Chater, KF
通讯作者：
Chater, KF
DOI：
10.1007/s10295-003-0062-0
发表时间：
2003-08-01
影响因子：
3.4
作者：
Del Vecchio, F;Petkovic, H;Leadlay, PF
通讯作者：
Leadlay, PF
影响因子：
3.2
作者：
li, Wen Li;Ju, Jianhua;Shen, Ben
通讯作者：
Shen, Ben
影响因子：
3.5
作者：
HAYDOCK, SF;APARICIO, JF;LEADLAY, PF
通讯作者：
LEADLAY, PF