Structural and functional insights into enzymes of the vitamin K cycle.
Structural and functional insights into enzymes of the vitamin K cycle.
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DOI：
10.1111/jth.13217
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Stafford DW
中科院分区：
文献类型：
--
作者：
Tie JK;Stafford DW
依赖维生素k的蛋白质需要某些谷氨酸的羧化才能发挥其生物学功能。参与维生素K依赖性羧化的酶包括：γ -谷氨酰羧化酶（GGCX），维生素K环氧化还原酶（VKOR）和尚未确定的维生素K还原酶（VKR）。由于维生素K的疏水性，这些酶可能是内质网中的整体膜蛋白。因此，对这些酶的结构-功能研究一直具有挑战性，其中一些结果存在明显的争议。这些酶自然发生突变的患者，主要表现为出血性疾病或对口服抗凝治疗有耐药性，为维生素K循环酶的功能研究提供了有价值的信息。本文综述了维生素K循环酶的酶活性的发现和基因鉴定；（ii）鉴定其功能重要区域及其活性位点残基；（iii） GGCX和VKOR的膜拓扑研究；（iv）关于这些酶的结构和功能研究的争议问题，特别是膜拓扑结构，保守半胱氨酸的作用和VKOR活性位点再生的机制。我们还讨论了VKOR的同源蛋白VKOR样1 （VKORL1）参与维生素K周期的可能性，以及鉴定未知VKR的重要性和可能的方法。总的来说，我们描述了关于维生素K循环中酶的结构和功能研究的成就和遗留问题。
Vitamin K-dependent proteins require carboxylation of certain glutamates for their biological functions. The enzymes involved in the vitamin K-dependent carboxylation include: gamma-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKOR) and an as-yet-unidentified vitamin K reductase (VKR). Due to the hydrophobicity of vitamin K, these enzymes are likely to be integral membrane proteins that reside in the endoplasmic reticulum. Therefore, structure-function studies on these enzymes have been challenging, and some of the results are notably controversial. Patients with naturally occurring mutations in these enzymes, who mainly exhibit bleeding disorders or are resistant to oral anticoagulant treatment, provide valuable information for the functional study of the vitamin K cycle enzymes. In this review, we discuss: (i) the discovery of the enzymatic activities and gene identifications of the vitamin K cycle enzymes; (ii) the identification of their functionally important regions and their active site residues; (iii) the membrane topology studies of GGCX and VKOR; and (iv) the controversial issues regarding the structure and function studies of these enzymes, particularly, the membrane topology, the role of the conserved cysteines and the mechanism of active site regeneration of VKOR. We also discuss the possibility that a paralogous protein of VKOR, VKOR-like 1 (VKORL1), is involved in the vitamin K cycle, and the importance of and possible approaches for identifying the unknown VKR. Overall, we describe the accomplishments and the remaining questions in regard to the structure and function studies of the enzymes in the vitamin K cycle.
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影响因子：
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