Factors affecting inosinate synthesis and inosine triphosphate accumulation in human erythrocytes

Henderson, J. Frank; Zombor, George; Fraser, Joyce H.; McCoy, Ernest E.; Verhoef, Vernon; Morris, Allan J.

doi:10.1139/o77-049

Cited by 11 publications

(2 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They also suggested that the following two phosphorylation steps are performed by nucleoside monophosphate kinase and NDP kinase with ATP serving as the phosphate donor. Next researchers found that ITP could be synthesized from hypoxanthine [31–33] favoring the second theory for the generation of IMP. All of these studies focused on erythrocytes.…”

Section: Origins Of Non-canonical Nucleotidesmentioning

confidence: 99%

See 1 more Smart Citation

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

Simone

Pavlov

Borgstahl

2013

Mutation Research/Reviews in Mutation Research

View full text Add to dashboard Cite

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.

show abstract

Section: Origins Of Non-canonical Nucleotidesmentioning

confidence: 99%

“…3, which could then be phosphorylated to ADP and ATP, which in turn could be deaminated to IDP and ITP. However, erythrocytes lack adenylosuccinate synthetase and thus cannot form AMP from IMP [33]. Nonetheless, this pathway to ITP is a possibility for the other cell types examined.…”

Section: Origins Of 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

View full text Add to dashboard Cite

show abstract

Inosine di‐ and triphosphate synthesis in erythrocytes and cell extracts

Vanderheiden

1979

Journal Cellular Physiology

View full text Add to dashboard Cite

The ability to synthesize inosinetriphosphate was demonstrated in blood cells as well as in a variety of tissue extracts in spite of the presence of ITP pyrophohydrolase. At the expense of having sub-optimal conditions, an assay system was selected that completely repressed the hydrolyzing enzyme, thus permitting the accumulation of ITP. In an attempt to define the biosynthetic pathway of ITP, and since guanylate kinase has been implicated in the formation of ITP, the rate of synthesis of ITP and GTP in cell extracts was compared. The comparison of the specific activities of the [14C]-labeled hypoxanthine and guanine moieties of the inosine and guanosine phosphates formed during incubation with [8-14C]-inosine and [8-14C]-guanosine respectively, revealed striking differences in the relative rates of isotope incorporation. Tentative mechanisms are proposed to explain these differences. The data obtained thus far does not discard the possibility that ITP may be formed by stepwise phosphorylation and (or) by direct pyrophosphorylation of IMP.

show abstract