UseCase18 Dicoumarol

Mechanism of Vitamin K Antagonism by Dicoumarol¶ ↑

Example of Competitive inhibition

Context¶ ↑

Dicoumarol is an anticoagulant that acts as a vitamin k antagonist. It is a derivative of coumarin and is converted to dicoumarol by several species of mold fungi.

Mechanism¶ ↑

Dicumarol inhibits vitamin K reductase, preventing the cyclic interconversion of vitamin K and 2,3 vitamin K epoxide(vitamin K12) -{Ansell 2004}-. This results in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins -{Wallin 1986, Stenflo 1974}-. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited -{Ansell 2004}-. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This results in the condition hypoprothrombinemia.

Knowledge base Challenges¶ ↑

Representational
   Biochemical
   Expression(language requirements)

Functional (Question and Answer)

Q. “Which mechanism(s) involves dicoumoral?” A. “The mechanism of vitamin K antagonism by dicoumarol” Query: ‘mechanistic toxicology process specification’ that ‘has part’ some (process that ‘has agent’ some dicoumarol) Q. “What are the result(s) of this mechanism?” A. “hypoprothrombinemia” Query: ‘disease process’ that ‘is result of’ some ‘mechanism of vitamin k antagonism by dicoumarol’ Q. “Which coagulation factors are inhibited by this mechanism?” A. “Vitamin k-dependent coagulation factors II,VII, and X” Query:‘chemical entity’ that ‘has disposition’ some ((‘to be inhibited’) and (‘is realized in’ some (process that ‘is part of’ some ‘mechanism of vitamin k antagonism by dicoumarol’))) Q. “Which mechanism of action affects vitamin k epoxide reductase?” A. “Inhibition of vitamin k epoxide reductase by dicoumarol” Query: process that ‘has target’ some ‘vitamin k epoxide reductase’

Process Model¶ ↑

1. Inhibition Vitamin K epoxide reductase 2. Depletion of Vitamin K 3. decreased gamma-carboxylation of vitamin K-dependent proteins 4. Inhibition of vitamin K-dependent coagulation factors and Inhibition of vitamin K-dependent anticoagulant proteins 5. Decreased prothrombin level and Decreased thrombin bound to fibrin 7. Hypoprothrombinemia ‘enzymatic conversion of vitamin K1 and 2,3 Vitamin K epoxide’ subClassOf ‘biochemical reaction’ that ‘has agent’ some ‘vitamin k epoxide reductase’ that ‘has target’ some ‘vitamin k1’ and ‘has product’ some ‘2,3 vitamin k epoxide’ and ‘realizes’ some (‘to covalently modify’ that ‘is disposition of’ some ‘vitamin K epoxide reductase’) ‘inhibition of vitamin K epoxide reductase’ subClassOf ‘inhibition’ that ‘has agent’ some ‘dicoumarol’ that ‘has target’ some ‘vitamin K epoxide reductase’ and ‘realizes’ some (‘to be inhibited’ and (‘is disposition of’ some ‘vitamin k epoxide reductase’ and (‘in relation to’ some ‘dicoumarol’))) and ‘realizes’ some (‘to inhibit’ and (‘is disposition of’ some ‘dicoumarol’) and (‘in relation to’ some ‘vitamin k epoxide reductase’)))

and ‘results in’ some ‘inhibition enzymatic conversion of vitamin K and 2,3 Vitamin K epoxide’ ‘decreased enzymatic conversion of vitamin K and 2,3 Vitamin K epoxide’ subClassOf ‘enzymatic conversion of vitamin K and 2,3 Vitamin K epoxide” that ’results in’ some ‘depletion of Vitamin K’ ‘depletion of vitamin k’ subClassOf ” that ‘results in’ some ‘inhibition of gamma-carboxylation of vitamin K-dependent proteins’ ‘gamma-carboxylation of vitamin K-dependent proteins’ subClassOf ‘gamma-carboxylation’ that ‘has agent’ some ‘vitamin K dependent gamma-carboxylase’ that ‘has agent’ some ‘vitamin k’ that ‘has target’ some ‘vitamin K-dependent protein’ and ‘has product’ some ‘gamma carboxylated vitamin K-dependent protein’ ‘vitamin k-dependent protein’ subClassOf ‘protein’ that ‘has part’ some ‘vitamin k’

