Functional analysis of pyrimidine 5'-nucleotidase mutants causing nonspherocytic hemolytic anemia

Blood
Laurent R ChiarelliGiovanna Valentini

Abstract

Inherited pyrimidine 5'-nucleotidase type I (P5'N-1) deficiency is the third most common erythrocyte enzymopathy that causes hemolysis. Fourteen different mutations have been identified to date. We have investigated the molecular bases of the disease by studying the biochemical properties of the recombinant wild-type human enzyme and 4 variant proteins (D87V, L131P, N179S, and G230R) bearing missense mutations found in patients affected by nonspherocytic hemolytic anemia. P5'N-1 is a relatively stable protein and has essentially identical catalytic efficiency toward cytidine monophosphate (CMP) and uridine monophosphate (UMP). All investigated mutant proteins display impaired catalytic properties and/or reduced thermostability, providing a rationale for the pathological effects of the mutations. Despite the substantial changes in the kinetic and thermostability parameters, the enzyme activity detected in the red blood cells of patients homozygous for mutations L131P and G230R exhibits moderate alterations. This suggests that P5'N-1 deficiency is compensated, possibly by other nucleotidases or alternative pathways in nucleotide metabolism. Therefore, nucleotidase activity may not be considered a prognostic indicator in patients ...Continue Reading

References

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Citations

Sep 6, 2007·Journal of Structural and Functional Genomics·George N PhillipsSimon N Twigger
Apr 14, 2006·British Journal of Haematology·Alberto ZanellaGiovanna Valentini
Aug 29, 2012·Journal of Molecular Biology·Christina L GroboskyEduard Bitto
Jul 7, 2016·Proteomics. Clinical Applications·Benjamin A BarasaMonique Slijper
Aug 16, 2005·Trends in Molecular Medicine·Monika LöfflerH A Simmonds
Nov 24, 2005·Hematology·Josef T Prchal, Xylina T Gregg
May 5, 2006·The Journal of Biological Chemistry·Eduard BittoGeorge N Phillips

Related Concepts

Microangiopathic Hemolytic Anemia
Catalysis
Enzyme Activation
5'-NUCLEOTIDASE
Missense Mutation

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