465:γ-Carboxyglutamic acid residues play an important role in coagulation. The high-affinity calcium binding sites in the GLA domain of factor IX, which is a serine protease of the coagulation system, were found to partially mediate the binding of factor IXa to platelets and in factor-X activation. In addition, upon mechanical injury to the blood vessel wall, a cell-associated tissue factor becomes exposed and initiates a series of enzymatic reactions localized on a membrane surface generally provided by cells and accumulating platelets. Gla residues partly govern the activation and binding of circulating blood-clotting enzymes and zymogens to this exposed cell membrane surface. Specifically, gla residues are needed in calcium binding and in exposing hydrophobic membrane binding regions to the cell bilayer. Lack of these gla residues results in impaired coagulation or even anticoagulation, which may lead to bleeding diathesis or thrombosis. In addition, removal of calcium ion from these proteins with an organic chelator, such as
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24:
402:
This reaction is catalyzed by a carboxylase that requires vitamin K as its cofactor. It is not exactly known how vitamin K participates, but it is hypothesized that a free cysteine residue in the carboxylase converts vitamin K into an active strong base that in turn abstracts a hydrogen from glutamic
469:
ion, causes their dysfunction, and prevents blood from coagulating. Thus, citrate addition to blood is the most common method of storing it in a liquid state between harvest and transfusion.
457:). The Gla domain is responsible for high-affinity binding of calcium ions (Ca) to Gla proteins, which is often necessary for their conformation, and always necessary for their function.
653:
Kalafatis, M.; Egan, J. O.; van't Veer, C.; Mann, K. G. (1996-01-01). "Regulation and regulatory role of γ-carboxyglutamic acid containing clotting factors".
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cid-rich ("GLA") domain. This GLA domain is known to be found in over a dozen known proteins, including coagulation factors X, VII, IX, and XIV,
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606:"Role of γ-carboxyglutamic acid residues in the binding of factor IXa to platelets and in factor-X activation"
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In the biosynthesis of γ-carboxyglutamic acid, the γ-proton on glutamic acid is abstracted, and CO
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J Stenflo, and J W Suttie (1977). "Vitamin K–dependent formation of γ-carboxyglutamic acid".
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and other proteins of the coagulation cascade. This modification introduces an affinity for
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Rawala-Sheikh, R.; Ahmad, S. S.; Monroe, D. M.; Roberts, H. R.; Walsh, P. N. (1992-01-15).
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581:"Gamma-carboxyglutamic acid-rich (GLA) domain (IPR000294) < InterPro < EMBL-EBI"
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InChI=1/C6H9NO6/c7-3(6(12)13)1-2(4(8)9)5(10)11/h2-3H,1,7H2,(H,8,9)(H,10,11)(H,12,13)
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is required to introduce γ-carboxylation of clotting factors II, VII, IX, X and
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is subsequently added. The reaction intermediate is a γ-glutamyl carbanion.
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A number of γ-carboxyglutamate residues are present in the γ-carboxy
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Except where otherwise noted, data are given for materials in their
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Furie, Bruce; Bouchard, Beth A.; Furie, Barbara C. (1999-03-15).
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535:"Vitamin K–dependent biosynthesis of γ-carboxyglutamic acid"
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is added to the γ-carbon to form γ-carboxyglutamic acid.
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residues. This modification is found, for example, in
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655:Critical Reviews in Eukaryotic Gene Expression
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451:inter-alpha trypsin inhibitor heavy chain H2
623:10.1182/blood.V79.2.398.bloodjournal792398
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551:10.1182/blood.V93.6.1798.406k22_1798_1808
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453:, and growth arrest-specific protein 6 (
411:γ-Carboxyglutamic acid-rich (GLA) domain
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41:3-Aminopropane-1,1,3-tricarboxylic acid
324:418 °C (784 °F; 691 K)
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667:10.1615/critreveukargeneexpr.v6.i1.60
7:
379:. In the blood coagulation cascade,
512:10.1146/annurev.bi.46.070177.001105
240:Key: UHBYWPGGCSDKFX-UHFFFAOYAH
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14:
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708:Post-translational modification
334:(at 25 °C , 100 kPa).
360:introduced into proteins by a
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718:Non-proteinogenic amino acids
500:Annual Review of Biochemistry
431:vitamin K-dependent protein
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479:Gamma-glutamyl carboxylase
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304:191.14 g/mol
261:O=C(O)C(C(=O)O)CC(N)C(=O)O
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403:acid's γ-carbon. Then CO
352:(or the conjugate base,
37:Systematic IUPAC name
17:Carboxyglutamic acid
350:Carboxyglutamic acid
713:Tricarboxylic acids
461:Role in coagulation
18:
447:matrix Gla protein
362:post-translational
356:), is an uncommon
338:Infobox references
50:γ-Carboxyglutamate
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346:Chemical compound
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193:CompTox Dashboard
97:Interactive image
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545:(6): 1798–1808.
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373:clotting factors
354:carboxyglutamate
277:Chemical formula
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588:. Retrieved
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377:calcium ions
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56:Identifiers
48:Other names
506:: 157–172.
443:osteocalcin
435:prothrombin
314:1.649 g/mL
270:Properties
135:100.054.607
697:Categories
590:2015-12-22
485:References
417:Gla domain
358:amino acid
300:Molar mass
181:16FQV4RZKL
108:ChemSpider
84:3D model (
73:53861-57-7
63:CAS Number
675:1045-4403
632:0006-4971
559:0006-4971
433:S and Z,
391:Synthesis
385:protein Z
381:vitamin K
567:10068650
473:See also
683:8882309
640:1730085
467:citrate
449:(MGP),
425:utamic
310:Density
294:
148:PubChem
681:
673:
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565:
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520:332061
518:
254:SMILES
31:Names
610:Blood
539:Blood
229:InChI
161:40772
117:37241
86:JSmol
679:PMID
671:ISSN
636:PMID
628:ISSN
563:PMID
555:ISSN
516:PMID
455:GAS6
172:UNII
663:doi
618:doi
547:doi
508:doi
367:of
198:EPA
151:CID
699::
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626:.
614:79
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608:.
583:.
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543:93
541:.
537:.
514:.
504:46
502:.
445:,
441:,
437:,
423:gl
387:.
290:NO
685:.
665::
659:6
642:.
620::
593:.
569:.
549::
522:.
510::
427:a
405:2
397:2
292:6
288:9
286:H
284:6
282:C
200:)
196:(
88:)
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