Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A flock of Rambouillet sheep experienced unexpected lamb mortality associated with excessive bleeding at the time of parturition. Most lambs died of blood loss through the umbilicus or into subcutaneous tissues. Subsequently, nine ewes which had previously delivered lambs that bled to death were bred to the suspected sire of the previous bleeding lambs. Fifteen lambs were born alive the following Spring, and three males and one female bled clinically. These lambs had markedly decreased factor IX (< 16%) and factor X (< 4%) activities, with variably decreased factor II (11-36%) and factor VII (20-37%) activities. Protein C chromogenic activity was also markedly decreased (< 1%) in these lambs. The results from crossed immunoelectrophoresis and 'protein-induced-in-vitamin-K-absence' determination of the plasma of affected lambs, with antiserum directed against coagulation factor X, protein C or proteins S, suggested that these proteins were not carboxylated normally. Examination of liver from one lamb in the first batch and the four subsequent lambs did not reveal a known vitamin K antagonist. The breeding data suggested that the coagulopathy in these sheep was inherited as an autosomal recessive trait. The genetic or molecular defect that exists in these lambs is unknown, but possibilities include abnormal gamma-glutamyl carboxylase activity or abnormal metabolism of vitamin K.
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PMID:Hereditary deficiency of vitamin-K-dependent coagulation factors in Rambouillet sheep. 1019 55

The vitamin K-dependent gamma-glutamyl carboxylase catalyzes the modification of specific glutamates in a number of proteins required for blood coagulation and associated with bone and calcium homeostasis. All known vitamin K-dependent proteins possess a conserved eighteen-amino acid propeptide sequence that is the primary binding site for the carboxylase. We compared the relative affinities of synthetic propeptides of nine human vitamin K-dependent proteins by determining the inhibition constants (Ki) toward a factor IX propeptide/gamma-carboxyglutamic acid domain substrate. The Ki values for six of the propeptides (factor X, matrix Gla protein, factor VII, factor IX, PRGP1, and protein S) were between 2-35 nM, with the factor X propeptide having the tightest affinity. In contrast, the inhibition constants for the propeptides of prothrombin and protein C are approximately 100-fold weaker than the factor X propeptide. The propeptide of bone Gla protein demonstrates severely impaired carboxylase binding with an inhibition constant of at least 200,000-fold weaker than the factor X propeptide. This study demonstrates that the affinities of the propeptides of the vitamin K-dependent proteins vary over a considerable range; this may have important physiological consequences in the levels of vitamin K-dependent proteins and the biochemical mechanism by which these substrates are modified by the carboxylase.
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PMID:The propeptides of the vitamin K-dependent proteins possess different affinities for the vitamin K-dependent carboxylase. 1035 41

The binding of the gamma-glutamyl carboxylase to its protein substrates is mediated by a conserved 18 amino acid propeptide sequence found in all vitamin K-dependent proteins. We recently found that the apparent affinities of the naturally occurring propeptides for the carboxylase vary over a 100-fold range and that the propeptide of bone Gla protein has severely impaired affinity for the carboxylase [Stanley, T. B., et al. (1999) J. Biol. Chem. 274, 16940-16944 (1)]. Here we report a consensus propeptide sequence that binds tighter (K(i) = 0.43 nM) to the carboxylase than any known propeptide sequence. Comparing the factor IX propeptide to the propeptides of protein C, bone Gla protein, and prothrombin, the weakest binding propeptides, allowed us to predict which residues might be responsible for these substrates' relatively weak binding to the carboxylase. We then made propeptides with the predicted amino acid changes and determined their binding affinities. The reduced binding affinity of these propeptides relative to that of FIX is due to residues -15 in protein C, -10 and -6 in bone Gla protein, and -9 in prothrombin. A role for the -9 position was not previously recognized but is further shown by our identification of a new, naturally occurring mutation at this position in factor IX which causes a warfarin-sensitive hemophilia B phenotype. In addition, we find that propeptides with mutations found in warfarin-sensitive patients have reduced affinity for the carboxylase, suggesting a physiological relevance of propeptide binding affinity.
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PMID:Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase. 1056 55

Hereditary combined deficiency of the vitamin K-dependent coagulation factors II, VII, IX, X, protein C, S and protein Z (VKCFD) is a very rare autosomal recessive inherited bleeding disorder. The phenotype may result from functional deficiency of either the gamma-glutamyl carboxylase (GGCX) or the vitamin K epoxide reductase (VKOR) complex. We report on the third case of VKCFD1 with mutations in the gamma-glutamyl carboxylase gene, which is remarkable because of compound heterozygosity. Two mutations were identified: a splice site mutation of exon 3 and a point mutation in exon 11, resulting in the replacement of arginine 485 by proline. Screening of 100 unrelated normal chromosomes by restriction fragment length polymorphism and denaturing high-performance liquid chromatography analysis excluded either mutation as a frequent polymorphism. Substitution of vitamin K could only partially normalize the levels of coagulation factors. It is suggested that the missense mutation affects either the propeptide binding site or the vitamin K binding site of GGCX.
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PMID:Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. 1528 48

gamma-Glutamyl carboxylation, a reaction essential for the activity of vitamin K-dependent proteins, requires the concerted actions of gamma-glutamyl carboxylase (GGCX), vitamin K 2, 3-epoxide reductase complex 1 (VKORC1), and the chaperone calumenin (CALU). We evaluated the contribution of genetic polymorphisms in VKORC1, GGCX, and CALU to interindividual variation in the activities of plasma protein C and protein S. We sequenced these 3 genes in 96 Japanese individuals and geno-typed 9 representative single-nucleotide polymorphisms in 3655 Japanese individuals representative of the general population. The mean activity of protein C in women bearing the GG genotype of GGCX 8016G>A (130.8% +/- 1.5%, n = 156) was significantly greater (P = .002) than that of individuals with either the AG (126.8% +/- 0.7%, n = 728) or the AA (125.4% +/- 0.6%, n = 881) genotype, after adjusting for confounding factors. The GGCX 8016G>A change leads to the substitution of Gin for Arg at amino acid residue 325 (Arg 325 Gln). This effect was comparable to that of a previously defined polymorphism in the protein C promoter. Mean protein S activity was influenced by the VKORC1 3730G>A and CALU 20943T>A genotypes, after adjusting for confounding factors. Thus, polymorphisms in genes involved in the vitamin K-dependent gamma-carboxylation reaction influence interindividual variation in the activities of protein C and protein S in the general population.
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PMID:Polymorphisms in vitamin K-dependent gamma-carboxylation-related genes influence interindividual variability in plasma protein C and protein S activities in the general population. 1718 18

Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.
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PMID:Hereditary combined deficiency of the vitamin K-dependent clotting factors. 2063 65