Glycine—tRNA ligase

GARS1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2PME, 2PMF, 2Q5H, 2Q5I, 2ZT5, 2ZT6, 2ZT7, 2ZT8, 2ZXF, 4KQE, 4KR2, 4QEI, 5E6M
Identifiers
Aliases	GARS1, CMT2D, DSMAV, GlyRS, HMN5, SMAD1, glycyl-tRNA synthetase, GARS, glycyl-tRNA synthetase 1, HMN5A, SMAJI
External IDs	OMIM: 600287; MGI: 2449057; HomoloGene: 1547; GeneCards: GARS1; OMA:GARS1 - orthologs
Gene location (Human)
Chr.	Chromosome 7 (human)
End	30,634,033 bp
Gene location (Mouse)
Chr.	Chromosome 6 (mouse)
End	55,056,485 bp
RNA expression pattern
	Top expressed in
	secondary oocyte; ; cartilage tissue; ; lateral nuclear group of thalamus; ; middle temporal gyrus; ; tibia; ; spinal ganglia; ; pars compacta; ; stromal cell of endometrium; ; islet of Langerhans; ; mucosa of pharynx;
	Top expressed in
	somite; ; fetal liver hematopoietic progenitor cell; ; epiblast; ; endocardial cushion; ; maxillary prominence; ; primitive streak; ; mandibular prominence; ; facial motor nucleus; ; Paneth cell; ; calvaria;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	aminoacyl-tRNA ligase activity; nucleotide binding; ligase activity; protein dimerization activity; ATP binding; bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity; hydrolase activity; protein binding; identical protein binding; glycine-tRNA ligase activity; transferase activity;
Cellular component	axon; mitochondrial matrix; cell projection; secretory granule; cytosol; extracellular exosome; extracellular region; cytoplasm; mitochondrion;
Biological process	diadenosine tetraphosphate biosynthetic process; protein biosynthesis; glycyl-tRNA aminoacylation; mitochondrial glycyl-tRNA aminoacylation; tRNA aminoacylation for protein translation;
	Sources:Amigo / QuickGO
Orthologs
	2617
	353172
	ENSG00000106105
	ENSMUSG00000029777
	P41250
	Q9CZD3
	NM_002047; NM_001316772
	NM_180678
	NP_001303701; NP_002038
	NP_851009
	Wikidata
View/Edit Human	View/Edit Mouse

Search
PMC	articles
PubMed	articles
NCBI	proteins

Glycine—tRNA ligase
Glycine—tRNA ligase
Identifiers
EC no.	6.1.1.14
CAS no.	9037-62-1
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
PMC
Search
PMC	articles
PubMed	articles
NCBI	proteins

Glycine—tRNA ligase also known as glycyl–tRNA synthetase is an enzyme that in humans is encoded by the GARS1 gene.^[5]^[6]^[7]

Function

This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases.^[7]

Reaction

In enzymology, a glycine—tRNA ligase (EC 6.1.1.14) is an enzyme that catalyzes the chemical reaction

ATP + glycine + tRNAGly

\rightleftharpoons

AMP + diphosphate + glycyl-tRNAGly

The 3 substrates of this enzyme are ATP, glycine, and tRNA(Gly), whereas its 3 products are AMP, diphosphate, and glycyl-tRNA(Gly).

This enzyme belongs to the family of ligases, to be specific those forming carbon-oxygen bonds in aminoacyl-tRNA and related compounds. The systematic name of this enzyme class is glycine:tRNAGly ligase (AMP-forming). Other names in common use include glycyl-tRNA synthetase, glycyl-transfer ribonucleate synthetase, glycyl-transfer RNA synthetase, glycyl-transfer ribonucleic acid synthetase, and glycyl translase. This enzyme participates in glycine, serine and threonine metabolism and aminoacyl-trna biosynthesis.

Interactions

Glycyl-tRNA synthetase has been shown to interact with EEF1D.^[8] Mutant forms of the protein associated with peripheral nerve disease have been shown to aberrantly bind to the transmembrane receptor proteins neuropilin 1^[9] and Trk receptors A-C.^[10]

Clinical relevance

Glycyl-tRNA synthetase has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis.^[7]

