Functionally nonequivalent interactions of guanosine 5′-triphosphate, inosine 5′-triphosphate, and xanthosine 5′-triphosphate with the retinal G-protein, transducin, and with Gi-proteins in HL-60 leukemia cell membranes

Klinker, Jan F.; Seifert, Roland

doi:10.1016/s0006-2952(97)00205-0

Cited by 18 publications

(18 citation statements)

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“…Additionally, ITP appears to be a substrate for the cartilage pyrophosphorylase associated with articular calcium crystal deposition (43) and a substrate for receptor/G proteins to activate effector systems (44,45).…”

Section: Discussionmentioning

confidence: 99%

Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene

Lin

McLennan

Kong

et al. 2001

Journal of Biological Chemistry

129

156

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ITP and dITP exist in all cells. dITP is potentially mutagenic, and the levels of these nucleotides are controlled by inosine triphosphate pyrophosphatase (EC 3.6.1.19). Here we report the cloning, expression, and characterization of a 21.5-kDa human inosine triphosphate pyrophosphatase (hITPase), an enzyme whose activity has been reported in many animal tissues and studied in populations but whose protein sequence has not been determined before. At the optimal pH of 10.0, recombinant hITPase hydrolyzed ITP, dITP, and xanthosine 5-triphosphate to their respective monophosphates whereas activity with other nucleoside triphosphates was low. K m values for ITP, dITP, and xanthosine 5-triphosphate were 0.51, 0.31, and 0.57 mM, respectively, and k cat values were 580, 360, and 640 s ؊1 , respectively. A divalent cation was absolutely required for activity. The gene encoding the hITPase cDNA sequence was localized by radiation hybrid mapping to chromosome 20p in the interval D20S113-D20S97, the same interval in which the ITPA inosine triphosphatase gene was previously localized. A BLAST search revealed the existence of many similar sequences in organisms ranging from bacteria to mammals. The function of this ubiquitous protein family is proposed to be the elimination of minor potentially mutagenic or clastogenic purine nucleoside triphosphates from the cell.

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Section: Discussionmentioning

confidence: 99%

Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene

Lin

McLennan

Kong

et al. 2001

Journal of Biological Chemistry

129

156

View full text Add to dashboard Cite

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“…Lastly, ITP and XTP are both able to activate G-proteins involved in signal transduction. Again, no direct negative effects have been reported, but given the different binding affinities and rates of hydrolysis of GTP, XTP, and ITP, it is possible that these NTPs could function as differential signal amplifiers [74]. …”

Section: Problems Arising From Non-canonical Nucleotidesmentioning

confidence: 99%

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

Simone

Pavlov

Borgstahl

2013

Mutation Research/Reviews in Mutation Research

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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.

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“…Additionally, hypoxanthine nucleotides bind to other prototypical GTP-utilizing/GTP-binding proteins such as sGC and G-proteins with lower affinity than the corresponding guanine nucleotides (Fig. 4) (39,43,60,64). Considering that MANT-GTP␥S is a potent competitive AC inhibitor (K i for S49 cyc Ϫ membrane AC, 53 nM) (37), we predicted MANT-ITP␥S to be a potent AC inhibitor with reduced affinity for sGC and G-proteins relative to MANT-GTP␥S.…”

Section: Potent and Selective Ac Inhibition By Mant-itp␥s Relative Tomentioning

confidence: 99%

Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides

Gille

Lushington

Mou

et al. 2004

Journal of Biological Chemistry

Self Cite

215

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ACs 1 catalyze the conversion of ATP into the second messenger cAMP, PP i being the second product of the cyclase reaction. Mammals express nine membranous ACs (ACs 1-9) (1, 2) and a sAC that is predominantly expressed in testis (3). Bacillus anthracis and Bacillus pertussis produce the AC toxins EF and ACT, respectively, that are activated by Ca 2ϩ /calmodulin and act through excessive cAMP accumulation in host cells (4,5). sGC is structurally related to ACs 1-9 in the catalytic site and is activated by [6][7][8]. sGC catalyzes the formation of the second messenger cGMP from GTP. ACs 1-9 contain a tandem repeat structure with two transmembrane domains and two cytosolic domains (1, 2). The cytosolic domains are referred to as C1 and C2, respectively. Together, C1 and C2 form the catalytic site of AC. C1 and C2 also contain the regulatory sites for the stimulatory G-protein, G␣ s , for the inhibitory G-protein, G␣ i , and for the diterpene, forskolin. Catalytic activity of all AC isoforms depends on the presence of divalent cations (Mg 2ϩ or Mn 2ϩ ). Membranous ACs possess two Me 2ϩ -binding sites (9 -11). When mixed together, purified C1 and C2 form a functional AC that is efficiently activated by forskolin and G␣ s -GTP␥S (12, 13).AC isoforms differ from each other in their regulation (1, 2). ACs 1-9 are all activated by G␣ s , whereas sAC is activated by HCO 3 Ϫ (14). Forskolin activates ACs 1-8 but not AC9 or sAC. G␣ i inhibits ACs 1, 5, and 6. G-protein ␤␥ subunits exhibit stimulatory or inhibitory effects on AC isoforms. Ca 2ϩ /calmodulin stimulates ACs 1, 3, and 8. In addition, Mg 2ϩ and Mn 2ϩ show differential stimulatory effects on AC isoforms (15). More-

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Functionally nonequivalent interactions of guanosine 5′-triphosphate, inosine 5′-triphosphate, and xanthosine 5′-triphosphate with the retinal G-protein, transducin, and with Gi-proteins in HL-60 leukemia cell membranes

Cited by 18 publications

References 50 publications

Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene

Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene

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

Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides

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