Zhu G, Marchewka M J, Woods K M, Upton S J, Keithly J S
New York State Department of Health, Wadsworth Center, Albany 12201-2002, USA.
Mol Biochem Parasitol. 2000 Feb 5;105(2):253-60. doi: 10.1016/s0166-6851(99)00183-8.
We report here the molecular analysis of a Type I fatty acid synthase in the apicomplexan Cryptosporidium parvum (CpFAS1). The CpFAS1 gene encodes a multifunctional polypeptide of 8243 amino acids that contains 21 enzymatic domains. This CpFAS1 structure is distinct from that of mammalian Type I FAS, which contains only seven enzymatic domains. The CpFAS1 domains are organized into: (i) a starter unit consisting of a fatty acid ligase and an acyl carrier protein; (ii) three modules, each containing a complete set of six enzymes (acyl transferase, ketoacyl synthase, ketoacyl reductase, dehydrase, enoyl reductase, and acyl carrier protein) for the elongation of fatty acid C2-units; and (iii) a terminating domain whose function is as yet unknown. The CpFAS1 gene is expressed throughout the life cycle of C. parvum, since its transcripts and protein were detected by RT-PCR and immunofluorescent localization, respectively. This cytosolic Type I CpFAS1 differs from the organellar Type II FAS enzymes identified from Toxoplasma gondii and Plasmodium falciparum which are targetted to the apicoplast, and are sensitive to inhibition by thiolactomycin. That the discovery of CpFAS1 may provide a new biosynthetic pathway for drug development against cryptosporidiosis, is indicated by the efficacy of the FAS inhibitor cerulenin on the growth of C. parvum in vitro.
我们在此报告对顶复门寄生虫微小隐孢子虫（CpFAS1）中I型脂肪酸合酶的分子分析。CpFAS1基因编码一个含有21个酶结构域的8243个氨基酸的多功能多肽。这种CpFAS1结构不同于仅含有7个酶结构域的哺乳动物I型脂肪酸合酶。CpFAS1结构域被组织成：（i）一个由脂肪酸连接酶和酰基载体蛋白组成的起始单元；（ii）三个模块，每个模块包含一套完整的六种酶（酰基转移酶、酮酰基合酶、酮酰基还原酶、脱水酶、烯酰基还原酶和酰基载体蛋白），用于脂肪酸C2单元的延伸；以及（iii）一个功能尚不清楚的终止结构域。由于分别通过逆转录聚合酶链反应（RT-PCR）和免疫荧光定位检测到其转录本和蛋白质，CpFAS1基因在微小隐孢子虫的整个生命周期中均有表达。这种胞质I型CpFAS1不同于从刚地弓形虫和恶性疟原虫中鉴定出的定位于质体且对硫霉素抑制敏感的细胞器II型脂肪酸合酶。FAS抑制剂浅蓝菌素对微小隐孢子虫体外生长的抑制效果表明，CpFAS1的发现可能为抗隐孢子虫病药物开发提供一条新的生物合成途径。
