gamma-carboxyglutamate

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/12 01:15:38」(JST)

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Carboxyglutamic acid (or the conjugate base, carboxyglutamate), is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and other proteins of the coagulation cascade. This modification introduces an affinity for calcium ions. In the blood coagulation cascade, Vitamin K is required to introduce gamma-carboxylation of clotting factors II, VII, IX, X and protein Z.^[1]

Synthesis

In the biosynthesis of $\gamma$ -carboxyglutamic acid, the $\gamma$ -proton on glutamic acid is abstracted, and CO₂ is subsequently added. The reaction intermediate is a $\gamma$ -glutamyl carbanion.

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 acid's $\gamma$ -carbon. Then CO₂ is added to the $\gamma$ -carbon to form $\gamma$ -carboxyglutamic acid. ^[2]

Fig. 1.

Gamma-carboxyglutamic acid-rich (GLA) domain

A number of gamma-carboxyglutamate (Gla) residues are present in the Gamma-carboxyglutamic acid-rich (GLA) domain. This GLA domain is known to be found in several proteins, including coagulation factors X, VII, IX, and XIV, vitamin K-dependent protein S and Z, prothrombin, transthyretin, osteocalcin, matrix Gla protein (MGP), inter-alpha trypsin inhibitor heavy chain H2, and growth arrest-specific protein 6 (Gas6). The Gla domain is responsible for the high-affinity binding of calcium ions.^[3]

Role in Coagulation

Gamma-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.^[4] 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.^[5]

References

^ J Stenflo, and J W Suttie. "Vitamin K-Dependent Formation of γ-Carboxyglutamic Acid". Annual Review of Biochemistry 46: 157–172. doi:10.1146/annurev.bi.46.070177.001105.
^ Furie, Bruce; Bouchard, Beth A.; Furie, Barbara C. (1999-03-15). "Vitamin K-Dependent Biosynthesis of γ-Carboxyglutamic Acid". Blood 93 (6): 1798–1808. ISSN 0006-4971. PMID 10068650.
^ "Gamma-carboxyglutamic acid-rich (GLA) domain (IPR000294) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2015-12-22.
^ Rawala-Sheikh, R.; Ahmad, S. S.; Monroe, D. M.; Roberts, H. R.; Walsh, P. N. (1992-01-15). "Role of gamma-carboxyglutamic acid residues in the binding of factor IXa to platelets and in factor-X activation". Blood 79 (2): 398–405. ISSN 0006-4971. PMID 1730085.
^ Kalafatis, M.; Egan, J. O.; van't Veer, C.; Mann, K. G. (1996-01-01). "Regulation and regulatory role of gamma-carboxyglutamic acid containing clotting factors". Critical Reviews in Eukaryotic Gene Expression 6 (1): 87–101. ISSN 1045-4403. PMID 8882309.

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1. ビタミンKの概要 overview of vitamin k

English Journal

Effects of apatite particle size in two apatite/collagen composites on the osteogenic differentiation profile of osteoblastic cells.

