Brautaset T, Sekurova O N, Sletta H, Ellingsen T E, StrŁm A R, Valla S, Zotchev S B
UNIGEN Center for Molecular Biology, Department of Biotechnology, Norwegian University of Science and Technology, Trondheim, N-7489, Norway.
Chem Biol. 2000 Jun;7(6):395-403. doi: 10.1016/s1074-5521(00)00120-4.
The polyene macrolide antibiotic nystatin produced by Streptomyces noursei ATCC 11455 is an important antifungal agent. The nystatin molecule contains a polyketide moiety represented by a 38-membered macrolactone ring to which the deoxysugar mycosamine is attached. Molecular cloning and characterization of the genes governing the nystatin biosynthesis is of considerable interest because this information can be used for the generation of new antifungal antibiotics.
A DNA region of 123,580 base pairs from the S. noursei ATCC 11455 genome was isolated, sequenced and shown by gene disruption to be involved in nystatin biosynthesis. Analysis of the DNA sequence resulted in identification of six genes encoding a modular polyketide synthase (PKS), genes for thioesterase, deoxysugar biosynthesis, modification, transport and regulatory proteins. One of the PKS-encoding genes, nysC, was found to encode the largest (11,096 amino acids long) modular PKS described to date. Analysis of the deduced gene products allowed us to propose a model for the nystatin biosynthetic pathway in S. noursei.
A complete set of genes responsible for the biosynthesis of the antifungal polyene antibiotic nystatin in S. noursei ATCC 11455 has been cloned and analyzed. This represents the first example of the complete DNA sequence analysis of a polyene antibiotic biosynthetic gene cluster. Manipulation of the genes identified within the cluster may potentially lead to the generation of novel polyketides and yield improvements in the production strains.
由诺尔斯链霉菌ATCC 11455产生的多烯大环内酯抗生素制霉菌素是一种重要的抗真菌剂。制霉菌素分子包含一个由38元大环内酯环代表的聚酮部分，脱氧糖霉菌胺连接在该环上。对控制制霉菌素生物合成的基因进行分子克隆和表征具有重要意义，因为这些信息可用于生成新的抗真菌抗生素。
从诺尔斯链霉菌ATCC 11455基因组中分离出一个123,580个碱基对的DNA区域，进行测序，并通过基因破坏证明其参与制霉菌素的生物合成。对DNA序列的分析导致鉴定出六个基因，分别编码模块化聚酮合酶（PKS）、硫酯酶、脱氧糖生物合成、修饰、转运和调节蛋白的基因。其中一个编码PKS的基因nysC被发现编码迄今为止描述的最大的模块化PKS（长度为11,096个氨基酸）。对推导的基因产物的分析使我们能够提出诺尔斯链霉菌中制霉菌素生物合成途径的模型。
已克隆并分析了负责诺尔斯链霉菌ATCC 11455中抗真菌多烯抗生素制霉菌素生物合成的完整基因集。这代表了多烯抗生素生物合成基因簇完整DNA序列分析的第一个例子。对该簇中鉴定出的基因进行操作可能会潜在地导致产生新的聚酮化合物并提高生产菌株的产量。
