Structural and functional insights into enzymes of the vitamin K cycle
Summary 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...
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Published in | Journal of thrombosis and haemostasis Vol. 14; no. 2; pp. 236 - 247 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
England
Wiley Subscription Services, Inc
01.02.2016
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Subjects | |
Online Access | Get full text |
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Summary: | Summary
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-2 |
ISSN: | 1538-7933 1538-7836 1538-7836 |
DOI: | 10.1111/jth.13217 |