Possible implication of an inosinetriphosphate metabolic error and glutamic acid decarboxylase in paranoid schizophrenia

Vanderheiden, Bernardo S.

doi:10.1016/0006-2944(79)90051-6

Cited by 9 publications

(7 citation statements)

References 19 publications

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“…In ITPase-deficient popula- tions, there is an obvious elevation of ITP concentration in erythrocytes and other cells, showing that hITPase may be the major enzyme responsible for regulating the ITP concentration in human cells. Although no clinical abnormalities have been reported to be associated with complete hITPase deficiency, one study has reported a significant reduction in tissue ITPase activity in paranoid schizophrenics (56.3 Ϯ 5.5 mol/h/g of Hb) compared with normal controls (94.1 Ϯ 5.3 mol/h/g of Hb) (p Ͻ 0.0002), and it has been suggested that the resulting elevated ITP may inhibit the activity of glutamate decarboxylase, the enzyme responsible for generating the neurotransmitter ␥-aminobutyric acid (27,28).…”

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

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“…Several examples of this have been found. For example, the enzyme l -glutamic acid decarboxylase, involved in the synthesis of the neurotransmitter γ-aminobutyric acid, from rat brain is inhibited by ITP [70]. Rabbit psoas muscle fibers did not contract well and had disordered striations in the presence of ITP.…”

Section: Problems Arising From Non-canonical Nucleotidesmentioning

confidence: 99%

“…As mentioned in section 4, ITP was shown to inhibit rat brain l -glutamic acid decarboxylase. Thus, ITPA deficiency could lead to ITP build up in the brain, which could inhibit synthesis of the neurotransmitter γ-aminobutyric acid, possibly producing neurological symptoms [70]. …”

Section: Itpa Deficiency In Humansmentioning

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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“…Genetic knock-out (Itpa-/-) mice present abnormal features of growth retardation and cardiac myofiber disarray and die within 2 weeks after birth, likely because of the accumulation of ITP in the nucleotide pool found in erythrocytes [51] . Some reports have associated ITPA variants to human diseases, such as psychiatric disorders, encephalopathy, young-onset tuberculosis and infertility [49,[52][53][54] . The human ITPA gene carries several polymorphisms associated with a reduction of enzymatic activity among which ITPA SNPs rs1127354 and rs7270101.…”

Section: Itpamentioning

confidence: 99%

Pharmacogenetics of thiopurines

Franca¹

2019

CDR

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Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes. Nevertheless, daily oral thiopurines remain the backbone maintenance or continuation therapy. Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available. Other genes of interest, such as ITPA and PACSIN2 , have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols. In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.

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Possible implication of an inosinetriphosphate metabolic error and glutamic acid decarboxylase in paranoid schizophrenia

Cited by 9 publications

References 19 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

Pharmacogenetics of thiopurines

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