The vitamin K cycle

Stafford, Darrel W.

doi:10.1111/j.1538-7836.2005.01419.x

Cited by 340 publications

(255 citation statements)

References 37 publications

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“…[3] for review and additional references). Inhibition of VKOR by the rodenticides prevents production of functional blood coagulation factors, such that susceptible rodents that consume the bait succumb to lethal internal hemorrhage (c.f.…”

Section: Introductionmentioning

confidence: 99%

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

et al. 2010

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BackgroundCertain mutations in the vitamin K epoxide reductase subcomponent 1 gene (vkorc1) mediate rodent resistance to warfarin and other anticoagulants. Testing for resistance often involves analysis of the vkorc1. However, a genetic test for the roof rat (Rattus rattus) has yet to be developed. Moreover, an available roof rat vkorc1 sequence would enable species identification based on vkorc1 sequence and the evaluation of natural selection on particular vkorc1 polymorphisms in the Norway rat (R. norvegicus).ResultsWe report the coding sequence, introns and 5' and 3' termini for the vkorc1 gene of roof rats (R. r. alexandrinus and R. r. frugivorus) from Uganda, Africa. Newly designed PCR primers now enable genetic testing of the roof rat and Norway rat. Only synonymous and noncoding polymorphisms were found in roof rats from Uganda. Both nominal subspecies of roof rats were indistinguishable from each other but were distinct from R. losea and R. flavipectus; however, the roof rat also shares at least three coding sequence polymorphisms with R. losea and R. flavipectus. Many of recently published vkorc1 synonymous and non-synonymous single nucleotide polymorphisms (SNPs) in Norway rats are likely SNPs from roof rats and/or other Rattus species. Tests applied to presumably genuine Norway rat vkorc1 SNPs are consistent with a role for selection in two populations carrying the derived Phe63Cys and Tyr139Cys mutations.ConclusionGeographic mapping of vkorc1 SNPs in roof rats should be facilitated by our report. Our assay should be applicable to most species of Rattus, which are intermediate in genetic distance from roof and Norway rats. Vkorc1-mediated resistance due to non-synonymous coding SNPs is not segregating in roof rats from Uganda. By using the roof rat sequence as a reference vkorc1, SNPs now can be assigned to the correct rat species with more confidence. Sampling designs and genotyping strategies employed so far have helped detect candidate mutations underlying vkorc1-mediated resistance, but generally provided unsuitable data to test for selection. We propose that our understanding of vkorc1-mediated evolution of resistance in rodents would benefit from the adoption of sampling and genotyping designs that enable tests for selection on vkorc1.

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Section: Introductionmentioning

confidence: 99%

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

et al. 2010

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“…functions of the vitamin K-dependent proteins involved in blood coagulation, bone metabolism, signal transduction, and cell proliferation (1)(2)(3). Concomitant with carboxylation vitamin K hydroquinone is oxidized to vitamin K epoxide (epoxidation).…”

mentioning

confidence: 99%

“…Concomitant with carboxylation vitamin K hydroquinone is oxidized to vitamin K epoxide (epoxidation). The epoxide must be converted back to the hydroquinone by the enzyme vitamin K epoxide reductase, thus completing the vitamin K cycle (3).…”

mentioning

confidence: 99%

Transmembrane Domain Interactions and Residue Proline 378 Are Essential for Proper Structure, Especially Disulfide Bond Formation, in the Human Vitamin K-Dependent γ-Glutamyl Carboxylase

