ITPase-deficient mice show growth retardation and die before weaning

Behmanesh, Mehrdad; Sakumi, Kunihiko; Abolhassani, Nona; Toyokuni, Shinya; Oka, Shogo; Ohnishi, Yoshinori N.; Tsuchimoto, Daisuke; Nakabeppu, Yusaku

doi:10.1038/cdd.2009.53

Cited by 60 publications

(113 citation statements)

References 33 publications

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“…2, the genes with the greatest effect on hypoxanthine incorporation into DNA and RNA are located early (purA, guaB) in the metabolic pathways or later at the "pool cleansing" step prior to incorporation of nucleotides into nucleic acids (rdgB). The latter is consistent with the observation that loss of the mammalian rdgB homolog, ITPA, leads to increases in ITP in the nucleotide pool and incorporation of hypoxanthine into DNA and RNA in a knockout mouse model (32)(33)(34). That loss of purA or guaB would cause twofold to 10-fold increases of hypoxanthine in DNA and RNA is reasonable given the accumulation of IMP that could be presumed to occur with loss of the enzymes, with excess IMP becoming a substrate for kinases and ribonucleotide reductases in the metabolic network (Fig.…”

Section: Discussionsupporting

confidence: 76%

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Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

Pang

McFaline

Burgis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

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Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelated mechanisms, including hydrolysis, nitrosative chemistry, and deaminase enzymes. Here we present a fourth mechanism contributing to the burden of nucleobase deamination: incorporation of hypoxanthine and xanthine into DNA and RNA caused by defects in purine nucleotide metabolism. Using Escherichia coli and Saccharomyces cerevisiae with defined mutations in purine metabolism in conjunction with analytical methods for quantifying deaminated nucleobases in DNA and RNA, we observed large increases (up to 600-fold) in hypoxanthine in both DNA and RNA in cells unable to convert IMP to XMP or AMP (IMP dehydrogenase, guaB; adenylosuccinate synthetase, purA, and ADE12), and unable to remove dITP/ITP and dXTP/XTP from the nucleotide pool (dITP/XTP pyrophosphohydrolase, rdgB and HAM1). Conversely, modest changes in xanthine levels were observed in RNA (but not DNA) from E. coli lacking purA and rdgB and the enzyme converting XMP to GMP (GMP synthetase, guaA). These observations suggest that disturbances in purine metabolism caused by known genetic polymorphisms could increase the burden of mutagenic deaminated nucleobases in DNA and interfere with gene expression and RNA function, a situation possibly exacerbated by the nitrosative stress of concurrent inflammation. The results also suggest a mechanistic basis for the pathophysiology of human inborn errors of purine nucleotide metabolism.DNA and RNA damage | mass spectrometry | nucleobase deamination | purine metabolism | DNA repair T he chemical modification of nucleobases in DNA and RNA can arise from both physiological and adventitious mechanisms at all stages of nucleic acid metabolism. This is particularly true for deaminated versions of the nucleobases. As shown in Fig. 1 for purines, nucleobase deamination in DNA and RNA leads to the formation of 2′-deoxy-and ribonucleoside forms of hypoxanthine (2′-deoxyinosine, dI; inosine, Ino) from adenine, xanthine (2′-deoxyxanthosine, dX; xanthosine, Xao) and oxanine (2′-deoxyoxanosine, dO; oxanosine, Oxo) from guanine, and uracil (2′-deoxyuridine, dU; uridine, Urd) from cytosine (1). All of these products are miscoding and mutagenic in DNA (2-4) and can interfere with RNA editing (5) and the function of noncoding RNAs (6).There are three recognized mechanisms that contribute to nucleobase deamination in DNA and RNA, the simplest of which is hydrolysis (7). A second source of nucleobase deamination is associated with the nitrosative stress caused by increases in nitric oxide-derived nitrous anhydride during inflammation (1). A third mechanism is associated with deaminase enzymes acting on RNA and DNA, with activation-induced cytidine deaminase converting cytidine to uridine during immunoglobulin diversification in B lymphocytes an...

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Section: Discussionsupporting

confidence: 76%

“…RdgB homologs in S. cerevisiae, mice, and humans (ITPA) possess similar activities (29,31). Indeed, loss of ITPA in mice, though perinatal lethal, leads to increased incorporation of hypoxanthine in DNA and RNA (32,33), which is alleviated by expression of the IDP-hydrolyzing activity of nudix-type motif 16 protein (NUDT16) (34).…”

mentioning

confidence: 99%

Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

Pang

McFaline

Burgis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

105

View full text Add to dashboard Cite

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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%

“…Indeed, the HPLC assay showed an augmented intracellular level of ITP when porcine coronary arteries were made hypoxic. ITP is primarily derived from ATP deamination (3,27). Exogenous ATP potently elevates endogenous cIMP (9).…”

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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“…Indeed, knock-out of the ITPA gene in mice, leads to an accumulation of ITP in the nucleotide pool, which is associated with fetal death in utero (>50%) and multiple birth defects [170].…”

Section: Genetic Factors Affecting Thiopurine Metabolismmentioning

confidence: 99%

The pharmacogenetic basis of individual variation in thiopurine metabolism

Blaker

Arenas-Hernandez

Sanderson

2012

Personalized Medicine

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Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy.

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ITPase-deficient mice show growth retardation and die before weaning

Cited by 60 publications

References 33 publications

Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

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

The pharmacogenetic basis of individual variation in thiopurine metabolism

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