Biology:Glycine—tRNA ligase

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Short description: Protein-coding gene in the species Homo sapiens
Glycine—tRNA ligase
Identifiers
EC number6.1.1.14
CAS number9037-62-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Glycine—tRNA ligase also known as glycyl–tRNA synthetase is an enzyme that in humans is encoded by the GARS1 gene.[1][2][3]

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.[3]

Reaction

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

ATP + glycine + tRNAGly [math]\displaystyle{ \rightleftharpoons }[/math] 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.[4] Mutant forms of the protein associated with peripheral nerve disease have been shown to aberrantly bind to the transmembrane receptor proteins neuropilin 1[5] and Trk receptors A-C.[6]

Clinical relevance

Glycyl-tRNA synthetase has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis.[3]

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.[7][8] CMT2D usually manifests during the teenage years, and results in muscle weakness predominantly in the hands and feet.[9] 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.[10] The CMT2D mice display peripheral nerve axon degeneration [11][12] and defective development[13] and function[14]> of the neuromuscular junction.

References

  1. ↑ "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. Nov 1995. doi:10.1006/geno.1995.0028. PMID 8595897. https://zenodo.org/record/1229644. 
  2. ↑ "Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D)". Human Molecular Genetics 5 (9): 1373–5. Sep 1996. doi:10.1093/hmg/5.9.1373. PMID 8872480. 
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: GARS glycyl-tRNA synthetase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2617. 
  4. ↑ "Interaction network of human aminoacyl-tRNA synthetases and subunits of elongation factor 1 complex". Biochemical and Biophysical Research Communications 291 (1): 158–64. Feb 2002. doi:10.1006/bbrc.2002.6398. PMID 11829477. 
  5. ↑ "CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase". Nature 526 (7575): 710–4. 2015. doi:10.1038/nature15510. PMID 26503042. Bibcode: 2015Natur.526..710H. 
  6. ↑ "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. 2017. doi:10.1073/pnas.1614557114. PMID 28351971. Bibcode: 2017PNAS..114E3324S. 
  7. ↑ "GARS axonopathy: not every neuron's cup of tRNA". Trends in Neurosciences 33 (2): 59–66. Feb 2010. doi:10.1016/j.tins.2009.11.001. PMID 20152552. 
  8. ↑ "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. 2003. doi:10.1086/375039. PMID 12690580. 
  9. ↑ "Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations". Brain 128 (Pt 10): 2304–14. Oct 2005. doi:10.1093/brain/awh590. PMID 16014653. 
  10. ↑ "Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels". PLOS Genetics 7 (12): e1002399. Dec 2011. doi:10.1371/journal.pgen.1002399. PMID 22144914. 
  11. ↑ "An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model". Neuron 51 (6): 715–26. Sep 2006. doi:10.1016/j.neuron.2006.08.027. PMID 16982418. 
  12. ↑ "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. Jul–Aug 2009. doi:10.1242/dmm.002527. PMID 19470612. 
  13. ↑ "Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice". Human Molecular Genetics 23 (10): 2639–50. May 2014. doi:10.1093/hmg/ddt659. PMID 24368416. 
  14. ↑ "Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d". The Journal of Neuroscience 36 (11): 3254–67. 2016. doi:10.1523/JNEUROSCI.1762-15.2016. PMID 26985035. 

Further reading

External links



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