et al. 2008

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We used recombinant techniques to create a two-chain form (residues 1-345 and residues 346-758) of the vitamin K-dependent γ-glutamyl carboxylase, a glycoprotein located in the endoplasmic reticulum containing five transmembrane domains. The two-chain carboxylase had carboxylase and epoxidase activities similar to those of one-chain carboxylase. In addition, it had normal affinity for the propeptide of factor IX. We employed this molecule to investigate formation of the one disulfide bond in carboxylase, the transmembrane structure of carboxylase, and the potential interactions among the carboxylase's transmembrane domains. Our results indicate that the two peptides of the two-chain carboxylase are joined by a disulfide bond. Proline 378 is important for the structure necessary for disulfide formation. Results with the P378L carboxylase indicate that noncovalent bonds maintain the two-chain structure even when the disulfide bond is disrupted. As we had previously proposed, the fifth transmembrane domain of carboxylase is the last and only transmembrane domain in the C-terminal peptide of the two-chain carboxylase. We show that the noncovalent association between the two chains of carboxylase involves an interaction between the fifth transmembrane domain and the second transmembrane domain. Results of a homology model of transmembrane domains 2 and 5 suggest that not only do these two domains associate but that transmembrane domain 2 may interact with another transmembrane domain. This latter interaction may be mediated at least in part by a motif of glycine residues in the second transmembrane domain.The vitamin K-dependent γ-glutamyl carboxylase is a 758-residue integral membrane glycoprotein of the endoplasmic reticulum (ER). 1 It catalyzes the posttranslational modification of specific glutamic acid residues of vitamin K-dependent proteins to γ-carboxyglutamic acid residues. This posttranslational modification is critical for the biological † This work was supported by National Institutes of Health (NIH) Grant HL48318 (to D.W.S.) and by the Intramural Research Program of the NIH and NIEHS (to L.P.).*Author to whom correspondence should be addressed. Phone: 919-962-2267. Fax: 919-962-9266. jktie@email.unc.edu. ‡ University of North Carolina at Chapel Hill. § National Institute of Environmental Health Sciences, NIH.1 Abbreviations: ER, endoplasmic reticulum; TMD, transmembrane domain; NEM, CHAPS,dimethylammonio]-1-propanesulfonate; DTT, dithiothreitol; MOPS, 3-(N-morpholino)propanesulfonic acid (4-morpholinepropanesulfonic acid); MES, 2-(N-morpholino)ethanesulfonic acid (4-morpholineethanesulfonic acid); vitamin K 1(20) , 2-methyl-3-phytyl-1,4-naphthoquinone; PNGase F, peptide:N-glycosidase F; proFIX, 19 amino acid peptide comprising residues TVFLDHENANKILNRPKRY of human profactor IX; SRII, sensory rhodopsin II; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; PVDF, polyvinylidene fluoride.

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“…(KH2) forms, in successive reactions catalysed by vitamin K reductases [8,22,23]. The two enzymes known to be involved in this vitamin K cycle are vitamin K epoxide reductase (VKOR) and vitamin K reductase (VKR), in a process known as the vitamin K cycle [8,22].…”

Section: Vitamin K Forms and Recyclingmentioning

confidence: 99%

New Perspectives for the Nutritional Value of Vitamin K in Human Health

Viegas¹,

Simes²

2016

J Nutr Disorders Ther

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Vitamin K is an essential micronutrient in the post-translational modification of specific glutamic acid residues (Glu) into γ-carboxyglutamic acid residues (Gla) in target proteins known as vitamin K-dependent proteins (VKDPs). In healthy conditions of sufficient vitamin K status, a vitamin K recycling system maintains sufficient vitamin K levels for proper γ-carboxylation of VKDPs, and vitamin K antagonists (VKAs) widely used as anticoagulants inhibit vitamin K recycling. Besides its well-known function in the maintenance of normal coagulation, vitamin K has been reported to have other diverse physiological functions with impact in human health. In extra-hepatic tissues vitamin K deficiency results in impairment of VKDPs γ-carboxylation with important implications in bone and cardiovascular health. Although most of the vitamin K effects have been associated with regulation of mineralization in connective tissues through the action of matrix Gla protein (MGP) and osteocalcin (OC), the discovery of Gla-rich protein (GRP) opens new perspectives on the potential therapeutic range of vitamin K.

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The vitamin K cycle

Cited by 340 publications

References 37 publications

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

Analysis of vkorc1 polymorphisms in Norway rats using the roof rat as outgroup

Transmembrane Domain Interactions and Residue Proline 378 Are Essential for Proper Structure, Especially Disulfide Bond Formation, in the Human Vitamin K-Dependent γ-Glutamyl Carboxylase

New Perspectives for the Nutritional Value of Vitamin K in Human Health

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