4f95

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Template:STRUCTURE 4f95

Contents

Crystal structure of human inosine triphosphate pyrophosphatase P32T variant

Template:ABSTRACT PUBMED 23528839

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]

About this Structure

4f95 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • 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
  1. ↑ 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
  2. ↑ 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
  3. ↑ 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

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