A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC)

Davis, Charles H.; Deerfield, David W.; Wymore, Troy; Stafford, Darrel W.; Pedersen, Lee G.

doi:10.1016/j.jmgm.2006.10.006

Cited by 10 publications

(2 citation statements)

References 23 publications

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“…Quantum chemical calculations are consistent with this model, but they also support a second possible mechanism for removal of the KH 2 proton involving only one lysine (24). Because both models are similar for our purposes, we will focus on the two-lysine model in this discussion.…”

Section: Discussionsupporting

confidence: 52%

Effect of Vitamin K-dependent Protein Precursor Propeptide, Vitamin K Hydroquinone, and Glutamate Substrate Binding on the Structure and Function of γ-Glutamyl Carboxylase

Mutucumarana

Lin

et al. 2010

Journal of Biological Chemistry

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The ␥-glutamyl carboxylase utilizes four substrates to catalyze carboxylation of certain glutamic acid residues in vitamin K-dependent proteins. How the enzyme brings the substrates together to promote catalysis is an important question in understanding the structure and function of this enzyme. The propeptide is the primary binding site of the vitamin K-dependent proteins to carboxylase. It is also an effector of carboxylase activity. We tested the hypothesis that binding of substrates causes changes to the carboxylase and in turn to the substrate-enzyme interactions. In addition we investigated how the sequences of the propeptides affected the substrate-enzyme interaction. To study these questions we employed fluorescently labeled propeptides to measure affinity for the carboxylase. We also measured the ability of several propeptides to increase carboxylase catalytic activity. Finally we determined the effect of substrates: vitamin K hydroquinone, the pentapeptide FLEEL, and NaHCO 3 , on the stability of the propeptide-carboxylase complexes. We found a wide variation in the propeptide affinities for carboxylase. In contrast, the propeptides tested had similar effects on carboxylase catalytic activity. FLEEL and vitamin K hydroquinone both stabilized the propeptide-carboxylase complex. The two together had a greater effect than either alone. We conclude that the effect of propeptide and substrates on carboxylase controls the order of substrate binding in such a way as to ensure efficient, specific carboxylation.The vitamin K-dependent ␥-glutamyl carboxylase is an endoplasmic reticulum integral membrane enzyme. It post-translationally modifies certain proteins important in several physiologically important areas, including blood coagulation. The modification involves the addition of a carboxyl group to the ␥-carbon of glutamic acid residues in the amino portion of the vitamin K-dependent substrate.In addition to the glutamic acid and CO 2 , which provides the added carboxyl group, other substrates required for the reaction are vitamin K hydroquinone (KH 2 ) 4 and oxygen. During carboxylation KH 2 is converted to the epoxide; thus carboxylase is also an epoxidase.The primary interaction between carboxylase and most of its protein substrates is through the propeptides of the substrates. Binding is of high affinity, which allows the substrate to bind long enough for multiple carboxylations to occur.In addition to being the primary binding site for carboxylase, the propeptide also exerts an effect on carboxylase catalysis. Factors IX and X and prothrombin propeptides, when bound to carboxylase, increase the activity of the enzyme toward small glutamate-containing substrates (1-5).For the most part these results suggest that the propeptides induce a conformational change or stabilize a more active conformation in the carboxylase active site. The efficiency of the change appears to be similar for the propeptides of prothrombin and factors IX and X. The fact that these propeptides have different sequences implies that ...

