ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

Simone, Peter D.; Pavlov, Youri I.; Borgstahl, Gloria E. O.

doi:10.1016/j.mrrev.2013.08.001

Cited by 56 publications

(64 citation statements)

References 130 publications

(197 reference statements)

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“…Under normal conditions, ITP is largely degraded by ITPase, and the intracellular level of ITP is rather low. When the enzyme is inhibited or defective, the ITP level is increased (3,29). Therefore, if hypoxia suppresses the activity of ITPase, sufficient ITP could accumulate for sGC to synthesize cIMP (2).…”

Section: Discussionmentioning

confidence: 99%

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Chen

Zhang

Lei

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries. Am J Physiol Heart Circ Physiol 307: H328 -H336, 2014. First published June 6, 2014; doi:10.1152/ajpheart.00132.2014cGMP is considered the only mediator synthesized by soluble guanylyl cyclase (sGC) in response to nitric oxide (NO). However, purified sGC can synthesize several other cyclic nucleotides, including inosine 3=,5=-cyclic monophosphate (cIMP). The present study was designed to determine the role of cIMP in hypoxic contractions of isolated porcine coronary arteries. Vascular responses were examined by measuring isometric tension. Cyclic nucleotides were assayed by HPLC tandem mass spectroscopy. Rho kinase (ROCK) activity was determined by measuring the phosphorylation of myosin phosphatase target subunit 1 using Western blot analysis and an ELISA kit. The level of cIMP, but not that of cGMP, was elevated by hypoxia in arteries with, but not in those without, endothelium [except if treated with diethylenetriamine (DETA) NONOate]; the increases in cIMP were inhibited by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ). Hypoxia (PO2: 25-30 mmHg) augmented contractions of arteries with and without endothelium if treated with DETA NONOate; these hypoxic contractions were blocked by ODQ. In arteries without endothelium, hypoxic augmentation of contraction was also obtained with exogenous cIMP. In arteries with endothelium, hypoxic augmentation of contraction was further enhanced by inosine 5=-triphosphate, the precursor for cIMP. The augmentation of contraction caused by hypoxia or cIMP was accompanied by increased phosphorylation of myosin phosphatase target subunit 1 at Thr 853 , which was prevented by the ROCK inhibitor Y-27632. ROCK activity in the supernatant of isolated arteries was stimulated by cIMP in a concentration-dependent fashion. These results demonstrate that cIMP synthesized by sGC is the likely mediator of hypoxic augmentation of coronary vasoconstriction, in part by activating ROCK. soluble guanylyl cyclase; inosine 3=,5=-cyclic monophosphate; hypoxic vasoconstriction; endothelium A PREVIOUS STUDY reported that acute hypoxia caused a rapid further increase in tension of contracted canine saphenous veins (31). Subsequent findings demonstrated that such a phenomenon, termed hypoxic augmentation of vasoconstriction (5, 15), occurs in a number of blood vessel types (5,7,8,15,21,23,25,26) contracted with norepinephrine (7, 8), phenylephrine (23), PGF 2␣ (15,25), and the TP receptor agonist U-46619 (21), indicating that it is not unique for a specific vasoconstrictor. It occurs in isolated coronary arteries with but not without endothelium (5,15,25,26). The phenomenon is not affected by bosentan, a blocker of endothelin receptors (5), but is prevented by inhibitors of nitric oxide (NO) synthase (5,15,25). Hypoxic augmentation also occurs in arteries without endothelium treated with an exogenous NO donor (5) However, hypoxic augmentation is not accompanied by changes in the intracellular leve...

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Section: Discussionmentioning

confidence: 99%

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Chen

Zhang

Lei

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Cells express enzymes counteracting such threats, for example inosine triphosphate pyrophosphatase (ITPA in mammalian cells, RdgB in E. coli) that hydrolyses dITP to its monophosphate form. Mutations in the ITPA orthologs in model organisms lead to genetic instability and, in mice, to severe developmental abnormalities [50]. It has been shown that Itpa À/À mice accumulates inosine in DNA and RNA [51 ,52].…”

