Pablo Pérez de la Ossa

IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcino, Catalonia, Spain

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Publications (8)27.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recently, we reported a new mutation of phosphoglycerate kinase (PGK), called PGK-Barcelona, which causes chronic hemolytic anemia associated with progressive neurological impairment. We found a 140T→A substitution that produces an Ile46Asn change located at the N-domain of the enzyme and we suggested that the decrease of the PGK activity is probably related to a loss of enzyme stability. In this paper, by analyzing whole hemolysates and cloned enzymes, we show that both enzymes possess similar kinetic properties (although some differences are observed in the Km values) and the same electrophoretic mobility. However, PGK-Barcelona has higher thermal instability. Therefore, we confirm that the decrease of the red blood cell (RBC) PGK activity caused by the PGK-Barcelona mutation is more closely related to a loss of enzyme stability than to a decrease of enzyme catalytic function. Furthermore, we have measured the levels of glycolytic metabolites and adenine nucleotides in the RBC from controls and from the patient. The increase of 2,3-bisphosphoglycerate and the decrease of ATP RBC levels are the only detected metabolic changes that could cause hemolytic anemia.
    Blood Cells Molecules and Diseases 01/2011; 46(3):206-11. · 2.26 Impact Factor
  • Fernando Climent, Feliu Roset, Ada Repiso, Pablo Pérez de la Ossa
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    ABSTRACT: Glycolysis is one of the principle pathways of ATP generation in cells and is present in all cell tissues; in erythrocytes, glycolysis is the only pathway for ATP synthesis since mature red cells lack the internal structures necessary to produce the energy vital for life. Red cell deficiencies have been detected in all erythrocyte glycolytic pathways, although their frequencies differ owing to diverse causes, such as the affected enzyme and severity of clinical manifestations. The number of enzyme deficiencies known is endless. The most frequent glycolysis abnormality is pyruvate kinase deficiency, since around 500 cases are known, the first of which was reported in 1961. However, only approximately 200 cases were due to mutations. In contrast, only one case of phosphoglycerate mutase BB type mutation, described in 2003, has been detected. Most mutations are located in the coding sequences of genes, while others, missense, deletions, insertions, splice defects, premature stop codons and promoter mutations, are also frequent. Understanding of the crystal structure of enzymes permits molecular modelling studies which, in turn, reveal how mutations can affect enzyme structure and function.
    Cardiovascular & hematological disorders drug targets. 07/2009; 9(2):95-106.
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    ABSTRACT: Different molecules have been studied as biochemical markers in heart transplantation. However, their utility is under discussion as results in human and animal models are controversial. In this work, lactate dehydrogenase (LDH), creatine kinase (CK) and cardiac troponin I (TnI) were studied as serologic markers of acute rejection after heterotopical heart transplantation in rats. In predictable rejection experiments, animals were divided into three groups: nonoperated (Lewis rats), control group (Lewis-Lewis isografts) and rejection group (Brown Norway-Lewis allografts). Nonpredictable rejection experiments were performed using nonconsanguineous Sprague-Dawley allografts. In predictable rejection experiments, LDH activity was similar between control and rejection groups. TnI values were heterogeneous in control and rejection groups. In contrast, the rejection group showed CK activity increased 4.5-fold compared with the control group. In addition to these predictable studies, we also presented novel nonpredictable experiments in which rats were divided into groups based on low and high CK activity. Histologic studies in these rats showed that none of those with low CK activity presented rejection signs, while all animals with high CK levels showed grade 2R rejection. These results suggest that CK might be an excellent marker for prediction of rejection in heart transplantation.
    Transplant International 03/2007; 20(2):184-9. · 3.16 Impact Factor
