Vitamin K Oxygenation, Glutamate Carboxylation, and Processivity: Defining the Three Critical Facets of Catalysis by the Vitamin K-Dependent Carboxylase
Vitamin K Oxygenation, Glutamate Carboxylation, and Processivity: Defining the Three Critical Facets of Catalysis by the Vitamin K-Dependent Carboxylase
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DOI：
10.3945/an.111.001719
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发表时间：
2012-03-01
影响因子：
9.3
通讯作者：
Berkner, Kathleen L.
中科院分区：
文献类型：
--
作者：
Rishavy, Mark A.;Berkner, Kathleen L.
维生素K依赖性羧化酶使用维生素K氧合来驱动维生素K依赖性蛋白中的多种谷氨酸的羧化，使其在多种生理学中具有活性。蛋白质的活性需要蛋白质的多次羧化，羧化酶是进行性的，因此不会发生蛋白质从羧化酶过早解离。羧化酶是独特的，与其他酶家族没有已知的同源性，并且尚未进行结构测定，使得对催化的理解难以捉摸。虽然已经建立了一个模型来解释氧化与羧化的关系，但直到最近，人们对羧化酶本身在催化中的功能几乎一无所知。在过去的十年中，对天然存在的羧化酶突变体的发现和分析已经鉴定出功能相关的残基和结构域。此外，非哺乳动物羧化酶直向同源物的鉴定为生物信息学分析提供了基础，以鉴定关键功能残基的候选物。合理选择的羧化酶突变体的生化分析导致了理解维生素K氧化，谷氨酸羧化，并通过羧化酶维持持续合成能力的突破。蛋白质羧化也在体内进行了评估，细胞内环境强烈影响羧化酶的功能。羧化酶是一个完整的膜蛋白，拓扑分析，加上生化测定，表明羧化酶与膜的相互作用是功能的一个重要方面。在一些细菌中发现了可能通过水平转移获得的羧化酶同系物，这些同系物的功能分析有可能导致发现维生素K在生物学中的新作用。高级Nutr. 3：135-748，2012.
The vitamin K dependent carboxylase uses vitamin K oxygenation to drive carboxylation of multiple glutamates in vitamin K dependent proteins, rendering them active in a variety of physiologies. Multiple carboxylations of proteins are required for their activity, and the carboxylase is processive, so that premature dissociation of proteins from the carboxylase does not occur. The carboxylase is unique, with no known homology to other enzyme families, and structural determinations have not been made, rendering an understanding of catalysis elusive. Although a model explaining the relationship of oxygenation to carboxylation had been developed, until recently almost nothing was known of the function of the carboxylase itself in catalysis. In the past decade, discovery and analysis of naturally occurring carboxylase mutants has led to identification of functionally relevant residues and domains. Further, identification of nonmammalian carboxylase orthologs has provided a basis for bioinformatic analysis to identify candidates for critical functional residues. Biochemical analysis of rationally chosen carboxylase mutants has led to breakthroughs in understanding vitamin K oxygenation, glutamate carboxylation, and maintenance of processivity by the carboxylase. Protein carboxylation has also been assessed in vivo, and the intracellular environment strongly affects carboxylase function. The carboxylase is an integral membrane protein, and topological analysis, coupled with biochemical determinations, suggests that interaction of the carboxylase with the membrane is an important facet of function. Carboxylase homologs, likely acquired by horizontal transfer, have been discovered in some bacteria, and functional analysis of these homologs has the potential to lead to the discovery of new roles of vitamin K in biology. Adv. Nutr. 3: 135-748, 2012.