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Brenda Garritson - One of the best experts on this subject based on the ideXlab platform.
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Carnitine Palmitoyltransferase ii deficiency successful anaplerotic diet therapy
Neurology, 2008Co-Authors: Bing-zhi Yang, Henri Brunengraber, Mary Wallace, Brenda GarritsonAbstract:Background: Carnitine Palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. Methods: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylCarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. Results: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. Conclusions: The triheptanoin diet seems to be an effective therapy for adult-onset Carnitine Palmitoyltransferase II deficiency.
George A. Cook - One of the best experts on this subject based on the ideXlab platform.
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Yonetani-Theorell analysis of hepatic Carnitine Palmitoyltransferase-I inhibition indicates two distinct inhibitory binding sites
Journal of Biological Chemistry, 1994Co-Authors: George A. Cook, Randall L. Mynatt, Khosrow KashfiAbstract:Abstract Analysis of inhibitor studies indicates that Carnitine Palmitoyltransferase-I has two separate sites for inhibitor binding. One site is located on the cytoplasmic side of the mitochondrial outer membrane. Malonyl-CoA, the most important physiological inhibitor of Carnitine Palmitoyltransferase-I, binds primarily to this site, but it can also bind to another site. A second inhibitory site is located at the active site of Carnitine palmitolytransferase-I. Coenzyme A, a product/inhibitor of Carnitine Palmitoyltransferase-I binds primarily at this site and can inhibit Carnitine Palmitoyltransferase-I at physiological concentrations, but can also attenuate malonyl-CoA inhibition. Analogs of malonyl-CoA and other simpler compounds containing two carbonyl groups but no coenzyme A moiety inhibit only at the cytoplasmic site, indicating that this site has an absolute requirement for two carbonyl groups but has no absolute requirement for a coenzyme A moiety. Inhibitors acting through the active site included the active-site-directed inhibitor (+)-hemipalmitoylcarnitinium. These studies support the existence of two regulatory binding sites for the control of hepatic fatty acid oxidation: (a) the active site, for regulation by the inhibitory binding of coenzyme A and acetyl-CoA, and (b) a separate regulatory malonyl-CoA-binding site that is physical separated from the active site.
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Carnitine Palmitoyltransferase in the Heart is Controlled by a Different Mechanism than the Hepatic Enzyme
Molecular and Cellular Biochemistry, 1992Co-Authors: George A. Cook, Michael D. LappiAbstract:Diminished sensitivity of hepatic Carnitine Palmitoyltransferase to inhibition by malonyl-CoA in the fasting and diabetic states is a well-recognized aspect of the regulatory mechanism forhepatic fatty acid oxidation. Inhibition of myocardial Carnitine Palmitoyltransferase by malonyl-CoA may play an important role in regulation of fatty acid oxidation in the heart, but there has been a discrepancy in data relating to changes in malonyl-CoA sensitivity of the myocardial Carnitine Palmitoyltransferase during fasting. Analysis of malonyl-CoA inhibition of myocardial Carnitine Palmitoyltransferase in fasting and fed states under a variety of conditions has indicated that under no condition could any difference be found in malonyl-CoA sensitivity that was attributable to fasting. Proteolysis of the outer Carnitine Palmitoyltransferase led to artifactual changes in sensitivity due to the appearance of partial inhibition. We have concluded that the sensitivity of myocardial Carnitine Palmitoyltransferase to malonyl-CoA does not change during fasting. Changes in fatty acid oxidation in the heart are probably due to changes in malonyl-CoA concentrations or to other inhibitors. (Mol Cell Biochem 116: 39–45, 1992)
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Myocardial Carnitine Palmitoyltransferase of the mitochondrial outer membrane is not altered by fasting.