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    ABSTRACT: Humans with heterozygous loss-of-function mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene develop beta-cell-deficient diabetes (maturity-onset diabetes of the young type 3), indicating that HNF1alpha gene dosage is critical in beta-cells. However, whether increased HNF1alpha expression might be beneficial or deleterious for beta-cells is unknown. Furthermore, although it is clear that HNF1alpha is required for beta-cell function, it is not known whether this role is cell autonomous or whether there is a restricted developmental time frame for HNF1alpha to elicit gene activation in beta-cells. To address this, we generated a tetracycline-inducible mouse model that transcribes HNF1alpha selectively in beta-cells in either wild-type or Hnf1alpha-null backgrounds. Short-term induction of HNF1alpha in islets from adult Hnf1alpha(-/-) mice that did not express HNF1alpha throughout development resulted in the activation of target genes, indicating that HNF1alpha has beta-cell-autonomous functions that can be rescued postnatally. However, transgenic induction throughout development, which inevitably resulted in supraphysiological levels of HNF1alpha, strikingly caused a severe reduction of cellular proliferation, increased apoptosis, and consequently beta-cell depletion and diabetes. Thus, HNF1alpha is sensitive to both reduced and excessive concentrations in beta-cells. This finding illustrates the paramount importance of using the correct concentration of a beta-cell transcription factor in both gene therapy and artificial differentiation strategies.
    Diabetes 09/2006; 55(8):2202-11. · 7.90 Impact Factor
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    ABSTRACT: We report two previously undescribed mutations of the phosphoglycerate kinase gene (PGK1) leading to enzyme deficiency. In both cases, the patients were of Spanish origin and they exhibited a severe life-long chronic haemolytic anaemia associated with progressive neurological impairment. Sequence analysis of the first patient's entire PGK1 gene found a novel missense mutation (140T > A). This mutation caused an amino acid change of Ile to Asn at 46th position from the NH(2)-terminal serine residue (Ile46Asn), which has been called PGK-Barcelona based on the place of origin of the patient. In the second patient, a G to A transversion was discovered at nucleotide 958 (958G > A). This caused a Ser319Asn amino acid substitution. Since this mutation had not been previously described, the provisional name of PGK-Murcia was given to this deficient enzyme. The crystal structure of porcine PGK was used as a molecular model to investigate how these mutations may affect enzyme structure and function. In both cases, the mutations did not modify any of the PGK binding sites for ATP or 3PG, so their consequence is related to a loss of enzyme stability rather than a decrease of enzyme catalytic function.
    British Journal of Haematology 03/2006; 132(4):523-9. · 4.94 Impact Factor
  • E Bañón Maneus, J L Pomar-Moya, F Climent, P Pérez de la Ossa
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    ABSTRACT: Metabolic alterations have been characterized in various heart diseases. However, no data are available concerning metabolic changes during acute rejection episodes. Heterotopic heart transplantations in rats were done using Lewis rats as donors and recipients as a control group. The rejection group included Brown-Norway rat donors to Lewis rat recipients. Nonoperated hearts were also studied. Enzyme activities were determined for phosphofructokinase, pyruvate kinase, and lactate dehydrogenase. There were no alterations in the control group compared to nonoperated hearts. However, the rejection cohort of hearts showed decreased glycolytic enzymes. Although lactate dehydrogenase maintained similar levels compared to the control group, phosphofructokinase showed only 50% activity, and pyruvate kinase showed less than 10% of the activity compared with controls. These results suggested that metabolic alterations in rejected hearts differ from other cardiomyopathies.
    Transplantation Proceedings 12/2005; 37(9):4122-3. · 0.95 Impact Factor
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    ABSTRACT: The effects of triiodothyronine (T(3)) and hypoxia on 2,3-bisphosphoglycerate (2,3-BPG) studied in vitro are unclear. To clarify these effects we selected a more physiologic approach: the in vivo study in rabbits. We also present the changes produced by T(3) and hypoxia on phosphoglycerate mutase (PGAM), which requires 2,3-BPG as a cofactor, and 2,3-BPG synthase (BPGS), the enzyme responsible for 2,3-BPG synthesis in erythroblasts and reticulocytes. Hyperthyroidism was induced by daily T(3) injection (250 microg/kg), hypoxia by a mixture of 90% nitrogen and 10% oxygen and hypothyroidism by propylthiouracil (PTU) added to drinking water. Both T(3) administration and hypoxic conditions increased 2,3-BPG levels and BPGS mRNA levels and activity in erythroblasts but not in reticulocytes. Unlike BPGS, both PGAM mRNA levels and activity were increased in erythroblasts and reticulocytes under hyperthyrodism and hypoxia. The antihormone PTU produced opposite effects to T(3). The results presented here suggest that both hyperthyroidism and hypoxia modulate in vivo red cell 2,3-BPG content by changes in the expression of BPGS. Similarly, the changes in PGAM activity are also explained by changes in its expression.
    Hormone Research 02/2004; 62(4):191-6. · 2.48 Impact Factor
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    Haematologica 04/2003; 88(3):ECR07. · 5.94 Impact Factor

Publication Stats

39 Citations
27.62 Total Impact Points

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Institutions

  • 2005–2011
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2009
    • University of Barcelona
      • Departament de Ciències Fisiològiques I
      Barcelona, Catalonia, Spain