GMP synthase

{{infobox enzyme | Name = GMP synthetase (glutamine-hydrolysing) | EC_number = 6.3.5.2 | CAS_number = 37318-71-1 | GO_code = 0003922 | image = 2vxo.jpg | width = 270 | caption = GMP synthetase, human }} {{Infobox protein family | Symbol = GMP_synt_C | Name = GMP synthetase C terminal domain | image = PDB 1gpm EBI.jpg | width = | caption = escherichia coli gmp synthetase complexed with amp and pyrophosphate.<ref name="Tesmer_1996">{{cite journal | vauthors = Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL | title = The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families | journal = Nature Structural Biology | volume = 3 | issue = 1 | pages = 74–86 | date = January 1996 | pmid = 8548458 | doi = 10.1038/nsb0196-74 | s2cid = 30864133 }}</ref> | Pfam = PF00958 | Pfam_clan = | InterPro = IPR001674 | SMART = | PROSITE = PDOC00405 | MEROPS = | SCOP = 1gpm | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} {{Infobox_gene}} '''Guanosine monophosphate synthetase''', ({{EnzExplorer|6.3.5.2}}) also known as '''GMPS''' is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.<ref name="entrez">{{cite web | title = Entrez Gene: GMPS guanine monophosphate synthetase| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=8833}}</ref>

In the de novo synthesis of purine nucleotides, IMP is the branch point metabolite at which point the pathway diverges to the synthesis of either guanine or adenine nucleotides. In the guanine nucleotide pathway, there are 2 enzymes involved in converting IMP to GMP, namely IMP dehydrogenase (IMPD1), which catalyzes the oxidation of IMP to XMP, and GMP synthetase, which catalyzes the amination of XMP to GMP.<ref name="entrez" />

==Enzymology==

In enzymology, a '''GMP synthetase (glutamine-hydrolysing)''' ({{EC number|6.3.5.2}}) is an enzyme that catalyzes the chemical reaction

:ATP + xanthosine 5'-phosphate + L-glutamine + H2O <math>\rightleftharpoons</math> AMP + diphosphate + GMP + L-glutamate

The 4 substrates of this enzyme are ATP, xanthosine 5'-phosphate, L-glutamine, and H2O, whereas its 4 products are AMP, diphosphate, GMP, and L-glutamate.

This enzyme belongs to the family of ligases, specifically those forming carbon-nitrogen bonds carbon-nitrogen ligases with glutamine as amido-N-donor. The systematic name of this enzyme class is '''xanthosine-5'-phosphate:L-glutamine amido-ligase (AMP-forming)'''.  This enzyme participates in purine metabolism and glutamate metabolism. At least one compound, Psicofuranin is known to inhibit this enzyme.

==Structural studies==

As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes {{PDB link|1GPM}}, {{PDB link|1WL8}}, {{PDB link|2A9V}}, {{PDB link|2D7J}}, and {{PDB link|2DPL}}.

== Role in metabolism ==

=== Purine metabolism === GMP synthase is the second step in the generation of GMP from IMP; the first step occurs when IMP dehydrogenase generates XMP, and then GMP synthetase is able to react with glutamine and ATP to generate GMP. IMP may also be generated into AMP by adenylosuccinate synthetase and then adenylosuccinate lyase.<ref name="Garrett_1998">{{Cite book| vauthors = Garrett RH |title=Biochemistry |date=1998|publisher=Harcourt College|isbn=0-03-044857-3|location=[Place of publication not identified]|oclc=947935503}}</ref>

=== Amino acid metabolism === GMP synthase is also involved in amino acid metabolism because it generates L-glutamate from L-glutamine.<ref name="Garrett_1998" />

== Organismal involvement == This enzyme is widely distributed and a number of crystal structures have been solved, including in ''Escherichia coli'', ''Pyrococcus Horikoshii'', ''Thermoplasma acidophil'', ''Homo sapiens'', ''Thermus thermophilus'' and ''Mycobacterium tuberculosis''. The most extensive structural studies have been done in E. coli.<ref name="Tesmer_1996">{{cite journal | vauthors = Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL | title = The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families | journal = Nature Structural Biology | volume = 3 | issue = 1 | pages = 74–86 | date = January 1996 | pmid = 8548458 | doi = 10.1038/nsb0196-74 | s2cid = 30864133 }}</ref>

== Structure and function == GMP synthase forms a tetramer in an open box shape, which is a dimer of dimers. The R interfaces are held together with a hydrophobic core and a beta sheet, while the P dimer interfaces do not have a hydrophobic core and are more variable than the R interfaces.<ref name="Tesmer_1996" /> This enzyme also binds several ligands, including phosphate, pyrophosphate, AMP, citrate and Magnesium.<ref>{{Cite web|title=Ligand/metal interactions: 1gpm|url=https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1gpm&template=ligands.html&l=1.1|access-date=2021-10-21|website=www.ebi.ac.uk}}</ref>