The peripheral nerve diseases Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) have been liked to dominant mutations in GARS.^[11]^[12] CMT2D usually manifests during the teenage years, and results in muscle weakness predominantly in the hands and feet.^[13] Two mouse models of CMT2D have been used to better understand the disease, identifying that the disorder is caused by a toxic gain-of-function of the mutant glycine-tRNA ligase protein.^[14] The CMT2D mice display peripheral nerve axon degeneration ^[15]^[16] and defective development^[17] and function^[18]> of the neuromuscular junction.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000106105 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000029777 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Nichols RC, Pai SI, Ge Q, Targoff IN, Plotz PH, Liu P (Nov 1995). "Localization of two human autoantigen genes by PCR screening and in situ hybridization--glycyl-tRNA synthetase locates to 7p15 and alanyl-tRNA synthetase locates to 16q22". Genomics. 30 (1): 131–2. doi:10.1006/geno.1995.0028. PMID 8595897.
^ Ionasescu V, Searby C, Sheffield VC, Roklina T, Nishimura D, Ionasescu R (Sep 1996). "Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D)". Human Molecular Genetics. 5 (9): 1373–5. CiteSeerX 10.1.1.588.4502. doi:10.1093/hmg/5.9.1373. PMID 8872480.
^ ^a ^b ^c "Entrez Gene: GARS glycyl-tRNA synthetase".
^ Sang Lee J, Gyu Park S, Park H, Seol W, Lee S, Kim S (Feb 2002). "Interaction network of human aminoacyl-tRNA synthetases and subunits of elongation factor 1 complex". Biochemical and Biophysical Research Communications. 291 (1): 158–64. doi:10.1006/bbrc.2002.6398. PMID 11829477.
^ He W, Bai G, Zhou H, Wei N, White NM, Lauer J, Liu H, Shi Y, Dumitru CD, Lettieri K, Shubayev V, Jordanova A, Guergueltcheva V, Griffin PR, Burgess RW, Pfaff SL, Yang XL (2015). "CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase". Nature. 526 (7575): 710–4. Bibcode:2015Natur.526..710H. doi:10.1038/nature15510. PMC 4754353. PMID 26503042.
^ Sleigh JN, Dawes JM, West SJ, Wei N, Spaulding EL, Gómez-Martín A, Zhang Q, Burgess RW, Cader MZ, Talbot K, Yang XL, Bennett DL, Schiavo G (2017). "Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations". Proc Natl Acad Sci U S A. 114 (16): E3324–E3333. Bibcode:2017PNAS..114E3324S. doi:10.1073/pnas.1614557114. PMC 5402433. PMID 28351971.
^ Motley WW, Talbot K, Fischbeck KH (Feb 2010). "GARS axonopathy: not every neuron's cup of tRNA". Trends in Neurosciences. 33 (2): 59–66. doi:10.1016/j.tins.2009.11.001. PMC 2822721. PMID 20152552.
^ Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED (2003). "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V". American Journal of Human Genetics. 72 (5): 1293–9. doi:10.1086/375039. PMC 1180282. PMID 12690580.
^ Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG (Oct 2005). "Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations". Brain. 128 (Pt 10): 2304–14. doi:10.1093/brain/awh590. PMID 16014653.
^ Motley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J, Antonellis A, Green ED, Talbot K, Yang XL, Fischbeck KH, Burgess RW (Dec 2011). "Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels". PLOS Genetics. 7 (12): e1002399. doi:10.1371/journal.pgen.1002399. PMC 3228828. PMID 22144914.
^ Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW (Sep 2006). "An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model". Neuron. 51 (6): 715–26. doi:10.1016/j.neuron.2006.08.027. PMID 16982418. S2CID 11035583.
^ Achilli F, Bros-Facer V, Williams HP, Banks GT, AlQatari M, Chia R, Tucci V, Groves M, Nickols CD, Seburn KL, Kendall R, Cader MZ, Talbot K, van Minnen J, Burgess RW, Brandner S, Martin JE, Koltzenburg M, Greensmith L, Nolan PM, Fisher EM (Jul–Aug 2009). "An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy". Disease Models & Mechanisms. 2 (7–8): 359–73. doi:10.1242/dmm.002527. PMC 2707104. PMID 19470612.
^ Sleigh JN, Grice SJ, Burgess RW, Talbot K, Cader MZ (May 2014). "Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice". Human Molecular Genetics. 23 (10): 2639–50. doi:10.1093/hmg/ddt659. PMC 3990164. PMID 24368416.
^ Spaulding EL, Sleigh JN, Morelli KH, Pinter MJ, Burgess RW, Seburn KL (2016). "Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d". The Journal of Neuroscience. 36 (11): 3254–67. doi:10.1523/JNEUROSCI.1762-15.2016. PMC 4792937. PMID 26985035.

External links

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000106105 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000029777 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid8595897-5] Nichols RC, Pai SI, Ge Q, Targoff IN, Plotz PH, Liu P (Nov 1995). "Localization of two human autoantigen genes by PCR screening and in situ hybridization--glycyl-tRNA synthetase locates to 7p15 and alanyl-tRNA synthetase locates to 16q22". Genomics. 30 (1): 131–2. doi:10.1006/geno.1995.0028. PMID 8595897.

[pmid8872480-6] Ionasescu V, Searby C, Sheffield VC, Roklina T, Nishimura D, Ionasescu R (Sep 1996). "Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D)". Human Molecular Genetics. 5 (9): 1373–5. CiteSeerX 10.1.1.588.4502. doi:10.1093/hmg/5.9.1373. PMID 8872480.

