Affinage

GLA

N-acetyltransferase 8 · UniProt Q9UHE5

Length
227 aa
Mass
25.6 kDa
Annotated
2026-06-10
100 papers in source corpus 1 papers cited in narrative 1 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLA encodes lysosomal α-galactosidase A (α-Gal A), an enzyme whose loss of activity underlies Fabry disease (PMID:19941952). Select missense mutations distant from the active site (p.C52Y, p.G183A, p.Y216C) reduce α-Gal A activity by destabilizing protein conformation rather than disrupting catalysis directly, defining a conformational class of Fabry-causing variants (PMID:19941952). The active-site-directed pharmacological chaperone 1-deoxygalactonojirimycin (DGJ) increases activity and stabilizes the p.G183A and p.Y216C mutant proteins, whereas p.C52Y is not DGJ-responsive, indicating that chaperone rescue is mutation-specific (PMID:19941952). Beyond this characterization of conformational mutants and their chaperone responsiveness, no further mechanistic detail of α-Gal A catalysis or substrate processing has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2009 Medium

    It was unknown whether GLA missense mutations outside the active site cause Fabry disease through conformational defects rather than direct catalytic disruption; this work established that such mutations reduce α-Gal A activity by destabilizing protein conformation and that some are rescuable by a pharmacological chaperone.

    Evidence In vitro expression of mutant α-Gal A in COS-1 cells and patient lymphocytes, with Western blot, enzyme activity assays, 3D structural analysis, and DGJ chaperone treatment

    PMID:19941952

    Open questions at the time
    • Does not establish why p.C52Y is unresponsive to DGJ at the structural level
    • Limited to three mutations; the conformational basis of most GLA variants is not defined
    • No direct measurement of substrate (e.g. globotriaosylceramide) processing by the mutant enzymes

Open questions

Synthesis pass · forward-looking unresolved questions
  • The catalytic mechanism, native substrate handling, and structural determinants distinguishing chaperone-responsive from non-responsive GLA mutations remain uncharacterized in the available corpus.
  • No mechanistic model linking specific mutation positions to chaperone responsiveness
  • No characterization of α-Gal A enzymatic mechanism or substrate kinetics in this corpus
  • No structural data on the wild-type or mutant enzyme beyond modeling

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 1
Pathway
R-HSA-1430728 Metabolism 1

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Three missense GLA mutations (p.C52Y, p.G183A, p.Y216C) reduce α-galactosidase A (α-Gal A) enzymatic activity without directly involving the active site, causing conformational Fabry disease; the p.G183A and p.Y216C mutant proteins showed increased activity and stabilization upon treatment with the pharmacological chaperone 1-deoxygalactonojirimycin (DGJ), while p.C52Y was not DGJ-responsive, as demonstrated by in vitro expression in COS-1 cells and patient lymphocytes with Western blot and activity assays. In vitro expression in COS-1 cells, Western blot, enzyme activity assays, 3D structural analysis, pharmacological chaperone (DGJ) treatment in patient lymphocytes Biochimica et biophysica acta Medium 19941952

