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Vitamin K Epoxide Reductase

Figure 1. Closed Conformation of VKOR due to Warfarin Binding

1 Introduction
- 1.1 Location of Enzyme
2 Structure
- 2.1 Transmembrane Helices
- 2.2 Cap Domain
3 Significant Cysteines
4 Vitamin K Epoxide
- 4.1 Binding
5 Warfarin

Introduction

Figure 2. Overview of Vitamin K Cycle

Vitamin K Epoxide Reductase (VKOR) is an endoplasmic membrane enzyme that generates the active form of Vitamin K to support blood coagulation. The vitamin K Cycle, and the VKOR enzyme specifically are common drug targets for thromboembolic diseases. This is because, as pictured, the vitamin K cycle is the process in which blood coagulant factors II, VII, IX, and X are activated. This promotes blood clotting, which (in extreme amounts) can be dangerous and cause thromboembolic diseases such as stroke, deep vein thrombosis, and/or pulmonary embolism.

Location of Enzyme

Vitamin K Epoxide Reductase is found and primarily synthesized in the liver. It is embedded in the membrane known as the endoplasmic reticulum.

Structure

VKOR WIKI The VKOR enzyme is made up of four transmembrane helices: T1, T2, T3, and T4.(Grey) Each of these helices come together to form a hydrophobic pocket, that is topped by a cap domain. In the cap domain are important regions that are significant for Vitamin K binding, and the overall function of Vitamin K Epoxide Reductase. These important regions are the Anchor(Green), Cap Region (Blue), Beta Hairpin (Purple), and 3-4 Loop (Pink).

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Transmembrane Helices

The Transmembrane helices are named Transmembrane Helix 1, Transmembrane Helix 2, Transmembrane Helix 3, and Transmembrane Helix 4. The residues on Transmembrane Helix 2 (TM2) and Transmembrane Helix 4 (TM4) are significant for the binding of Vitamin K to the hydrophobic pocket of the enzyme. Asparagine 83 on TM2 and Tyrosine 142 hydrogen bond to Vitamin K Epoxide, in order to hold it in place so that it may be reduced. The angle in which Vitamin K Epoxide binds is significant to the placement of the beta hairpin, and loop 3-4. Cysteine residues from the beta hairpin and loop 3-4 will donate their electrons to Vitamin K Epoxide to open the epoxide ring, and reform Vitamin K Quinone.

Cap Domain

Significant Cysteines

A set of four cysteines is consistently conserved in all VKOR homologs. In the human homolog (HsVKOR) these cysteines are Cys43, Cys51, Cys132, and Cys 135. In the Pufferfish homolog (TrVKORL) these cysteines, due to Cryo-EM differences,are Cys52, Cys55, Cys141, and Cys144. These cysteines are the key factor that allow for Vitamin K Epoxide Reductase to perform its function, which is to open the epoxide ring on Vitamin K Epoxide in order to re-make Vitamin K Quinone. In the closed conformation, that is induced when Vitamin K binds in the hydrophobic pocket, Cys-132 binds to Cys-51 and Cys-135 will bind to the 3' hydroxyl group on Vitamin K Epoxide, which allows for the electron transfer to open up the epoxide ring.

Vitamin K Epoxide

Figure 1. Vitamin K Epoxide structure

As mentioned above, Vitamin K epoxide is a part of the Vitamin K cycle, necessary for blood coagulation. In the cycle, Vitamin K epoxide reductase (VKOR) reduces Vitamin K epoxide to quinone, or the active form of Vitamin K. What is occurring is VKOR donated electrons to Vitamin K epoxide, and those electrons come from the S-H of one of the cysteine pairs discussed above. The one cysteine pair has to be reduced for the transfer of electrons to the substrate can occur.

Binding

To start, VKOR is in its open conformation. The Vitamin K epoxide enters. The oxygens of the ketones bind to . With Vitamin K epoxide in its place, the conformation of VKOR is partially oxidized in regards to the cysteine pairs, which overall leads to the reduction of the substrate. A disulfide bond forms between Cys51 and Cys132, resulting in the closed conformation. This leaves the sulfur on Cys43 and the sulfur on Cys135 protonated. The available hydrogens on these cysteines are utilized in reducing the epoxide. First, the sulfur on Cys51 and Cys43 form a new bond. The hydrogen from Cys43 binds to the oxygen in the epoxide. The sulfur on Cys132 and the sulfur on Cys15 then form a new disulfide bond. The hydrogen that was present on Cys135 forms a new bond with the oxygen of the epoxide. With these cysteine pairs formed, VKOR is left in an open conformation. The end products are the Vitamin K/quinone and water.

Warfarin

Figure 4. Warfarin

scene name='90/904321/Closedconformation/4'>Warfarin Binding</scene>

References

↑ Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn(2+) /Mn(2+) heterobinucleation. FEBS Lett. 2017 Jul;591(13):2003-2010. doi: 10.1002/1873-3468.12677. Epub 2017, Jun 14. PMID:28504306 doi:http://dx.doi.org/10.1002/1873-3468.12677

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  <ref name="Ransey">PMID:28504306</ref>
 ===Transmembrane Helices===
-The Transmembrane helices are named Transmembrane Helix 1, Transmembrane Helix 2, Transmembrane Helix 3, and Transmembrane Helix 4. The residues on Transmembrane Helix 2 (TM2) and Transmembrane Helix 4 (TM4) are significant for the binding of Vitamin K to the hydrophobic pocket of the enzyme. Asparagine 222 (make sure this is right) on TM2 and Tyrosine 281(make sure this is right) hydrogen bond to Vitamin K Epoxide, in order to hold it in place so that it may be reduced. Cysteine residues from the cap domain will donate their electrons to Vitamin K Epoxide to open the epoxide ring, and reform Vitamin K Quinone.
+The Transmembrane helices are named Transmembrane Helix 1, Transmembrane Helix 2, Transmembrane Helix 3, and Transmembrane Helix 4. The residues on Transmembrane Helix 2 (TM2) and Transmembrane Helix 4 (TM4) are significant for the binding of Vitamin K to the hydrophobic pocket of the enzyme. Asparagine 83 on TM2 and Tyrosine 142 hydrogen bond to Vitamin K Epoxide, in order to hold it in place so that it may be reduced. The angle in which Vitamin K Epoxide binds is significant to the placement of the beta hairpin, and loop 3-4. Cysteine residues from the beta hairpin and loop 3-4 will donate their electrons to Vitamin K Epoxide to open the epoxide ring, and reform Vitamin K Quinone.
 ===Cap Domain===