TY - JOUR

T1 - ITPA (inosine triphosphate pyrophosphatase)

T2 - From surveillance of nucleotide pools to human disease and pharmacogenetics

AU - Simone, Peter D.

AU - Pavlov, Youri I.

AU - Borgstahl, Gloria E.O.

N1 - Funding Information: This work was supported by the following research grants: UNMC Eppley Cancer Center seed grants (Y.I.P. and G.E.O.B.), NCI Eppley Cancer Center Support Grant P30CA036727 (G.E.O.B.), Department of Education GAANN grant P200A070554 (P.D.S.), National Center for Research Resources grant 5P20RR016469 and the National Institute for General Medical Science grant 8P20GM103427 (G.E.O.B. and CAB); and NCI grant CA129925 , by the Russian federal program “Innovation scientific personnel” State contracts 14.740.11.0916 and the Federal Grant-in-Aid Program «Human Capital for Science and Education in Innovative Russia» (Government Contract No. 8654) (Y.I.P.).

PY - 2013/10

Y1 - 2013/10

N2 - Cellular nucleotide pools are often contaminated by base analog nucleotides which interfere with a plethora of biological reactions, from DNA and RNA synthesis to cellular signaling. An evolutionarily conserved inosine triphosphate pyrophosphatase (ITPA) removes the non-canonical purine (d)NTPs inosine triphosphate and xanthosine triphosphate by hydrolyzing them into their monophosphate form and pyrophosphate. Mutations in the ITPA orthologs in model organisms lead to genetic instability and, in mice, to severe developmental anomalies. In humans there is genetic polymorphism in ITPA. One allele leads to a proline to threonine substitution at amino acid 32 and causes varying degrees of ITPA deficiency in tissues and plays a role in patients' response to drugs. Structural analysis of this mutant protein reveals that the protein is destabilized by the formation of a cavity in its hydrophobic core. The Pro32Thr allele is thought to cause the observed dominant negative effect because the resulting active enzyme monomer targets both homo- and heterodimers to degradation.

AB - Cellular nucleotide pools are often contaminated by base analog nucleotides which interfere with a plethora of biological reactions, from DNA and RNA synthesis to cellular signaling. An evolutionarily conserved inosine triphosphate pyrophosphatase (ITPA) removes the non-canonical purine (d)NTPs inosine triphosphate and xanthosine triphosphate by hydrolyzing them into their monophosphate form and pyrophosphate. Mutations in the ITPA orthologs in model organisms lead to genetic instability and, in mice, to severe developmental anomalies. In humans there is genetic polymorphism in ITPA. One allele leads to a proline to threonine substitution at amino acid 32 and causes varying degrees of ITPA deficiency in tissues and plays a role in patients' response to drugs. Structural analysis of this mutant protein reveals that the protein is destabilized by the formation of a cavity in its hydrophobic core. The Pro32Thr allele is thought to cause the observed dominant negative effect because the resulting active enzyme monomer targets both homo- and heterodimers to degradation.

KW - Base analogs

KW - Dominant negative

KW - DSB

KW - HAM1

KW - HAP

KW - HGPRT

KW - ITP

KW - ITPA

KW - ITPA gene polymorphism

KW - MEF

KW - Mercaptopurines

KW - Nucleotide pool

KW - NUDT16

KW - Pharmacogenetics

KW - Protein stability

KW - SSB

KW - TPMT

KW - XTP

UR - http://www.scopus.com/inward/record.url?scp=84887021703&partnerID=8YFLogxK

U2 - 10.1016/j.mrrev.2013.08.001

DO - 10.1016/j.mrrev.2013.08.001

M3 - Review article

AN - SCOPUS:84887021703

VL - 753

SP - 131

EP - 146

JO - Mutation Research - Reviews in Mutation Research

JF - Mutation Research - Reviews in Mutation Research

SN - 1383-5742

IS - 2

ER -