Tomoda H, Omura S
Research Center for Biological Function, Kitasato Institute, Tokyo, Japan.
Kitasato Arch Exp Med. 1993 Apr;65 Suppl:1-12.
Thiotetromycin is isolated from Streptomyces sp. OM-674 discovered in the course of the screening for antibacterial antibiotics. The antibiotic was found to be a specific inhibitor of type II fatty acid synthase. In order to search acyl-CoA synthetase inhibitors, a kind of yeast, Candida lipolytica, was utilized as test organism for the primary screening. Four structurally related compounds named triacsin were isolated from Streptomyces sp. SK-1894 as a specific inhibitor of acyl-CoA synthetase I of C. lipolytica. Further biochemical studies revealed that triacsins inhibit acyl-CoA synthetases from widely different sources. The inhibition is competitive with respect to long chain fatty acids. The common N-hydroxytriazene moiety of triacsins is essential for inhibition. To discover inhibitors of mevalonate biosynthesis, Vero cells were used as test organism for the screening. A beta-lactone 1233A(F-244) isolated from Scopulariopsis sp. F-244 was demonstrated to inhibit mevalonate biosynthesis with assays using cell and enzyme systems. Further studies demonstrated that the compound inhibits 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase specifically and irreversibly. The geometry of the (2R, 3R)-beta-lactone ring in the structure is essential for specific inhibition against the enzyme.
硫代四霉素是从在抗菌抗生素筛选过程中发现的链霉菌属OM-674中分离得到的。该抗生素被发现是II型脂肪酸合酶的特异性抑制剂。为了寻找酰基辅酶A合成酶抑制剂，一种酵母，解脂耶氏酵母，被用作初筛的测试生物体。从链霉菌属SK-1894中分离出四种结构相关的化合物，称为三氮菌素，作为解脂耶氏酵母酰基辅酶A合成酶I的特异性抑制剂。进一步的生化研究表明，三氮菌素能抑制来自广泛不同来源的酰基辅酶A合成酶。这种抑制作用对长链脂肪酸具有竞争性。三氮菌素的共同N-羟基三氮烯部分对抑制作用至关重要。为了发现甲羟戊酸生物合成的抑制剂，将非洲绿猴肾细胞用作筛选的测试生物体。从拟青霉属F-244中分离出的一种β-内酯1233A（F-244），通过细胞和酶系统检测证明能抑制甲羟戊酸生物合成。进一步的研究表明，该化合物能特异性且不可逆地抑制3-羟基-3-甲基戊二酰（HMG）-辅酶A合酶。结构中（2R，3R）-β-内酯环的几何形状对于对该酶的特异性抑制至关重要。