[entrez-7] "Entrez Gene: GARS glycyl-tRNA synthetase".

[pmid11829477-8] Sang Lee J, Gyu Park S, Park H, Seol W, Lee S, Kim S (Feb 2002). "Interaction network of human aminoacyl-tRNA synthetases and subunits of elongation factor 1 complex". Biochemical and Biophysical Research Communications. 291 (1): 158–64. doi:10.1006/bbrc.2002.6398. PMID 11829477.

[pmid26503042-9] He W, Bai G, Zhou H, Wei N, White NM, Lauer J, Liu H, Shi Y, Dumitru CD, Lettieri K, Shubayev V, Jordanova A, Guergueltcheva V, Griffin PR, Burgess RW, Pfaff SL, Yang XL (2015). "CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase". Nature. 526 (7575): 710–4. Bibcode:2015Natur.526..710H. doi:10.1038/nature15510. PMC 4754353. PMID 26503042.

[pmid28351971-10] Sleigh JN, Dawes JM, West SJ, Wei N, Spaulding EL, Gómez-Martín A, Zhang Q, Burgess RW, Cader MZ, Talbot K, Yang XL, Bennett DL, Schiavo G (2017). "Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations". Proc Natl Acad Sci U S A. 114 (16): E3324–E3333. Bibcode:2017PNAS..114E3324S. doi:10.1073/pnas.1614557114. PMC 5402433. PMID 28351971.

[pmid20152552-11] Motley WW, Talbot K, Fischbeck KH (Feb 2010). "GARS axonopathy: not every neuron's cup of tRNA". Trends in Neurosciences. 33 (2): 59–66. doi:10.1016/j.tins.2009.11.001. PMC 2822721. PMID 20152552.

[pmid12690580-12] Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED (2003). "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V". American Journal of Human Genetics. 72 (5): 1293–9. doi:10.1086/375039. PMC 1180282. PMID 12690580.

[pmid16014653-13] Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG (Oct 2005). "Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations". Brain. 128 (Pt 10): 2304–14. doi:10.1093/brain/awh590. PMID 16014653.

[pmid22144914-14] Motley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J, Antonellis A, Green ED, Talbot K, Yang XL, Fischbeck KH, Burgess RW (Dec 2011). "Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels". PLOS Genetics. 7 (12): e1002399. doi:10.1371/journal.pgen.1002399. PMC 3228828. PMID 22144914.

[pmid16982418-15] Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW (Sep 2006). "An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model". Neuron. 51 (6): 715–26. doi:10.1016/j.neuron.2006.08.027. PMID 16982418. S2CID 11035583.

[pmid19470612-16] Achilli F, Bros-Facer V, Williams HP, Banks GT, AlQatari M, Chia R, Tucci V, Groves M, Nickols CD, Seburn KL, Kendall R, Cader MZ, Talbot K, van Minnen J, Burgess RW, Brandner S, Martin JE, Koltzenburg M, Greensmith L, Nolan PM, Fisher EM (Jul–Aug 2009). "An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy". Disease Models & Mechanisms. 2 (7–8): 359–73. doi:10.1242/dmm.002527. PMC 2707104. PMID 19470612.

[pmid24368416-17] Sleigh JN, Grice SJ, Burgess RW, Talbot K, Cader MZ (May 2014). "Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice". Human Molecular Genetics. 23 (10): 2639–50. doi:10.1093/hmg/ddt659. PMC 3990164. PMID 24368416.

[pmid26985035-18] Spaulding EL, Sleigh JN, Morelli KH, Pinter MJ, Burgess RW, Seburn KL (2016). "Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d". The Journal of Neuroscience. 36 (11): 3254–67. doi:10.1523/JNEUROSCI.1762-15.2016. PMC 4792937. PMID 26985035.

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v t e Enzymes: CO CS and CN ligases (EC 6.1-6.3)
6.1: Carbon-Oxygen	Aminoacyl tRNA synthetase Alanine Arginine Asparagine Aspartate Cysteine D-alanine—poly(phosphoribitol) ligase Glutamate Glutamine Glycine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan Tyrosine Valine
6.2: Carbon-Sulfur	Succinyl coenzyme A synthetase Acetyl—CoA synthetase Long-chain-fatty-acid—CoA ligase
6.3: Carbon-Nitrogen	Glutamine synthetase Ubiquitin ligase Cullin Von Hippel–Lindau tumor suppressor UBE3A Mdm2 Anaphase-promoting complex UBR1 Glutathione synthetase CTP synthetase Adenylosuccinate synthase Argininosuccinate synthase Holocarboxylase synthetase GMP synthase Asparagine synthetase Carbamoyl phosphate synthetase I II Glutamate–cysteine ligase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)