Structure and function of carnitine acyltransferases
Structure and function of carnitine acyltransferases
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DOI：
10.1196/annals.1320.002
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Tong, L
中科院分区：
文献类型：
--
作者：
Jogl, G;Hsiao, YS;Tong, L
肉毒碱酰基转移酶催化肉毒碱和辅酶A（CoA）之间的酰基交换。这些酶包括肉毒碱乙酰转移酶（CrAT）。肉毒碱辛酰基转移酶（CrOT）和肉毒碱棕榈酰基转移酶（CPT）。CPT-I和CPT-II通过使长链脂肪酸能够穿过线粒体膜而对线粒体中长链脂肪酸的β-氧化至关重要。CPT-I的活性受到丙二酰辅酶A的抑制，丙二酰辅酶A是大鼠酸氧化的重要调节机制。CPT酶的突变或失调与许多严重的、Eden致命的人类疾病有关，并且这些酶是开发针对2型糖尿病和肥胖症的治疗剂的有希望的靶点。我们已经确定了小鼠CrAT的晶体结构。单独或与其底物肉毒碱或CoA复合。该结构包含两个域。令人惊讶的是，这两个结构域共享相同的骨架折叠。其也类似于氯霉素乙酰转移酶和二氢硫辛酰转乙酰酶。活性位点位于两个结构域之间的界面处，在延伸穿过中心或酶的隧道中。肉毒碱和辅酶A都在这个通道里。或催化His 343残基。这些结构信息为理解肉毒碱酰基转移酶的催化作用和设计其抑制剂提供了分子基础。此外，我们的结构信息表明，底物肉毒碱可能有助于稳定的反应中间体中的含氧阴离子的催化。
Carnitine acyltransferases catalyze the exchange or acyl groups between carnitine and coenzyme A (CoA). These enzymes include carnitine acetyltransferase (CrAT). carnitine octanoyltransferase (CrOT), and carnitine palmitoyltransferases (CPTs). CPT-I and CPT-II are crucial for the beta-oxidation of long-chain ratty acids in the mitochondria by enabling their transport across the mitochondrial membrane. The activity of CPT-I is inhibited by malonyl-CoA, a crucial regulatory mechanism for ratty acid oxidation. Mutation or dysregulation of the CPT enzymes has been linked to many serious, Eden fatal human diseases, and these enzymes are promising targets for the development of therapeutic agents against type 2 diabetes and obesity. We have determined the crystal structures or murine CrAT. alone and in complex with its substrate carnitine or CoA. The structure contains two domains. Surprisingly, these two domains share the same backbone fold. which is also similar to that or chloramphenicol acetyltransferase and dihydrolipoyl transacetylase. The active site is located at the interface between the two domains, in a tunnel that extends through the center or the enzyme. Carnitine and CoA are bound in this tunnel. on opposite sides or the catalytic His343 residue. The structural information provides a molecular basis for understanding the catalysis by carnitine acyltransferases and for designing their inhibitors. In addition, our structural information suggests that the substrate carnitine may assist the catalysis by stabilizing the oxyanion in the reaction intermediate.