Hatakeyama W, Taira M, Chosa N, Kihara H, Ishisaki A, Kondo H.Author information Department of Prosthodontics and Oral Implantology, Iwate Medical University School of Dentistry, Morioka, Iwate 020-8505, Japan.AbstractThe development of new osteoconductive bone substitute materials is expected in medicine. In this study, we attempted to produce new hydroxylapatite (HAP)/collagen (Col) composites using two HAP particles of different sizes and porcine type I collagen. The two HAP particles were either nano-sized (40 nm in average diameter; n-HAP) or had macro-pore sizes of 0.5‑1.0 mm in length with fully interconnected pores (m-HAP). The aim of this study was to investigate the effects of apatite particle size in two HAP/Col composites on the osteogenic differentiation profile in osteoblast-like cells (SaOS-2). We created a collagen control sponge (Col) and two HAP/Col composite sponges (n-HAP/Col and m-HAP/Col) using freeze-drying and dehydrothermal cross-linking techniques, and then punched out samples of 6 mm in diameter and 1 mm in height. The SaOS-2 cells were cultured on three test materials for 1, 2, 3 and 4 weeks. Total RNA was extracted from the cultured cells and the expression of osteogenic differentiation-related genes was evaluated by reverse transcription PCR (RT-PCR) using primer sets of alkaline phosphatase (ALP), type 1 collagen (COL1), bone sialoprotein (BSP) and osteocalcin precursor [bone gamma-carboxyglutamate (gla) protein (BGLAP)] genes, as well as the β-actin gene. The cells were also cultured on Col, n-HAP/Col and m-HAP/Col specimens for 1 and 4 weeks, and were then observed under a scanning electron microscope (SEM). The experimental results were as follows: RT-PCR indicated that osteogenic differentiation, particularly the gene expression of BSP, was most accelerated when the cells were cultured on n-HAP/Col specimens, followed by m-HAP/Col, whilst the weakest accelaeration was observed when the cells were cultured on Col specimens. As shown by the SEM images, the SaOS-2 cells were fibroblastic when cultured on Col specimens for up to 4 weeks; they were fibroblastic when cultured on n-HAP/Col specimens for 1 week, but appeared as spheroids, while actively phagocytizing n-HAP particles at 4 weeks; however, they appeared as deformed fibroblasts when cultured on m-HAP/Col specimens, detached from the particles. Despite limited experimental results, our study suggests that n-HAP/Col may be employed as a new osteoconductive bone substitute material.
International journal of molecular medicine.Int J Mol Med.2013 Dec;32(6):1255-61. doi: 10.3892/ijmm.2013.1516. Epub 2013 Oct 2.
The development of new osteoconductive bone substitute materials is expected in medicine. In this study, we attempted to produce new hydroxylapatite (HAP)/collagen (Col) composites using two HAP particles of different sizes and porcine type I collagen. The two HAP particles were either nano-sized (
PMID 24100550

Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease.

Heuvel EG, van Schoor NM, Lips P, Magdeleyns EJ, Deeg DJ, Vermeer C, Heijer MD.Author information Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands; Royal FrieslandCampina, Amersfoort, The Netherlands. Electronic address: ellen.vandenheuvel@frieslandcampina.com.AbstractOBJECTIVES: Vitamin K plays a pivotal role in the synthesis of Matrix Gla protein (MGP), a calcification inhibitor in vascular tissue. Vascular calcification has become an important predictor of cardiovascular disease. The aim of the current study was to examine the potential association of circulating desphospho-carboxylated and -uncarboxylated MGP (dp-cMGP and dp-ucMGP), reflecting vitamin K status, with the incidence of cardiovascular events and disease (CVD) in older individuals.
Maturitas.Maturitas.2013 Oct 24. pii: S0378-5122(13)00319-8. doi: 10.1016/j.maturitas.2013.10.008. [Epub ahead of print]
OBJECTIVES: Vitamin K plays a pivotal role in the synthesis of Matrix Gla protein (MGP), a calcification inhibitor in vascular tissue. Vascular calcification has become an important predictor of cardiovascular disease. The aim of the current study was to examine the potential association of circulat
PMID 24210635

Mouse adipose tissue-derived adult stem cells expressed osteogenic specific transcripts of osteocalcin and parathyroid hormone receptor during osteogenesis.

Teotia PK, Hussein KE, Park KM, Hong SH, Park SM, Park IC, Yang SR, Woo HM.Author information Stem Cell Institute, Kangwon National University, Chuncheon, South Korea; College of Veterinary Medicine, Kangwon National University, Chuncheon, South Korea.AbstractINTRODUCTION: Adult mesenchymal stem cells (MSCs) have potential to differentiate into various lineages, replacing cells during normal turnover and tissue regeneration to replace damaged or lost adult tissues during osteoporosis and arthritis, or traumatic injuries. We investigated the osteogenic signature in mouse adipose tissue (AD)- and bone marrow (BM)-derived MSCs.
Transplantation proceedings.Transplant Proc.2013 Oct;45(8):3102-7. doi: 10.1016/j.transproceed.2013.08.017.
INTRODUCTION: Adult mesenchymal stem cells (MSCs) have potential to differentiate into various lineages, replacing cells during normal turnover and tissue regeneration to replace damaged or lost adult tissues during osteoporosis and arthritis, or traumatic injuries. We investigated the osteogenic si
PMID 24157044