=== Class I Amidotransferase Domain === The amidotransferase domain is responsible for removal of the amide nitrogen from the glutamine substrate. The class I amidotransferase domain is made of the N terminal 206 residues of the enzyme, and consists of 12 beta strands and 5 alpha helices; the core of this domain is an open 7-stranded mixed beta sheet. Its catalytic triad includes Cys86, His181 and Glu183. His181 is a base and Glu183 is a Hydrogen bond acceptor from the Histidine imidazole ring. Cys86 is the catalytic residue and is conserved. It falls into a nucleophile elbow, where it is at the end of a beta strand and the beginning of an alpha helix, and has little flexibility in its phi and psi angles; thus, Gly84 and Gly88 are conserved and allow for the tight packing of amino acids surrounding the catalytic residue.<ref name="Tesmer_1996" />

=== Synthetase Domain: ATP Pyrophosphatase domain === The synthetase domain is responsible for the addition of the abstracted Nitrogen to the acceptor substrate. The ATP Pyrophosphatase domain consists of a beta sheet containing 5 parallel strands with several alpha helices on each side. The P loop is the nucleotide binding motif; residues 235-241 make up the P loop which specifically binds to pyrophosphate.<ref name="Tesmer_1996" />

The structure of this domain is what creates the specificity of this enzyme for ATP. The binding pocket forms hydrophobic interactions with the adenine ring, and the backbone of Val260 forms H bonds with multiple Nitrogens in the ring of AMP, which excludes substituents on the C2 purine ring. This creates extreme specificity for adenine and ATP binding.<ref name="Tesmer_1996" />

== References == {{reflist}}

== Further reading == {{refbegin | 2}}

* {{cite journal | vauthors = Page T, Bakay B, Nyhan WL | title = Human GMP synthetase | journal = The International Journal of Biochemistry | volume = 16 | issue = 1 | pages = 117–20 | year = 1984 | pmid = 6698284 | doi = 10.1016/0020-711X(84)90061-2 }} * {{cite journal | vauthors = Nakamura J, Straub K, Wu J, Lou L | title = The glutamine hydrolysis function of human GMP synthetase. Identification of an essential active site cysteine | journal = The Journal of Biological Chemistry | volume = 270 | issue = 40 | pages = 23450–5 | date = October 1995 | pmid = 7559506 | doi = 10.1074/jbc.270.40.23450 | doi-access = free }} * {{cite journal | vauthors = Nakamura J, Lou L | title = Biochemical characterization of human GMP synthetase | journal = The Journal of Biological Chemistry | volume = 270 | issue = 13 | pages = 7347–53 | date = March 1995 | pmid = 7706277 | doi = 10.1074/jbc.270.13.7347 | doi-access =free }} * {{cite journal | vauthors = Hirst M, Haliday E, Nakamura J, Lou L | title = Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA | journal = The Journal of Biological Chemistry | volume = 269 | issue = 38 | pages = 23830–7 | date = September 1994 | doi = 10.1016/S0021-9258(17)31590-9 | pmid = 8089153 | doi-access = free }} * {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }} * {{cite journal | vauthors = Fedorova L, Kost-Alimova M, Gizatullin RZ, Alimov A, Zabarovska VI, Szeles A, Protopopov AI, Vorobieva NV, Kashuba VI, Klein G, Zelenin AV, Sheer D, Zabarovsky ER | display-authors = 6 | title = Assignment and ordering of twenty-three unique NotI-linking clones containing expressed genes including the guanosine 5'-monophosphate synthetase gene to human chromosome 3 | journal = European Journal of Human Genetics | volume = 5 | issue = 2 | pages = 110–6 | year = 1997 | pmid = 9195163 | doi = 10.1159/000484744 }} * {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }} * {{cite journal | vauthors = Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rowley JD, Rappaport EF, Felix CA | title = t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene | journal = Blood | volume = 96 | issue = 13 | pages = 4360–2 | date = December 2000 | pmid = 11110714 | doi = 10.1182/blood.V96.13.4360 }} * {{cite journal | vauthors = Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, Eizirik DL, She JX, Wang CY | display-authors = 6 | title = Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress | journal = Biochemical and Biophysical Research Communications | volume = 337 | issue = 4 | pages = 1308–18 | date = December 2005 | pmid = 16236267 | doi = 10.1016/j.bbrc.2005.09.191 | bibcode = 2005BBRC..337.1308G }} * {{cite journal | vauthors = Abrams R, Bentley M | year = 1959 | title = Biosynthesis of nucleic acid purines. III. Guanosine 5'-phosphate formation from xanthosine 5'-phosphate and L-glutamine | journal = Arch. Biochem. Biophys. | volume = 79 | pages = 91–110 | doi = 10.1016/0003-9861(59)90383-2 }} * {{cite journal | vauthors = Lagerkvist U | title = Biosynthesis of guanosine 5'-phosphate. II. Amination of xanthosine 5'-phosphate by purified enzyme from pigeon liver | journal = The Journal of Biological Chemistry | volume = 233 | issue = 1 | pages = 143–9 | date = July 1958 | doi = 10.1016/S0021-9258(19)68044-0 | pmid = 13563458 | doi-access = free }} {{refend}}

== External links == * {{MeshName|GMP+synthetase}} * [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P49915 PDBe-KB] provides an overview of all the structure information available in the PDB for Human GMP synthase [glutamine-hydrolyzing]

{{DEFAULTSORT:GMP synthase (glutamine-hydrolysing)}} Category:EC 6.3.5 Category:Enzymes of known structure