Pemble Charles W, Johnson Lynnette C, Kridel Steven J, Lowther W Todd
Center for Structural Biology and Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
Nat Struct Mol Biol. 2007 Aug;14(8):704-9. doi: 10.1038/nsmb1265. Epub 2007 Jul 8.
Human fatty acid synthase (FAS) is uniquely expressed at high levels in many tumor types. Pharmacological inhibition of FAS therefore represents an important therapeutic opportunity. The drug Orlistat, which has been approved by the US Food and Drug Administration, inhibits FAS, induces tumor cell-specific apoptosis and inhibits the growth of prostate tumor xenografts. We determined the 2.3-A-resolution crystal structure of the thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in the active sites of two thioesterase molecules as a stable acyl-enzyme intermediate and as the hydrolyzed product. The details of these interactions reveal the molecular basis for inhibition and suggest a mechanism for acyl-chain length discrimination during the FAS catalytic cycle. Our findings provide a foundation for the development of new cancer drugs that target FAS.
人类脂肪酸合酶（FAS）在许多肿瘤类型中均有独特的高表达。因此，对FAS进行药理抑制代表了一个重要的治疗机会。已获美国食品药品监督管理局批准的药物奥利司他可抑制FAS，诱导肿瘤细胞特异性凋亡，并抑制前列腺肿瘤异种移植物的生长。我们确定了被奥利司他抑制的FAS硫酯酶结构域的2.3埃分辨率晶体结构。奥利司他作为稳定的酰基-酶中间体和水解产物，被捕获在两个硫酯酶分子的活性位点中。这些相互作用的细节揭示了抑制的分子基础，并提示了FAS催化循环中酰基链长度识别的机制。我们的研究结果为开发靶向FAS的新型抗癌药物奠定了基础。
