The vitamin K-dependent (VKD) carboxylase uses the oxygenation of vitamin K to convert glutamyl residues (Glus) to carboxylated Glus (Glas) in VKD proteins, rendering them active in a broad range of physiologies that include hemostasis, apoptosis, bone development, arterial calcification, signal transduction, and growth control. The carboxylase has a high-affinity site that selectively binds VKD proteins, usually through their propeptide, and also has a second low-affinity site of VKD protein interaction. Propeptide binding increases carboxylase affinity for the Glu substrate, and the coordinated binding of the VKD propeptide and Glu substrate increases carboxylase affinity for vitamin K and activity, possibly through a mechanism of substrate-assisted catalysis. Tethering of VKD proteins to the carboxylase allows clusters of Glus to be modified to Glas by a processive mechanism that becomes disrupted during warfarin therapy. Warfarin inhibits a vitamin K oxidoreductase that generates the reduced vitamin K cofactor required for continuous carboxylation and causes decreased carboxylase catalysis and increased dissociation of partially carboxylated, inactive VKD proteins. The availability of reduced vitamin K may also control carboxylation in r-VKD protein-expressing cells, where the amounts of reduced vitamin K are sufficient for full carboxylation of low, but not high, expression levels of VKD proteins, and where carboxylation is not improved by overexpression of r-carboxylase. This review discusses these recent advances in understanding the mechanism of carboxylation. Also covered is the identification of functional carboxylase residues, a brief description of the role of VKD proteins in mammalian and lower organisms, and the potential impact of quality control components on carboxylation, which occurs in the endoplasmic reticulum during the secretion of VKD proteins.

中文翻译：

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维生素K依赖的羧化酶。

依赖于维生素K的（VKD）羧化酶利用维生素K的氧合作用将VKD蛋白中的谷氨酰胺残基（Glus）转化为羧化的Glus（Glas），从而使其在包括止血，凋亡，骨骼发育，动脉钙化，信号转导和生长控制。羧化酶具有通常通过其前肽选择性结合VKD蛋白的高亲和力位点，并且还具有VKD蛋白相互作用的第二个低亲和力位点。前肽结合增加了对Glu底物的羧化酶亲和力，而VKD前肽与Glu底物的协同结合增加了对维生素K和活性的羧化酶亲和力，这可能是通过底物辅助催化的机制实现的。VKD蛋白与羧化酶的连接可以使Glus簇通过一种在华法林治疗期间被破坏的过程性机制修饰为Glas。华法林抑制维生素K氧化还原酶，该酶产生连续羧化所需的减少的维生素K辅因子，并导致羧化酶催化作用降低和部分羧化的非活性VKD蛋白解离增加。还原的维生素K的可用性还可以控制表达r-VKD的细胞中的羧化作用，其中还原的维生素K的量足以使低但不高的VKD蛋白表达水平完全羧化，并且羧化没有改善通过r-羧化酶的过表达。这篇综述讨论了在理解羧化机理方面的这些最新进展。