Structure, mechanism and regulation of pyruvate carboxylase.
Structure, mechanism and regulation of pyruvate carboxylase.
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DOI：
10.1042/bj20080709
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发表时间：
2008-08-01
期刊：
影响因子：
--
通讯作者：
Attwood PV
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文献类型：
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作者：
Jitrapakdee S;St Maurice M;Rayment I;Cleland WW;Wallace JC;Attwood PV
丙酮酸羧化酶（英语：Pyruvate carboxylase，PC）是一种含生物素的酶，催化丙酮酸的HCO3−和MgATP依赖性羧化反应形成草酰乙酸。这是一个非常重要的回补反应，为各种关键的生化途径补充从克雷布斯循环中提取的草酰乙酸。因此，PC被认为是一种酶，是至关重要的中间代谢，控制燃料分配向脂肪生成，脂肪生成和胰岛素分泌。该酶于1959年被发现，在过去的十年里，人们对其结构和功能的了解取得了很大进展。来自大多数生物体的PC是由乙酰辅酶A和天冬氨酸变构调节的四聚体蛋白。最近已经确定了具有各种配体结合的全酶的高分辨率晶体结构，并且已经揭示了生物素羧化酶、羧基转移酶和生物素羧基载体结构域的细节和相对位置，以及独特的变构效应结构域。在存在变构效应物乙酰辅酶A的情况下，生物素部分在一条多肽链上的生物素羧化酶结构域活性位点和相邻反平行多肽链上的羧基转移酶活性位点之间转移羧基中间体。此外，已经使用经典生物化学和遗传学方法的组合研究了PC在非致炎组织中的真正作用。哺乳动物PC基因启动子的首次克隆和随后的转录研究揭示了一些关键的同源转录因子调节组织特异性表达。本文综述了这些进展，并提出了一些未来的研究方向，为这一重要的酶。
Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways. PC is therefore considered as an enzyme that is crucial for intermediary metabolism, controlling fuel partitioning toward gluconeogenesis, lipogenesis and insulin secretion. The enzyme was discovered in 1959 and over the last decade there has been much progress in understanding its structure and function. PC from most organisms is a tetrameric protein that is allosterically regulated by acetyl CoA and aspartate. High resolution crystal structures of the holoenzyme with various ligands bound have recently been determined, and have revealed details and the relative positions of the biotin carboxylase, carboxyltransferase and biotin carboxyl carrier domains, and also a unique allosteric effector domain. In the presence of the allosteric effector, acetyl CoA, the biotin moiety transfers the carboxyl group intermediate between the biotin carboxylase domain active site on one polypeptide chain and the carboxyltransferase active site on the adjacent antiparallel polypeptide chain. In addition, the bona fide role of PC in the non-gluconeogenic tissues has been studied using a combination of classical biochemistry and genetic approaches. The first cloning of the promoter of the PC gene in mammals and subsequent transcriptional studies reveal some key cognate transcription factors regulating tissue-specific expression. This review summarizes these advances and also offers some prospects in terms of future directions for the study of this important enzyme.