Section: Inosine and Association With Pathology And Diseasementioning

confidence: 99%

Inosine in DNA and RNA

Alseth¹,

Dalhus²,

Bjørås³

2014

Current Opinion in Genetics & Development

125

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Deamination of the nucleobases in DNA and RNA is a result of spontaneous hydrolysis, endogenous or environmental factors as well as deaminase enzymes. Adenosine is deaminated to inosine which is miscoding and preferentially base pairs with cytosine. In the case of DNA, this is a premutagenic event that is counteracted by DNA repair enzymes specifically engaged in recognition and removal of inosine. However, in RNA, inosine is an essential modification introduced by specialized enzymes in a highly regulated manner to generate transcriptome diversity. Defect editing is seen in various human disease including cancer, viral infections and neurological and psychiatric disorders. Enzymes catalyzing the deaminase reaction are well characterized and recently an unexpected function of Endonuclease V in RNA processing was revealed. Whereas bacterial Endonuclease V enzymes are classified as DNA repair enzymes, it appears that the mammalian enzymes are involved in processing of inosine in RNA. This yields an interesting yet unexplored, link between DNA and RNA processing. Further work is needed to gain understanding of the impact of inosine in DNA and RNA under normal physiology and disease progression.

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“…U/CBSVs belong to the Ipomovirus genus of the Potyviridae family; both viral species share several unusual genome features in that they encode a P1 protein, lack a HC‐Pro protein, and encode Maf/Ham1‐like proteins (Mbanzibwa et al , ). Maf/Ham1 proteins belong to the inosine triphosphate (ITP) pyrophosphohydrolase (ITPase) protein family, which in prokaryotes, eukaryotes, and archaea function to specifically hydrolyse non‐canonical, mutagenic nucleotide triphosphates (NTPs) and thereby reduce mutation rates (Simone et al , ; Waisertreiger et al , ; Zamzami et al , ). The non‐canonical NTPs xanthine and inosine triphosphate (XTP/ITP) are formed as by‐products of purine NTP biosynthesis or through oxidative deamination of canonical purine NTPs (Simone et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…Maf/Ham1 proteins belong to the inosine triphosphate (ITP) pyrophosphohydrolase (ITPase) protein family, which in prokaryotes, eukaryotes, and archaea function to specifically hydrolyse non‐canonical, mutagenic nucleotide triphosphates (NTPs) and thereby reduce mutation rates (Simone et al , ; Waisertreiger et al , ; Zamzami et al , ). The non‐canonical NTPs xanthine and inosine triphosphate (XTP/ITP) are formed as by‐products of purine NTP biosynthesis or through oxidative deamination of canonical purine NTPs (Simone et al , ). If incorporated into nucleic acid, XTP and ITP can cause deleterious mispairing mutations, nucleic acid strand breaks, and recombinations (Budke and Kuzminov, ; Burgis et al , ; Simone et al , ).…”

Section: Introductionmentioning

confidence: 99%

Cassava brown streak virus Ham1 protein hydrolyses mutagenic nucleotides and is a necrosis determinant

Tomlinson

Pablo‐Rodriguez

Bunawan

et al. 2019

Molecular Plant Pathology

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Summary Cassava brown streak disease (CBSD) is a leading cause of cassava losses in East and Central Africa, and is currently having a severe impact on food security. The disease is caused by two viruses within the Potyviridae family: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV), which both encode atypical Ham1 proteins with highly conserved inosine triphosphate (ITP) pyrophosphohydrolase (ITPase) domains. ITPase proteins are widely encoded by plant, animal, and archaea. They selectively hydrolyse mutagenic nucleotide triphosphates to prevent their incorporation into nucleic acid and thereby function to reduce mutation rates. It has previously been hypothesized that U/CBSVs encode Ham1 proteins with ITPase activity to reduce viral mutation rates during infection. In this study, we investigate the potential roles of U/CBSV Ham1 proteins. We show that both CBSV and UCBSV Ham1 proteins have ITPase activities through in vitro enzyme assays. Deep‐sequencing experiments found no evidence of the U/CBSV Ham1 proteins providing mutagenic protection during infections of Nicotiana hosts. Manipulations of the CBSV_Tanza infectious clone were performed, including a Ham1 deletion, ITPase point mutations, and UCBSV Ham1 chimera. Unlike severely necrotic wild‐type CBSV_Tanza infections, infections of Nicotiana benthamiana with the manipulated CBSV infectious clones do not develop necrosis, indicating that that the CBSV Ham1 is a necrosis determinant. We propose that the presence of U/CBSV Ham1 proteins with highly conserved ITPase motifs indicates that they serve highly selectable functions during infections of cassava and may represent a euphorbia host adaptation that could be targeted in antiviral strategies.

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ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

Cited by 56 publications

References 130 publications

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Inosine in DNA and RNA

Cassava brown streak virus Ham1 protein hydrolyses mutagenic nucleotides and is a necrosis determinant

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