Japanese Journal

Regulation of Osteoblast and Odontoblast Differentiation by RUNX2

Komori Toshihisa
Journal of Oral Biosciences 52(1), 22-25, 2010
… Further, dentin sialophosphoprotein (Dspp) expression was lost and nestin (NES) expression was markedly decreased, while the expressions of bone gamma-carboxyglutamate (gla) protein 1/osteocalcin (BGLAP), osteopontin (SPP1), and dentin matrix protein 1 (DMP1) were up-regulated in the odontoblasts, resulting in the formation of a bone structure. …
NAID 130004939843

Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase

VERMEER C.
Biochem J 266, 625-636, 1990
NAID 80005104796

A New Approach for the Total Synthesis of L-γ-Carboxyglutamic Acid : Utility of Ruthenium Tetroxide Oxidation

田中憲一,吉藤茂行,新田義博
Chemical & pharmaceutical bulletin 34(9), 3879-3884, 1986-09-25
… Cleavage of the lactam bond of 10b with excess benzyl alcohol in the presence of triethylamine gave γ, γ, α-tribenzyl N-Boc-L-γ-carboxyglutamate (11). …
NAID 110003626624

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拡張検索	「gamma-carboxyglutamate」

「gamma-carboxyglutamate」

Carboxyglutamic acid
Names
	IUPAC name 3-Aminopropane-1,1,3-tricarboxylic acid
	Other names γ-Carboxyglutamate
Identifiers
CAS Number	53445-96-8
ChemSpider	37241
Jmol 3D model	Interactive image
PubChem	40772
	InChI 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) Key: UHBYWPGGCSDKFX-UHFFFAOYAH ;
	SMILES O=C(O)C(C(=O)O)CC(N)C(=O)O ;
Properties
Chemical formula	C6H9NO6
Molar mass	191.14 g/mol
Density	1.649 g/mL
Boiling point	418 °C (784 °F; 691 K)
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	Infobox references

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γカルボキシグルタミン酸、γ-カルボキシグルタミン酸

関: 1-carboxyglutamic acid、gamma-carboxyglutamic acid、Gla

[1] J Stenflo, and J W Suttie. "Vitamin K-Dependent Formation of γ-Carboxyglutamic Acid". Annual Review of Biochemistry 46: 157–172. doi:10.1146/annurev.bi.46.070177.001105.

[2] Furie, Bruce; Bouchard, Beth A.; Furie, Barbara C. (1999-03-15). "Vitamin K-Dependent Biosynthesis of γ-Carboxyglutamic Acid". Blood 93 (6): 1798–1808. ISSN 0006-4971. PMID 10068650.

[3] "Gamma-carboxyglutamic acid-rich (GLA) domain (IPR000294) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2015-12-22.

[4] Rawala-Sheikh, R.; Ahmad, S. S.; Monroe, D. M.; Roberts, H. R.; Walsh, P. N. (1992-01-15). "Role of gamma-carboxyglutamic acid residues in the binding of factor IXa to platelets and in factor-X activation". Blood 79 (2): 398–405. ISSN 0006-4971. PMID 1730085.

[5] Kalafatis, M.; Egan, J. O.; van't Veer, C.; Mann, K. G. (1996-01-01). "Regulation and regulatory role of gamma-carboxyglutamic acid containing clotting factors". Critical Reviews in Eukaryotic Gene Expression 6 (1): 87–101. ISSN 1045-4403. PMID 8882309.

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carboxyglutamate