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Functional analysis of pyrimidine 5'-nucleotidase mutants causing nonspherocytic hemolytic anemia
- Source :
- Blood. 105(8)
- Publication Year :
- 2004
-
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 affected by the enzymopathy. (Blood. 2005;105:3340-3345)
- Subjects :
- Cytidine monophosphate
Hemolytic anemia
Anemia, Hemolytic
Hot Temperature
Nucleotidase activity
Genotype
Immunology
Mutation, Missense
Biology
medicine.disease_cause
Biochemistry
Catalysis
chemistry.chemical_compound
Nucleotidase
medicine
Uridine monophosphate
Humans
5'-Nucleotidase
chemistry.chemical_classification
Mutation
Cell Biology
Hematology
medicine.disease
Molecular biology
Hemolysis
Enzyme Activation
Enzyme
Phenotype
chemistry
Subjects
Details
- ISSN :
- 00064971
- Volume :
- 105
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....bc0ae4347a19cee36d69f9e2983caee9