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 GALA: a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Advanced drug delivery reviews 422 15066755
1999 Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nature genetics 315 9916809
2001 Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. The Journal of biological chemistry 295 11741887
2013 Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends in molecular medicine 246 23375872
2008 Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thrombosis and haemostasis 223 18841280
2010 Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thrombosis and haemostasis 197 20694284
2003 Matrix GLA protein and BMP-2 regulate osteoinduction in calcifying vascular cells. Journal of cellular biochemistry 155 14587031
1999 Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb. The Journal of cell biology 155 10579728
1998 The role of Gla proteins in vascular calcification. Critical reviews in eukaryotic gene expression 142 9807700
1995 The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 123 7754814
2011 Bone Gla protein increases HIF-1alpha-dependent glucose metabolism and induces cartilage and vascular calcification. Arteriosclerosis, thrombosis, and vascular biology 118 21757657
2000 Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arteriosclerosis, thrombosis, and vascular biology 116 11073842
2006 Molecular mechanisms mediating vascular calcification: role of matrix Gla protein. Nephrology (Carlton, Vic.) 115 17014561
1989 Gla-containing proteins of bone. Connective tissue research 115 2691199
2000 Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Current opinion in clinical nutrition and metabolic care 106 11085828
1990 Molecular structure, chromosome assignment, and promoter organization of the human matrix Gla protein gene. The Journal of biological chemistry 105 2394711
2014 Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arteriosclerosis, thrombosis, and vascular biology 102 25538207
2004 Matrix GLA protein stimulates VEGF expression through increased transforming growth factor-beta1 activity in endothelial cells. The Journal of biological chemistry 97 15456771
2006 Multifunctional specificity of the protein C/activated protein C Gla domain. The Journal of biological chemistry 95 16867987
2020 The Role of Matrix Gla Protein (MGP) in Vascular Calcification. Current medicinal chemistry 86 30009696
2009 Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification. Thrombosis and haemostasis 79 19350115
2023 DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases. International journal of molecular sciences 78 37445890
2011 Matrix Gla protein deficiency causes arteriovenous malformations in mice. The Journal of clinical investigation 78 21765215
2018 Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease? International journal of molecular sciences 77 30477121
2018 Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review. Nutrients 76 29584693
2019 The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes. The Journal of experimental medicine 74 31175140
2001 Coordinated expression of matrix Gla protein is required during endochondral ossification for chondrocyte survival. The Journal of cell biology 73 11489922
1991 Developmental expression and hormonal regulation of the rat matrix Gla protein (MGP) gene in chondrogenesis and osteogenesis. Journal of cellular biochemistry 69 1757478
2003 Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connective tissue research 68 12952208
2018 mRNA Polyplexes with Post-Conjugated GALA Peptides Efficiently Target, Transfect, and Activate Antigen Presenting Cells. Bioconjugate chemistry 66 30188694
2011 Matrix Gla protein metabolism in vascular smooth muscle and role in uremic vascular calcification. The Journal of biological chemistry 65 21705322
1998 Expression of matrix Gla protein (MGP) in an in vitro model of vascular calcification. FEBS letters 63 9738924
2013 Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency. Proceedings of the National Academy of Sciences of the United States of America 60 24191040
1992 Expression of the matrix Gla protein in urogenital malignancies. International journal of cancer 58 1399132
2015 Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis. Cellular and molecular life sciences : CMLS 56 26337479
2006 Matrix GLA protein function in human trabecular meshwork cells: inhibition of BMP2-induced calcification process. Investigative ophthalmology & visual science 53 16505034
2010 Calcium scores and matrix Gla protein levels: association with vitamin K status. European journal of clinical investigation 51 20486996
2023 Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study. Blood advances 50 35696759
2009 Matrix gla protein (MGP): an overexpressed and migration-promoting mesenchymal component in glioblastoma. BMC cancer 50 19712474
2007 A polymorphism of matrix Gla protein gene is associated with kidney stones. The Journal of urology 48 17509359
2007 Matrix GLA protein, an inhibitory morphogen in pulmonary vascular development. The Journal of biological chemistry 48 17670744
1979 GM1-gangliosidosis: chromosome 3 assignment of the beta-galactosidase-A gene (beta GALA). Somatic cell genetics 48 113895
2005 Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification. Circulation research 47 16100044
1992 Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations. Blood 46 1347706
2009 Functional studies of new GLA gene mutations leading to conformational Fabry disease. Biochimica et biophysica acta 45 19941952
2018 Correlates of GLA family adjuvants' activities. Seminars in immunology 44 30366662
2015 NOTCH1 regulates matrix gla protein and calcification gene networks in human valve endothelium. Journal of molecular and cellular cardiology 44 25871831
1991 Carboxyl-terminal proteolytic processing of matrix Gla protein. The Journal of biological chemistry 43 1939157
2017 Fabry disease due to D313Y and novel GLA mutations. BMJ open 42 28988177
2016 Matrix gla protein: An extracellular matrix protein regulates myostatin expression in the muscle developmental program. Life sciences 42 28012893
2010 Increase in fruit size of a spontaneous mutant of 'Gala' apple (Malus x domestica Borkh.) is facilitated by altered cell production and enhanced cell size. Journal of experimental botany 42 20484321
2006 Expression of osteonectin and matrix Gla protein in scleroderma patients with and without calcinosis. Rheumatology (Oxford, England) 42 17050587
