GMP synthase

GMP synthase (glutamine-hydrolysing)
GMP synthetase, human
Identifiers
EC no.	6.3.5.2
CAS no.	37318-71-1
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
Search PMC articles PubMed articles NCBI proteins

GMP synthetase C terminal domain
escherichia coli gmp synthetase complexed with amp and pyrophosphate.[1]
Identifiers
Symbol	GMP_synt_C
Pfam	PF00958
InterPro	IPR001674
PROSITE	PDOC00405
SCOP2	1gpm / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

GMPS
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2VPI, 2VXO
Identifiers
Aliases	GMPS, GMP synthase, guanine monophosphate synthase, GATD7, GMP synthase
External IDs	OMIM: 600358; MGI: 2448526; HomoloGene: 68367; GeneCards: GMPS; OMA:GMPS - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[2] Band 3q25.31 Start 155,870,650 bp[2] End 155,944,020 bp[2]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[3] Band 3|3 E1 Start 63,883,527 bp[3] End 63,930,000 bp[3]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left testis right testis ventricular zone ganglionic eminence stromal cell of endometrium Achilles tendon islet of Langerhans smooth muscle tissue body of pancreas epithelium of colon Top expressed in otic vesicle hand seminiferous tubule mandibular prominence maxillary prominence primitive streak abdominal wall Rostral migratory stream mammillary body dorsomedial hypothalamic nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding ligase activity pyrophosphatase activity ATP binding GMP synthase (glutamine-hydrolyzing) activity GMP synthase activity Cellular component cytoplasm cytosol Biological process purine nucleotide biosynthetic process glutamine metabolic process purine nucleobase biosynthetic process purine ribonucleoside monophosphate biosynthetic process GMP biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8833 229363 Ensembl ENSG00000163655 ENSMUSG00000027823 UniProt P49915 Q3THK7 RefSeq (mRNA) NM_003875 NM_001033300 RefSeq (protein) NP_003866 NP_001028472 Location (UCSC) Chr 3: 155.87 – 155.94 Mb Chr 3: 63.88 – 63.93 Mb PubMed search [4] [5]
Wikidata
View/Edit Human View/Edit Mouse

Guanosine monophosphate synthetase, (EC 6.3.5.2) also known as GMPS is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.^[6]

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.^[6]

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

ATP + xanthosine 5'-phosphate + L-glutamine + H₂O ${\displaystyle \rightleftharpoons }$ 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.

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

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.^[7]

GMP synthase is also involved in amino acid metabolism because it generates L-glutamate from L-glutamine.^[7]

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.^[1]

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.^[1] This enzyme also binds several ligands, including phosphate, pyrophosphate, AMP, citrate and Magnesium.^[8]

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.^[1]

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.^[1]

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.^[1]

• GMP+synthetase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• PDBe-KB provides an overview of all the structure information available in the PDB for Human GMP synthase [glutamine-hydrolyzing]