‘decreased gamma-carboxylation of vitamin K-dependent proteins’ subClassOf ‘gamma-carboxylation of vitamin K-dependent proteins’ and ‘has quality’ some (‘process rate’ that ‘is less than’ some (‘process rate’ that ‘is quality of’ some ‘gamma-carboxylation of vitamin K-dependent proteins’)) that ‘results in’ some ‘inhibition of vitamin K-dependent coagulation factors’ that ‘results in’ some ‘inhibition of vitamin K-dependent anticoagulant proteins’ that ‘is part of some ’mechanism of vitamin K antagonism by Dicoumarol’ ‘inhibition of vitamin K-dependent coagulation factors’ subClassOf ‘inhibition’ that ‘has target’ some ‘vitamin K-dependent coagulation factor II’ that ‘has target’ some ‘vitamin K-dependent coagulation factor VII’ that ‘has target’ some ‘vitamin K-dependent coagulation factor X’ and ‘results in’ some ‘decreased prothrombin’ that ‘is part of some ’mechanism of vitamin K antagonism by Dicoumarol’ ‘vitamin K-dependent coagulation factor II’ subClassOf ‘chemical entity’ that ‘has disposition’ some ((‘to be inhibited’) and (‘is realized in’ some ‘inhibition of vitamin K-dependent coagulation factors’)) ‘vitamin K-dependent coagulation factor VII’ subClassOf ‘chemical entity’ that ‘has disposition’ some ((‘to be inhibited’) and (‘is realized in’ some ‘inhibition of vitamin K-dependent coagulation factors’)) ‘vitamin K-dependent coagulation factor X’ subClassOf ‘chemical entity’ that ‘has disposition’ some ((‘to be inhibited’) and (‘is realized in’ some ‘inhibition of vitamin K-dependent coagulation factors’)) ‘inhibition of vitamin K-dependent anticoagulant proteins’ subClassOf ‘inhibition’ that ‘has target’ some ‘vitamin K-dependent anticoagulant protein S’ that ‘has target’ some ‘vitamin K-dependent anticoagulant protein C’ ‘decrease in prothrombin synthesis’ subClassOf ‘prothrombin synthesis’ that ‘is part of some ’mechanism of vitamin K antagonism by Dicoumarol’ that ‘results in’ some ‘hypoprothrombinemia’ ‘hypoprothrombinemia’ subClassOf ‘disease process’ that ‘is result of’ some ‘mechanism of vitamin K antagonism by Dicoumarol’ ‘decreased thrombin bound to fibrin’ subClassOf ” ‘mechanism of vitamin K antagonism by Dicoumarol’ subClassOf ‘mechanistic toxicology process specification’ that ‘has part’ some ‘inhibition of vitamin K epoxide reductase’ that ‘has part’ some ‘decreased enzymatic conversion of vitamin K and 2,3 Vitamin K epoxide’ that ‘has part’ some ‘depletion of vitamin k’ that ‘has part’ some ‘decreased gamma-carboxylation of vitamin K-dependent proteins’ that ‘has part’ some ‘inhibition of vitamin K-dependent coagulation factors’ that ‘has part’ some ‘inhibition of vitamin K-dependent anticoagulant proteins’ that ‘has part’ some ‘decrease in prothrombin’ that ‘has result’ some hypoprothrombinemia

References¶ ↑

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Notes¶ ↑

1. Complicated multi step effect with multiple routes.

2. need to find product of gamma-carboxylation of vitamin K-dependent protein.

3. there are two paths of vitamin K antagonism the inhibition of coagulation factors and the inhibition of anticoagulant proteins. The endpoint of each route needs to be found.