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| | ==Crystal structure of human inosine triphosphate pyrophosphatase P32T variant== | | ==Crystal structure of human inosine triphosphate pyrophosphatase P32T variant== |
| - | <StructureSection load='4f95' size='340' side='right' caption='[[4f95]], [[Resolution|resolution]] 2.07Å' scene=''> | + | <StructureSection load='4f95' size='340' side='right'caption='[[4f95]], [[Resolution|resolution]] 2.07Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4f95]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F95 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F95 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4f95]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F95 FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2i5d|2i5d]], [[2car|2car]], [[2j4e|2j4e]]</td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4f95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f95 OCA], [https://pdbe.org/4f95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f95 RCSB], [https://www.ebi.ac.uk/pdbsum/4f95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f95 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">C20orf37, ITPA, ITPA (P32T MUTANT), My049, OK/SW-cl.9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nucleoside-triphosphate_diphosphatase Nucleoside-triphosphate diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.19 3.6.1.19] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4f95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f95 OCA], [http://pdbe.org/4f95 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f95 RCSB], [http://www.ebi.ac.uk/pdbsum/4f95 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f95 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ITPA_HUMAN ITPA_HUMAN]] Defects in ITPA are the cause of inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:[http://omim.org/entry/613850 613850]]. It is a common inherited trait characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes and also leukocytes and fibroblasts. The pathological consequences of ITPA deficiency, if any, are unknown. However, it might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Note=Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme.[:]<ref>PMID:12384777</ref> <ref>PMID:12436200</ref> | + | [https://www.uniprot.org/uniprot/ITPA_HUMAN ITPA_HUMAN] Defects in ITPA are the cause of inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:[https://omim.org/entry/613850 613850]. It is a common inherited trait characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes and also leukocytes and fibroblasts. The pathological consequences of ITPA deficiency, if any, are unknown. However, it might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Note=Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme.[:]<ref>PMID:12384777</ref> <ref>PMID:12436200</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ITPA_HUMAN ITPA_HUMAN]] Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions.<ref>PMID:17090528</ref> | + | [https://www.uniprot.org/uniprot/ITPA_HUMAN ITPA_HUMAN] Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions.<ref>PMID:17090528</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Nucleoside-triphosphate diphosphatase]] | + | [[Category: Large Structures]] |
| - | [[Category: Borgstahl, G E.O]] | + | [[Category: Borgstahl GEO]] |
| - | [[Category: Pavlov, Y I]] | + | [[Category: Pavlov YI]] |
| - | [[Category: Simone, P D]] | + | [[Category: Simone PD]] |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Disease
ITPA_HUMAN Defects in ITPA are the cause of inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:613850. It is a common inherited trait characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes and also leukocytes and fibroblasts. The pathological consequences of ITPA deficiency, if any, are unknown. However, it might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Note=Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme.[:][1] [2]
Function
ITPA_HUMAN Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions.[3]
Publication Abstract from PubMed
Inosine triphosphate pyrophosphatase (ITPA), a key enzyme involved in maintaining the purity of cellular nucleoside triphosphate pools, specifically recognizes inosine triphosphate and xanthosine triphosphate (including the deoxyribose forms) and detoxifies them by catalyzing the hydrolysis of a phosphoanhydride bond, releasing pyrophosphate. This prevents their inappropriate use as substrates in enzymatic reactions utilizing (d)ATP or (d)GTP. A human genetic polymorphism leads to the substitution of Thr for Pro32 (P32T) and causes ITPA deficiency in erythrocytes, with heterozygotes having on average 22.5% residual activity, and homozygotes having undetectable activity. This polymorphism has been implicated in modulating patients' response to mercaptopurines and ribavirin. Human fibroblasts containing this variant have elevated genomic instability upon treatment with base analogs. We find that the wild-type and P32T forms are dimeric in solution and in the crystal structure. This abolishes the previous speculation that the P32T change disrupts dimerization as a mechanism of inactivation. The only difference in structure from the wild-type protein is that the area surrounding Thr32 is disrupted. Phe31 is flipped from the hydrophobic core out into the solvent, leaving a hole in the hydrophobic core of the protein which likely accounts for the reduced thermal stability of P32T ITPA and ultimately leads to its susceptibility to degradation in human cells. Circular dichroism and thermal denaturation studies confirm these structural results. We propose that the dimer of P32T variant subunit with wild-type subunit is degraded in cells similarly to the P32T homodimer explaining the level of loss of ITPA activity in heterozygotes.
The human ITPA polymorphic variant P32T is destabilized by the unpacking of the hydrophobic core.,Simone PD, Struble LR, Kellezi A, Brown CA, Grabow CE, Khutsishvili I, Marky LA, Pavlov YI, Borgstahl GE J Struct Biol. 2013 Mar 23. pii: S1047-8477(13)00078-6. doi:, 10.1016/j.jsb.2013.03.007. PMID:23528839[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, Thein SL, Ansari A, Sanderson J, De Abreu RA, Simmonds HA, Duley JA. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet. 2002 Oct;111(4-5):360-7. Epub 2002 Aug 15. PMID:12384777 doi:10.1007/s00439-002-0798-z
- ↑ Cao H, Hegele RA. DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. J Hum Genet. 2002;47(11):620-2. PMID:12436200 doi:10.1007/s100380200095
- ↑ Burgis NE, Cunningham RP. Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase. J Biol Chem. 2007 Feb 9;282(6):3531-8. Epub 2006 Nov 6. PMID:17090528 doi:M608708200
- ↑ Simone PD, Struble LR, Kellezi A, Brown CA, Grabow CE, Khutsishvili I, Marky LA, Pavlov YI, Borgstahl GE. The human ITPA polymorphic variant P32T is destabilized by the unpacking of the hydrophobic core. J Struct Biol. 2013 Mar 23. pii: S1047-8477(13)00078-6. doi:, 10.1016/j.jsb.2013.03.007. PMID:23528839 doi:10.1016/j.jsb.2013.03.007
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