Glycine—tRNA ligase explained

Align:	left
Glycine—tRNA ligase
Ec Number:	6.1.1.14
Cas Number:	9037-62-1
Go Code:	0004820

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 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.^[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.

Further reading

• Fraser MJ . Glycyl-RNA synthetase of rat liver: partial purification and effects of some metal ions on its activity . Canadian Journal of Biochemistry and Physiology . 41 . 1123–33 . May 1963 . 5 . 13959340 . 10.1139/o63-128 .
• Niyomporn B, Dahl JL, Strominger JL . Biosynthesis of the peptidoglycan of bacterial cell walls. IX. Purification and properties of glycyl transfer ribonucleic acid synthetase from Staphylococcus aureus . The Journal of Biological Chemistry . 243 . 4 . 773–8 . Feb 1968 . 10.1016/S0021-9258(19)81732-5 . 4295604 . free .
• Hipps D, Shiba K, Henderson B, Schimmel P . Operational RNA code for amino acids: species-specific aminoacylation of minihelices switched by a single nucleotide . Proceedings of the National Academy of Sciences of the United States of America . 92 . 12 . 5550–2 . Jun 1995 . 7539919 . 41733 . 10.1073/pnas.92.12.5550 . 1995PNAS...92.5550H . free .
• Williams J, Osvath S, Khong TF, Pearse M, Power D . Cloning, sequencing and bacterial expression of human glycine tRNA synthetase . Nucleic Acids Research . 23 . 8 . 1307–10 . Apr 1995 . 7753621 . 306854 . 10.1093/nar/23.8.1307 .
• Ge Q, Trieu EP, Targoff IN . Primary structure and functional expression of human Glycyl-tRNA synthetase, an autoantigen in myositis . The Journal of Biological Chemistry . 269 . 46 . 28790–7 . Nov 1994 . 10.1016/S0021-9258(19)61975-7 . 7961834 . free .
• Shiba K, Schimmel P, Motegi H, Noda T . Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation . The Journal of Biological Chemistry . 269 . 47 . 30049–55 . Nov 1994 . 10.1016/S0021-9258(18)43986-5 . 7962006 . free .
• Rho SB, Lee KH, Kim JW, Shiba K, Jo YJ, Kim S . Interaction between human tRNA synthetases involves repeated sequence elements . Proceedings of the National Academy of Sciences of the United States of America . 93 . 19 . 10128–33 . Sep 1996 . 8816763 . 38348 . 10.1073/pnas.93.19.10128 . 1996PNAS...9310128R . free .
• Mudge SJ, Williams JH, Eyre HJ, Sutherland GR, Cowan PJ, Power DA . Grant Robert Sutherland . Complex organisation of the 5'-end of the human glycine tRNA synthetase gene . Gene . 209 . 1–2 . 45–50 . Mar 1998 . 9524218 . 10.1016/S0378-1119(98)00007-9 .
• Kneussel M, Hermann A, Kirsch J, Betz H . Hydrophobic interactions mediate binding of the glycine receptor beta-subunit to gephyrin . Journal of Neurochemistry . 72 . 3 . 1323–6 . Mar 1999 . 10037506 . 10.1046/j.1471-4159.1999.0721323.x . 24302707 . free .
• Sang Lee J, Gyu Park S, Park H, Seol W, Lee S, Kim S . 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 . 11829477 . 10.1006/bbrc.2002.6398 .
• 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 . 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 . May 2003 . 12690580 . 1180282 . 10.1086/375039 .
• Del Bo R, Locatelli F, Corti S, Scarlato M, Ghezzi S, Prelle A, Fagiolari G, Moggio M, Carpo M, Bresolin N, Comi GP . Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation . Neurology . 66 . 5 . 752–4 . Mar 2006 . 16534118 . 10.1212/01.wnl.0000201275.18875.ac . 1143879 .
• James PA, Cader MZ, Muntoni F, Childs AM, Crow YJ, Talbot K . Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene . Neurology . 67 . 9 . 1710–2 . Nov 2006 . 17101916 . 10.1212/01.wnl.0000242619.52335.bc . 16491162 .
• Xie W, Schimmel P, Yang XL . Crystallization and preliminary X-ray analysis of a native human tRNA synthetase whose allelic variants are associated with Charcot-Marie-Tooth disease . Acta Crystallographica Section F . 62 . Pt 12 . 1243–6 . Dec 2006 . 17142907 . 2225372 . 10.1107/S1744309106046434 .
• Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK . Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy . FEBS Letters . 581 . 16 . 2959–64 . Jun 2007 . 17544401 . 10.1016/j.febslet.2007.05.046 . 24584635 . free .
• Xie W, Nangle LA, Zhang W, Schimmel P, Yang XL . Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase . Proceedings of the National Academy of Sciences of the United States of America . 104 . 24 . 9976–81 . Jun 2007 . 17545306 . 1891255 . 10.1073/pnas.0703908104 . 2007PNAS..104.9976X . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2
• GeneReviews/NCBI/NIH/UW entry on GARS-Associated Axonal Neuropathy, Charcot-Marie-Tooth Neuropathy Type 2D, Distal Spinal Muscular Atrophy V

Notes and References

1. Nichols RC, Pai SI, Ge Q, Targoff IN, Plotz PH, Liu P . 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 . 8595897 . 10.1006/geno.1995.0028 .
2. Ionasescu V, Searby C, Sheffield VC, Roklina T, Nishimura D, Ionasescu R . Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D) . Human Molecular Genetics . 5 . 9 . 1373–5 . Sep 1996 . 8872480 . 10.1093/hmg/5.9.1373 . 10.1.1.588.4502 .
3. Web site: Entrez Gene: GARS glycyl-tRNA synthetase.
4. Sang Lee J, Gyu Park S, Park H, Seol W, Lee S, Kim S . 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 . 11829477 . 10.1006/bbrc.2002.6398 .
5. 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 . CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase . Nature . 526 . 7575 . 710–4 . 2015 . 26503042 . 4754353 . 10.1038/nature15510 . 2015Natur.526..710H .
6. 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 . 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 . 28351971 . 5402433 . 10.1073/pnas.1614557114 . 2017PNAS..114E3324S . free .
7. Motley WW, Talbot K, Fischbeck KH . GARS axonopathy: not every neuron's cup of tRNA . Trends in Neurosciences . 33 . 2 . 59–66 . Feb 2010 . 20152552 . 2822721 . 10.1016/j.tins.2009.11.001 .
8. 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 . 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 . 12690580 . 1180282 . 10.1086/375039 .
9. 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 . Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations . Brain . 128 . Pt 10 . 2304–14 . Oct 2005 . 16014653 . 10.1093/brain/awh590 . free .
10. Motley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J, Antonellis A, Green ED, Talbot K, Yang XL, Fischbeck KH, Burgess RW . Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels . PLOS Genetics . 7 . 12 . e1002399 . Dec 2011 . 22144914 . 3228828 . 10.1371/journal.pgen.1002399 . free .
11. Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW . 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 . 16982418 . 10.1016/j.neuron.2006.08.027 . 11035583 . free .
12. 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 . 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 . 19470612 . 2707104 . 10.1242/dmm.002527 .
13. Sleigh JN, Grice SJ, Burgess RW, Talbot K, Cader MZ . 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 . 24368416 . 10.1093/hmg/ddt659 . 3990164 .
14. Spaulding EL, Sleigh JN, Morelli KH, Pinter MJ, Burgess RW, Seburn KL . Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d . The Journal of Neuroscience . 36 . 11 . 3254–67 . 2016 . 26985035 . 4792937 . 10.1523/JNEUROSCI.1762-15.2016 .