Summary: GMP synthase C terminal domain
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GMP synthase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
|GMP synthetase C terminal domain|
|SCOP2||1gpm / SCOPe / SUPFAM|
|, GMP synthase, guanine monophosphate synthase, GATD7, GMP synthase|
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.
- ATP + xanthosine 5'-phosphate + L-glutamine + H2O AMP + diphosphate + GMP + 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). Other names in common use include GMP synthetase (glutamine-hydrolysing), guanylate synthetase (glutamine-hydrolyzing), guanosine monophosphate synthetase (glutamine-hydrolyzing), xanthosine 5'-phosphate amidotransferase, and guanosine 5'-monophosphate synthetase. This enzyme participates in purine metabolism and glutamate metabolism. At least one compound, Psicofuranin is known to inhibit this enzyme.
Role in 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.
Amino Acid Metabolism
GMP synthase is also involved in amino acid metabolism because it generates L-glutamate from L-glutamine.
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.
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. This enzyme also binds several ligands, including phosphate, pyrophosphate, AMP, citrate and Magnesium.
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.
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.
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.
- Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL (January 1996). "The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families". Nature Structural Biology. 3 (1): 74â€“86. doi:10.1038/nsb0196-74. PMIDÂ 8548458. S2CIDÂ 30864133.
- GRCh38: Ensembl release 89: ENSG00000163655 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000027823 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Entrez Gene: GMPS guanine monphosphate synthetase".
- Garrett RH (1998). Biochemistry. [Place of publication not identified]: Harcourt College. ISBNÂ 0-03-044857-3. OCLCÂ 947935503.
- Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL (January 1996). "The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families". Nature Structural Biology. 3 (1): 74â€“86. doi:10.1038/nsb0196-74. PMIDÂ 8548458.
- "Ligand/metal interactions: 1gpm". www.ebi.ac.uk. Retrieved 2021-10-21.
- Page T, Bakay B, Nyhan WL (1984). "Human GMP synthetase". The International Journal of Biochemistry. 16 (1): 117â€“20. doi:10.1016/0020-711X(84)90061-2. PMIDÂ 6698284.
- Nakamura J, Straub K, Wu J, Lou L (October 1995). "The glutamine hydrolysis function of human GMP synthetase. Identification of an essential active site cysteine". The Journal of Biological Chemistry. 270 (40): 23450â€“5. doi:10.1074/jbc.270.40.23450. PMIDÂ 7559506.
- Nakamura J, Lou L (March 1995). "Biochemical characterization of human GMP synthetase". The Journal of Biological Chemistry. 270 (13): 7347â€“53. doi:10.1074/jbc.270.13.7347. PMIDÂ 7706277.
- Hirst M, Haliday E, Nakamura J, Lou L (September 1994). "Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA". The Journal of Biological Chemistry. 269 (38): 23830â€“7. PMIDÂ 8089153.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1â€“2): 171â€“4. doi:10.1016/0378-1119(94)90802-8. PMIDÂ 8125298.
- Fedorova L, Kost-Alimova M, Gizatullin RZ, Alimov A, Zabarovska VI, Szeles A, etÂ al. (1997). "Assignment and ordering of twenty-three unique NotI-linking clones containing expressed genes including the guanosine 5'-monophosphate synthetase gene to human chromosome 3". European Journal of Human Genetics. 5 (2): 110â€“6. doi:10.1159/000484744. PMIDÂ 9195163.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1â€“2): 149â€“56. doi:10.1016/S0378-1119(97)00411-3. PMIDÂ 9373149.
- Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rowley JD, Rappaport EF, Felix CA (December 2000). "t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene". Blood. 96 (13): 4360â€“2. doi:10.1182/blood.V96.13.4360. PMIDÂ 11110714.
- Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, etÂ al. (December 2005). "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochemical and Biophysical Research Communications. 337 (4): 1308â€“18. doi:10.1016/j.bbrc.2005.09.191. PMIDÂ 16236267.
- Abrams R, Bentley M (1959). "Biosynthesis of nucleic acid purines. III. Guanosine 5'-phosphate formation from xanthosine 5'-phosphate and L-glutamine". Arch. Biochem. Biophys. 79: 91â€“110. doi:10.1016/0003-9861(59)90383-2.
- Lagerkvist U (July 1958). "Biosynthesis of guanosine 5'-phosphate. II. Amination of xanthosine 5'-phosphate by purified enzyme from pigeon liver". The Journal of Biological Chemistry. 233 (1): 143â€“9. PMIDÂ 13563458.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
GMP synthase C terminal domain Provide feedback
GMP synthetase is a glutamine amidotransferase from the de novo purine biosynthetic pathway. This family is the C-terminal domain specific to the GMP synthases P49915 EC:188.8.131.52. In prokaryotes this domain mediates dimerisation. Eukaryotic GMP synthases are monomers. This domain in eukaryotes includes several large insertions that may form globular domains.
Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL; , Nat Struct Biol 1996;3:74-86.: The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families. PUBMED:8548458 EPMC:8548458
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001674
The amidotransferase family of enzymes utilises the ammonia derived from the hydrolysis of glutamine for a subsequent chemical reaction catalyzed by the same enzyme. The ammonia intermediate does not dissociate into solution during the chemical transformations [ PUBMED:10387030 ]. GMP synthetase is a glutamine amidotransferase from the de novo purine biosynthetic pathway. The C-terminal domain is specific to the GMP synthases EC . In prokaryotes this domain mediates dimerisation. Eukaryotic GMP synthases are monomers. This domain in eukaryotes includes several large insertions that may form globular domains [ PUBMED:8548458 ].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||GMP synthase (glutamine-hydrolyzing) activity (GO:0003922)|
|ATP binding (GO:0005524)|
|Biological process||GMP biosynthetic process (GO:0006177)|
|purine nucleotide biosynthetic process (GO:0006164)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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Key: available, not generated, — not available.
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|Seed source:||Pfam-B_1137 (release 3.0)|
|Author:||Finn RD , Bateman A , Griffiths-Jones SR|
|Number in seed:||197|
|Number in full:||10094|
|Average length of the domain:||91.80 aa|
|Average identity of full alignment:||54 %|
|Average coverage of the sequence by the domain:||17.63 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||25|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GMP_synt_C domain has been found. There are 37 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.