Biochimica et Biophysica Acta, 1992Co-Authors: Randall L. Mynatt, Michael D. Lappi, George A. CookAbstract:Abstract The regulation of heart Carnitine Palmitoyltransferase was studied during the transition to the fasting state. Using decanoyl-CoA or palmitoyl-CoA as substrates, we found no differences in Carnitine Palmitoyltransferase activity on in its sensitivity to inhibition by malonyl-CoA between fed and fasted states. No cooperativity was seen with either substrate, and the malonyl-CoA-induced shift to sigmoid kinetics normally observed with liver mitochondria was not obvious with heart mitochondria. Analysis of malonyl-CoA inhibition data revealed that mitochondria from rat heart exhibited incomplete maximum inhibition of Carnitine Palmitoyltransferase (partial inhibition). Homogenization of intact liver mitochondria resulted in a similar pattern of incomplete inhibition and suggested that the malonyl-CoA-insensitive Carnitine Palmitoyltransferase of the inner membrane was also being assayed. Carnitine Palmitoyltransferase in mitochondrial outer membranes, isolated from the heart, proved to be extremely sensitive to malonyl-CoA inhibition and had maximum inhibition values of 90–100% with either decanoyl-CoA or palmitoyl-CoA as substrates, but fasting had no effect. Fasting produced no change in the Ki for malonyl-CoA (0.10 ± 0.04 and 0.14 ± 0.02 μM for the fed and fasted groups, respectively). Acyl-CoA chain length specificity was C10 > C16 > C14 > C12 > C18 = C8 for Carnitine Palmitoyltransferase in heart mitochondrial outer membranes. It is concluded that the regulation of Carnitine Palmitoyltransferase of heart mitochondrial outer membranes differs from regulation of the liver enzyme in three characteristics — the heart enzyme (a) has greater sensitivity to malonyl-CoA inhibition, (b) is resistant to the effects of fasting and (c) has somewhat different acyl-CoA substrate specificity.
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Malonyl-CoA inhibits proteolysis of Carnitine Palmitoyltransferase.
Biochemical and Biophysical Research Communications, 1991Co-Authors: Khosrow Kashfi, George A. CookAbstract:Incubation of isolated mitochondria in the presence of malonyl-CoA prevented proteolysis of the outer Carnitine Palmitoyltransferase by Nagarse and trypsin. Malonyl-CoA had no direct action on trypsin when present in a chromogenic assay system for proteolysis or when preincubated with the proteases in the absence of mitochondria. As reported previously, Nagarse had a differential effect on Carnitine Palmitoyltransferase in which malonyl-CoA inhibition was diminished to a greater extent than activity was lost, but all effects were blocked by malonyl-CoA in a concentration-dependent manner. These data suggest a specific effect of binding of malonyl-CoA to Carnitine Palmitoyltransferase as the protective mechanism.
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Effects of cholesterol loading of mouse macrophages on Carnitine Palmitoyltransferase activity and sensitivity to inhibition by malonyl-CoA
Biochemical and Biophysical Research Communications, 1991Co-Authors: Khosrow Kashfi, Ladislav Dory, George A. CookAbstract:Scavenger receptor-mediated uptake of acetylated low density lipoprotein-derived cholesterol by peritoneal mouse macrophages resulted in decreased activity of the malonyl-CoA inhibitable Carnitine Palmitoyltransferase and a decrease in the sensitivity of this enzyme to inhibition by malonyl-CoA.
Thomas Wieser - One of the best experts on this subject based on the ideXlab platform.
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No Carnitine Palmitoyltransferase deficiency in skeletal muscle in 18 malignant hyperthermia susceptible individuals.
Neuromuscular Disorders, 2008Co-Authors: Thomas Wieser, Birgit Kraft, Hans G. KressAbstract:Abstract Malignant hyperthermia is a rare, potentially life threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. The clinical picture comprises rhabdomyolysis, metabolic and respiratory acidosis, and hyperthermia. Carnitine Palmitoyltransferase II deficiency is a metabolic myopathy affecting the transport of fatty acids into the mitochondria, leading to impaired energy supply under stressful conditions resulting in muscle weakness and rhabdomyolysis. It was postulated in a previous study that some patients with the MH phenotype have a Carnitine Palmitoyltransferase deficiency. To investigate a potential association, we tested 18 individuals with proven MH susceptibility for impairment of Carnitine Palmitoyltransferase enzyme activity in muscle. Enzyme activity was normal in all individuals tested indicating no impairment of the CPT system in this sample of malignant hyperthermia susceptible individuals. Thus our data do not support the hypothesis that susceptibility to malignant hyperthermia has an effect on the Carnitine Palmitoyltransferase enzyme system.
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Carnitine Palmitoyltransferase ii deficiency molecular and biochemical analysis of 32 patients
Neurology, 2003Co-Authors: Thomas Wieser, M Deschauer, K Olek, Thomas Hermann, Stephan ZierzAbstract:The authors investigated 32 patients with the muscle form of CPT II deficiency. Total Carnitine Palmitoyltransferase enzyme system (CPT) activity was normal but abnormally inhibited by malonyl-CoA, palmitoyl-CoA, and the detergents Triton X and Tween 20. Mutation analysis identified three described mutations (S113L, P50H, and F448L) and two novel mutations (M214T and Y479F). Using modeling techniques, a structure could be identified anchoring the protein in the membrane. Only one of the five mutations (Y479F) is located within this region.
