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2vxo

HUMAN GMP SYNTHETASE

An ample supply of nucleotides is essential for many life processes, including cell maturation, cell division and transmission of the genetic information. Indeed, nucleotides are the activated precursors of nucleic acids, but they also are major energy carriers, and precursors for the synthesis of nucleotide cofactors. Among these molecules is the guanosine monophosphate (GMP), also known as 5'-guanidylic acid or guanylic acid, a nucleotide that is used as a monomer in RNA. Like other nucleotides, GMP can be synthesized by 2 main pathways : de novo pathway and salvage pathway. De novo synthesis of nucleotide involves several enzymatic reaction and enzymes. Here, we will focus on the final step of the process, which is catalyzed by a glutamine amidotransferase called GMP synthetase (GMPS; E.C. 6.3.5.2). This enzyme belongs to the family of ligases, and catalyzes the conversion of xanthine monophosphate (XMP) to GMP in the presence of glutamine and ATP. [1]


2vxo, resolution 2.50Å

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References

  1. 1.0 1.1 1.2 1.3 1.4 Welin M, Lehtio L, Johansson A, Flodin S, Nyman T, Tresaugues L, Hammarstrom M, Graslund S, Nordlund P. Substrate Specificity and Oligomerization of Human GMP Synthetase. J Mol Biol. 2013 Jun 28. pii: S0022-2836(13)00427-0. doi:, 10.1016/j.jmb.2013.06.032. PMID:23816837 doi:10.1016/j.jmb.2013.06.032
  2. http://www.uniprot.org/uniprot/P49915
  3. http://www.uniprot.org/uniprot/P49915
  4. 4.0 4.1 4.2 Nakamura J, Lou L. Biochemical characterization of human GMP synthetase. J Biol Chem. 1995 Mar 31;270(13):7347-53. doi: 10.1074/jbc.270.13.7347. PMID:7706277 doi:http://dx.doi.org/10.1074/jbc.270.13.7347
  5. 5.0 5.1 Oliver JC, Linger RS, Chittur SV, Davisson VJ. Substrate activation and conformational dynamics of guanosine 5'-monophosphate synthetase. Biochemistry. 2013 Aug 6;52(31):5225-35. doi: 10.1021/bi3017075. Epub 2013 Jul, 23. PMID:23841499 doi:http://dx.doi.org/10.1021/bi3017075
  6. http://https://en.wikipedia.org/wiki/GMP_synthase_(glutamine%E2%80%94hydrolysing)
  7. Lui MS, Kizaki H, Weber G. Biochemical pharmacology of acivicin in rat hepatoma cells. Biochem Pharmacol. 1982 Nov 1;31(21):3469-73. PMID:7150366
  8. Oliver JC, Linger RS, Chittur SV, Davisson VJ. Substrate activation and conformational dynamics of guanosine 5'-monophosphate synthetase. Biochemistry. 2013 Aug 6;52(31):5225-35. doi: 10.1021/bi3017075. Epub 2013 Jul, 23. PMID:23841499 doi:http://dx.doi.org/10.1021/bi3017075
  9. Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rowley JD, Rappaport EF, Felix CA. t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. Blood. 2000 Dec 15;96(13):4360-2. PMID:11110714
  10. Rodriguez-Suarez R, Xu D, Veillette K, Davison J, Sillaots S, Kauffman S, Hu W, Bowman J, Martel N, Trosok S, Wang H, Zhang L, Huang LY, Li Y, Rahkhoodaee F, Ransom T, Gauvin D, Douglas C, Youngman P, Becker J, Jiang B, Roemer T. Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus. Chem Biol. 2007 Oct;14(10):1163-75. PMID:17961828 doi:http://dx.doi.org/10.1016/j.chembiol.2007.09.009
  11. Faesen AC, Dirac AM, Shanmugham A, Ovaa H, Perrakis A, Sixma TK. Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase. Mol Cell. 2011 Oct 7;44(1):147-59. PMID:21981925 doi:10.1016/j.molcel.2011.06.034

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