1992 Cell adhesion to matrix Gla protein and its inhibition by an Arg-Gly-Asp-containing peptide. The Journal of biological chemistry 42 1577789
2016 Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus. American journal of hypertension 41 27927630
2012 Role of matrix Gla protein in angiotensin II-induced exacerbation of vascular calcification. American journal of physiology. Heart and circulatory physiology 39 22796540
2008 Matrix Gla protein inhibition of tooth mineralization. Journal of dental research 37 18719210
2012 Matrix gla protein and alkaline phosphatase are differently modulated in human dermal fibroblasts from PXE patients and controls. The Journal of investigative dermatology 36 23223140
2005 Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation. The FEBS journal 36 15634335
2001 Down-regulation of matrix Gla protein messenger RNA in human colorectal adenocarcinomas. Cancer letters 35 11248420
2014 Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and γ-carboxylation status. Molecular nutrition & food research 34 24867294
2020 Uncarboxylated matrix Gla-protein: A biomarker of vitamin K status and cardiovascular risk. Clinical biochemistry 33 32422228
2013 Peptides of Matrix Gla protein inhibit nucleation and growth of hydroxyapatite and calcium oxalate monohydrate crystals. PloS one 33 24265810
2021 GALA-Modified Lipid Nanoparticles for the Targeted Delivery of Plasmid DNA to the Lungs. Molecular pharmaceutics 32 33492961
2018 Smart Polymersomes Dually Functionalized with cRGD and Fusogenic GALA Peptides Enable Specific and High-Efficiency Cytosolic Delivery of Apoptotic Proteins. Biomacromolecules 32 30289705
2017 PEGylation of the GALA Peptide Enhances the Lung-Targeting Activity of Nanocarriers That Contain Encapsulated siRNA. Journal of pharmaceutical sciences 31 28483420
2012 Gla-rich protein, a new player in tissue calcification? Advances in nutrition (Bethesda, Md.) 31 22516725
2020 Matrix Gla protein regulates adipogenesis and is serum marker of visceral adiposity. Adipocyte 30 32000575
2019 Unexpected Role of Matrix Gla Protein in Osteoclasts: Inhibiting Osteoclast Differentiation and Bone Resorption. Molecular and cellular biology 30 30988158
2014 Matrix Gla protein and osteocalcin: from gene duplication to neofunctionalization. Archives of biochemistry and biophysics 30 25068814
2005 Role of matrix Gla protein in parathyroid hormone inhibition of osteoblast mineralization. Cells, tissues, organs 30 16612082
2020 Intracellular matrix Gla protein promotes tumor progression by activating JAK2/STAT5 signaling in gastric cancer. Molecular oncology 29 32086862
2019 A study of the endocytosis mechanism and transendothelial activity of lung-targeted GALA-modified liposomes. Journal of controlled release : official journal of the Controlled Release Society 29 31185231
2017 Matrix Gla protein deficiency impairs nasal septum growth, causing midface hypoplasia. The Journal of biological chemistry 29 28487368
2019 Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP. Arthritis research & therapy 28 31215457
2012 Matrix Gla protein reinforces angiogenic resolution. Microvascular research 28 23110920
2015 Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells. Angiogenesis 27 26364300
2013 Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys. World journal of urology 27 23475213
2002 Gla domain-mutated human protein C exhibiting enhanced anticoagulant activity and increased phospholipid binding. Blood 27 12446455
2011 Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Clinical genetics 26 21517827
2004 Expression analysis of the matrix GLA protein and VE-cadherin gene promoters in the outflow pathway. Investigative ophthalmology & visual science 26 15111593
2016 The influence of phosphate, calcium and magnesium on matrix Gla-protein and vascular calcification: a systematic review. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia 25 28134400
2016 Matrix Gla protein in tumoral pathology. Clujul medical (1957) 24 27547048
2010 The incorporation of GALA peptide into a protein cage for an acid-inducible molecular switch. Biomaterials 24 20359742
2009 Identification of four alternatively spliced transcripts of the Ucma/GRP gene, encoding a new Gla-containing protein. Experimental cell research 24 19819238
1999 Expression of the gene encoding the matrix gla protein by mature osteoblasts in human fracture non-unions. Molecular pathology : MP 24 10474688
2022 Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin. Breast cancer research : BCR 22 36284362
2019 Relationship of matrix Gla protein and vitamin K with vascular calcification in hemodialysis patients. Renal failure 22 31538831
1993 Matrix Gla protein mRNA expression in cultured type II pneumocytes. The American journal of physiology 21 8214087
2015 Matrix Gla protein regulates calcification of the aortic valve. The Journal of surgical research 20 25990696
2019 Natural alleles of GLA for grain length and awn development were differently domesticated in rice subspecies japonica and indica. Plant biotechnology journal 19 30663245
2019 The GalNAc-T Activation (GALA) Pathway: Drivers and markers. PloS one 19 30889231
2012 New mutations in the GLA gene in Brazilian families with Fabry disease. Journal of human genetics 19 22551898
2004 Expression of matrix Gla protein and osteonectin mRNA by human aortic smooth muscle cells. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 19 15210134
2001 Matrix Gla protein in Xenopus laevis: molecular cloning, tissue distribution, and evolutionary considerations. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 18 11550673
2001 Synthesis and characterization of membrane-active GALA-OKT9 conjugates. Bioconjugate chemistry 18 11562192
2014 Matrix gla protein binds to fibronectin and enhances cell attachment and spreading on fibronectin. International journal of cell biology 17 25210519
2022 Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study. Biomolecules 16 35740923
2018 Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension. Journal of the American Society of Hypertension : JASH 15 30033123
2017 Functional Role of Matrix gla Protein in Glioma Cell Migration. Molecular neurobiology 15 28707070
2015 Molecular and clinical studies in five index cases with novel mutations in the GLA gene. Gene 15 26691501

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