Sandbox Reserved 1724: Difference between revisions

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[https://en.wikipedia.org/wiki/Warfarin Warfarin] is the most widely prescribed oral anticoagulant and targets blood clotting via inhibition of VKOR. The FDA approved uses for cardiac conditions (myocardial infarction, atrial fibrillation) as well as for deep vein thrombosis and pulmonary embolism. Due to the inhibition of the normal blood clotting cycle, patients taking warfarin are at risk for hemorrhage which can occur anywhere in the body. <ref name="Patel">PMID:29261922</ref>

Warfarin is a <scene name='90/904330/Bothsubstratevkor/2'>structural mimic</scene> of Vitamin K that occupies the VKOR binding site, acting as a competitive inhibitor. Warfarin mimics vitamin K by binding to the same <scene name='90/904329/Warfarinhbond/7'>substrate binding residues</scene>(Asn80 and Tyr139) in the active site. Warfarin also shares the same <scene name='90/904329/Warfarinhydroaa/1'>hydrophobic interactions</scene> within the binding site that KOH experiences (Phe83, Phe87, and Tyr88). Warfarin binding also depends on the VKOR catalytic cysteines. Warfarin is able to bind to the fully oxidized open form of VKOR as shown in <scene name='90/904329/Cat_cycle_step1_warf/3'>step I</scene> of the catalytic cycle. Once Warfarin binds, VKOR is considered to be in a closed conformation since the substrate cannot enter, despite the lack of disulfide bridge changes. Warfarin can also bind to the partially oxidized form of VKOR as shown in <scene name='90/904329/Cat_cycle_step2_warf/2'>step II</scene> of the catalytic cycle.

Warfarin is a <scene name='90/904330/Bothsubstratevkor/2'>structural mimic</scene> of Vitamin K that occupies the VKOR binding site, acting as a competitive inhibitor. Warfarin mimics vitamin K by binding to the same <scene name='90/904329/Warfarinhbond/7'>substrate binding residues</scene>(Asn80 and Tyr139) in the active site. Warfarin also shares the same <scene name='90/904329/Warfarinhydroaa/2'>hydrophobic interactions</scene> within the binding site that KOH experiences (Phe83, Phe87, and Tyr88). Warfarin binding also depends on the VKOR catalytic cysteines. Warfarin is able to bind to the fully oxidized open form of VKOR as shown in <scene name='90/904329/Cat_cycle_step1_warf/3'>step I</scene> of the catalytic cycle. Once Warfarin binds, VKOR is considered to be in a closed conformation since the substrate cannot enter, despite the lack of disulfide bridge changes. Warfarin can also bind to the partially oxidized form of VKOR as shown in <scene name='90/904329/Cat_cycle_step2_warf/2'>step II</scene> of the catalytic cycle.

There are around 30 known missense mutations that lead to warfarin resistance in patients, but these mutations do not affect Vitamin K binding for reasons which are not yet fully understood. Such patients require higher doses of warfarin to reach therapeutic level or require a different anticoagulant drug. <ref name="Wu">PMID:29743176</ref>

Sandbox Reserved 1724: Difference between revisions

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 [https://en.wikipedia.org/wiki/Warfarin Warfarin] is the most widely prescribed oral anticoagulant and targets blood clotting via inhibition of VKOR. The FDA approved uses for cardiac conditions (myocardial infarction, atrial fibrillation) as well as for deep vein thrombosis and pulmonary embolism. Due to the inhibition of the normal blood clotting cycle, patients taking warfarin are at risk for hemorrhage which can occur anywhere in the body. <ref name="Patel">PMID:29261922</ref>
-Warfarin is a <scene name='90/904330/Bothsubstratevkor/2'>structural mimic</scene> of Vitamin K that occupies the VKOR binding site, acting as a competitive inhibitor. Warfarin mimics vitamin K by binding to the same <scene name='90/904329/Warfarinhbond/7'>substrate binding residues</scene>(Asn80 and Tyr139) in the active site. Warfarin also shares the same <scene name='90/904329/Warfarinhydroaa/1'>hydrophobic interactions</scene> within the binding site that KOH experiences (Phe83, Phe87, and Tyr88). Warfarin binding also depends on the VKOR catalytic cysteines. Warfarin is able to bind to the fully oxidized open form of VKOR as shown in <scene name='90/904329/Cat_cycle_step1_warf/3'>step I</scene> of the catalytic cycle. Once Warfarin binds, VKOR is considered to be in a closed conformation since the substrate cannot enter, despite the lack of disulfide bridge changes. Warfarin can also bind to the partially oxidized form of VKOR as shown in <scene name='90/904329/Cat_cycle_step2_warf/2'>step II</scene> of the catalytic cycle.
+Warfarin is a <scene name='90/904330/Bothsubstratevkor/2'>structural mimic</scene> of Vitamin K that occupies the VKOR binding site, acting as a competitive inhibitor. Warfarin mimics vitamin K by binding to the same <scene name='90/904329/Warfarinhbond/7'>substrate binding residues</scene>(Asn80 and Tyr139) in the active site. Warfarin also shares the same <scene name='90/904329/Warfarinhydroaa/2'>hydrophobic interactions</scene> within the binding site that KOH experiences (Phe83, Phe87, and Tyr88). Warfarin binding also depends on the VKOR catalytic cysteines. Warfarin is able to bind to the fully oxidized open form of VKOR as shown in <scene name='90/904329/Cat_cycle_step1_warf/3'>step I</scene> of the catalytic cycle. Once Warfarin binds, VKOR is considered to be in a closed conformation since the substrate cannot enter, despite the lack of disulfide bridge changes. Warfarin can also bind to the partially oxidized form of VKOR as shown in <scene name='90/904329/Cat_cycle_step2_warf/2'>step II</scene> of the catalytic cycle.
 There are around 30 known missense mutations that lead to warfarin resistance in patients, but these mutations do not affect Vitamin K binding for reasons which are not yet fully understood. Such patients require higher doses of warfarin to reach therapeutic level or require a different anticoagulant drug.  <ref name="Wu">PMID:29743176</ref>