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Section: Discussionsupporting

confidence: 52%

Effect of Vitamin K-dependent Protein Precursor Propeptide, Vitamin K Hydroquinone, and Glutamate Substrate Binding on the Structure and Function of γ-Glutamyl Carboxylase

Mutucumarana

Lin

et al. 2010

Journal of Biological Chemistry

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“…Mechanism of action of vitamin K (see [7] and references therein, and [8][9][10][11]) and its photophysical and photobiological properties [12][13][14][15][16][17][18] have been studied extensively. Structure and vibrational spectra of the model molecule of both vitamin K 1 and K 2 having an allyl group instead of a phytyl side chain (designated further as model 1, see Fig.…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of vitamin K1 model molecule: a theoretical study

Захаров

Vogt

2010

Struct Chem

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Isomerism, conformations, and molecular structure of a model molecule of vitamin K 1 with a truncated side chain have been studied by the density functional theory calculations using B3LYP method and double-and triple-f correlation consistent basis sets. The conformations of two possible (E and Z) isomers, formed by the rotations around three single C-C bonds closest to the naphthoquinone ring, have been studied. The lowest energy conformers are stabilized by additional hydrogen bonds between hydrogen atoms of the side chain and an oxygen atom in the naphthoquinone subunit. It is interesting to note that the structure of the energetically preferred conformer of the E-isomer (3c) has been found to be similar to the solid state structures of phylloquinones in the photosystem I of cyanobacterium Synechococcus elongatus. The excited electronic states of two lowest energy conformers have also been investigated.

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Anticoagulants

Henry

Desai

2010

Burger's Medicinal Chemistry and Drug Discovery

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Thrombotic disorders are a major cause of morbidity and mortality in humans. Examples of thrombotic disorders include pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, acute myocardial infarction, unstable angina, and cerebrovascular thrombosis. Anticoagulants are the mainstay of treatment and prevention of these disorders. The most widely used anticoagulants include unfractionated heparin, low molecular weight heparins and warfarin. Newer agents introduced in the past decade include bivalirudin, fondaparinux, and argatroban. Mechanistically, these anticoagulants either directly inhibit thrombin or indirectly reduce the activity of thrombin and factor Xa. Several new molecules have been recently designed to directly inhibit thrombin and factor Xa with high potency and considerable selectivity, of which dabigatran and rivaroxaban were approved for clinical use in few countries in 2008. Molecules being pursued in clinical trials include AZD0837, LB‐30870, otamixaban, apixaban, YM‐150, and others. Ximelagatran, which was introduced in 2004 as a direct thrombin inhibitor, was taken off the market within 20 months due to significant hepatotoxicity. Indirect anticoagulants utilize the antithrombin‐mediated conformational activation and bridging mechanisms for inhibiting coagulation enzymes. Among the indirect anticoagulants that are currently being investigated in clinical trials are a biotinylated idraparinux and SR123781. Over the last two decades, major conceptual strides have been made including the design of the first anticoagulant based solely on factor Xa inhibition (fondaparinux) and the establishment of the paradigm that anticoagulation is possible without frequent laboratory monitoring (ximelagatran). Current work attempts to establish other concepts such as the dual inhibition of free and clot‐bound thrombin by a heparin‐based molecule (ORG42675) and the applicability of neutral P1‐group containing active site‐directed molecules as effective inhibitors of coagulation enzymes (rivaroxaban). To date, no molecule has been designed that satisfies all the properties of an ideal anticoagulant including a broad therapeutic window, absence of bleeding risk, no requirement for frequent coagulation monitoring, oral bioavailability, availability of an effective antidote, lack of hepatoxicity and absence other adverse effects. Yet, the newer agents are likely to be more attractive than the heparin‐ and coumarin‐based therapy. In this chapter, we review the structure, design, and mechanism of action of clinically used and new potential anticoagulants. Special emphasis is placed on the molecular interaction of anticoagulants with their targets.

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A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC)

Cited by 10 publications

References 23 publications

Effect of Vitamin K-dependent Protein Precursor Propeptide, Vitamin K Hydroquinone, and Glutamate Substrate Binding on the Structure and Function of γ-Glutamyl Carboxylase

Effect of Vitamin K-dependent Protein Precursor Propeptide, Vitamin K Hydroquinone, and Glutamate Substrate Binding on the Structure and Function of γ-Glutamyl Carboxylase

Conformational analysis of vitamin K1 model molecule: a theoretical study

Anticoagulants

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