Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exercise intolerance syndromes are well known to be associated with inborn errors of metabolism affecting glycolysis (phosphorylase and phosphofructokinase deficiency) and fatty acid oxidation (palmitoyl carnitine transferase deficiency). We have identified a canine model for profound exercise intolerance caused by a deficit in PDP1 (EC 3.1.3.43), the phosphatase enzyme that activates the pyruvate dehydrogenase complex (PDHc). The Clumber spaniel breed was originated in 1760 by the Duc de Noailles, as a hunting dog with a gentle temperament suitable for the 'elderly gentleman'. Here we report that 20% of the current Clumber and Sussex spaniel population are carriers for a null mutation in PDP1, and that homozygosity produces severe exercise intolerance. Human pyruvate dehydrogenase phosphatase deficiency was recently characterized at the molecular level. However, the nature of the human mutation (loss of a single amino acid altering PDP1 activity) made it impossible to discern the role of the second phosphatase isoform, PDP2, in the deficient phenotype. Here we show that the null mutation in dogs provides a valuable animal model with which to study the effects of dysregulation of the PDHc. Knowledge of the molecular defect has allowed for the institution of a rapid restriction enzyme test for the canine mutation that will allow for selective breeding and has led to a suggested dietary therapy for affected dogs that has proven to be beneficial. Pharmacological and genetic therapies for PDP1 deficiency can now be investigated and the role of PDP2 can be fully characterized.
Mol Genet Metab 2007 Jan
PMID:Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency. 1709 75

Exercise intolerance is a component of heart failure (HF) syndrome. We aimed to identify the defects in skeletal muscle mitochondria which may contribute to the development of peripheral myopathy. Subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria were isolated from gastrocnemius muscle of control dogs (N=5) and dogs with pacing-induced HF (N=5). The measurement of integrated mitochondrial function (oxidative phosphorylation) and of individual activities of mitochondrial electron transport chain (ETC) complexes was complemented with the assessment of the amount and activity of the components of the phosphorylation apparatus. Both populations of skeletal muscle mitochondria isolated from HF have significantly decreased ADP-stimulated (state 3) respiratory rates with complex I, II and III substrates. The decrease in respiratory rates of skeletal muscle SSM are neither relieved upon collapsing the mitochondrial potential with an uncoupler nor increased in the presence of maximal ADP concentrations showing a defect in the ETC, which needs further investigation. In contrast, respiratory rates of skeletal muscle IFM from HF were relieved with the uncoupler and partially improved in the presence of maximal ADP concentrations. In these IFM, alterations in the phosphorylation apparatus were detected with a decreased amount of ANT isoform 2 and increased amount of isoform 1. The IFM dysfunction may be explained by this shift in ANT isoforms. In conclusion, pacing-induced HF causes a decrease in the oxidative phosphorylation of skeletal muscle mitochondria due to defects in the ETC and phosphorylation apparatus.
J Mol Cell Cardiol 2009 Jun
PMID:Altered expression of the adenine nucleotide translocase isoforms and decreased ATP synthase activity in skeletal muscle mitochondria in heart failure. 1923 97