Stephan Zierz - One of the best experts on this subject based on the ideXlab platform.
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Carnitine Palmitoyltransferase ii deficiency molecular and biochemical analysis of 32 patients
Neurology, 2003Co-Authors: Thomas Wieser, M Deschauer, K Olek, Thomas Hermann, Stephan ZierzAbstract:The authors investigated 32 patients with the muscle form of CPT II deficiency. Total Carnitine Palmitoyltransferase enzyme system (CPT) activity was normal but abnormally inhibited by malonyl-CoA, palmitoyl-CoA, and the detergents Triton X and Tween 20. Mutation analysis identified three described mutations (S113L, P50H, and F448L) and two novel mutations (M214T and Y479F). Using modeling techniques, a structure could be identified anchoring the protein in the membrane. Only one of the five mutations (Y479F) is located within this region.
Randall L. Mynatt - One of the best experts on this subject based on the ideXlab platform.
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examination of Carnitine Palmitoyltransferase 1 abundance in white adipose tissue implications in obesity research
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2017Co-Authors: Jaycob D Warfel, Bolormaa Vandanmagsar, Olga S Dubuisson, Sydney M Hodgeson, Carrie M Elks, Eric Ravussin, Randall L. MynattAbstract:Carnitine Palmitoyltransferase 1 (CPT1) is essential for the transport of long-chain fatty acids into the mitochondria for oxidation. Recently, it was reported that decreased CPT1b mRNA in adipose ...
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Yonetani-Theorell analysis of hepatic Carnitine Palmitoyltransferase-I inhibition indicates two distinct inhibitory binding sites
Journal of Biological Chemistry, 1994Co-Authors: George A. Cook, Randall L. Mynatt, Khosrow KashfiAbstract:Abstract Analysis of inhibitor studies indicates that Carnitine Palmitoyltransferase-I has two separate sites for inhibitor binding. One site is located on the cytoplasmic side of the mitochondrial outer membrane. Malonyl-CoA, the most important physiological inhibitor of Carnitine Palmitoyltransferase-I, binds primarily to this site, but it can also bind to another site. A second inhibitory site is located at the active site of Carnitine palmitolytransferase-I. Coenzyme A, a product/inhibitor of Carnitine Palmitoyltransferase-I binds primarily at this site and can inhibit Carnitine Palmitoyltransferase-I at physiological concentrations, but can also attenuate malonyl-CoA inhibition. Analogs of malonyl-CoA and other simpler compounds containing two carbonyl groups but no coenzyme A moiety inhibit only at the cytoplasmic site, indicating that this site has an absolute requirement for two carbonyl groups but has no absolute requirement for a coenzyme A moiety. Inhibitors acting through the active site included the active-site-directed inhibitor (+)-hemipalmitoylcarnitinium. These studies support the existence of two regulatory binding sites for the control of hepatic fatty acid oxidation: (a) the active site, for regulation by the inhibitory binding of coenzyme A and acetyl-CoA, and (b) a separate regulatory malonyl-CoA-binding site that is physical separated from the active site.
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Myocardial Carnitine Palmitoyltransferase of the mitochondrial outer membrane is not altered by fasting.
Biochimica et Biophysica Acta, 1992Co-Authors: Randall L. Mynatt, Michael D. Lappi, George A. CookAbstract:Abstract The regulation of heart Carnitine Palmitoyltransferase was studied during the transition to the fasting state. Using decanoyl-CoA or palmitoyl-CoA as substrates, we found no differences in Carnitine Palmitoyltransferase activity on in its sensitivity to inhibition by malonyl-CoA between fed and fasted states. No cooperativity was seen with either substrate, and the malonyl-CoA-induced shift to sigmoid kinetics normally observed with liver mitochondria was not obvious with heart mitochondria. Analysis of malonyl-CoA inhibition data revealed that mitochondria from rat heart exhibited incomplete maximum inhibition of Carnitine Palmitoyltransferase (partial inhibition). Homogenization of intact liver mitochondria resulted in a similar pattern of incomplete inhibition and suggested that the malonyl-CoA-insensitive Carnitine Palmitoyltransferase of the inner membrane was also being assayed. Carnitine Palmitoyltransferase in mitochondrial outer membranes, isolated from the heart, proved to be extremely sensitive to malonyl-CoA inhibition and had maximum inhibition values of 90–100% with either decanoyl-CoA or palmitoyl-CoA as substrates, but fasting had no effect. Fasting produced no change in the Ki for malonyl-CoA (0.10 ± 0.04 and 0.14 ± 0.02 μM for the fed and fasted groups, respectively). Acyl-CoA chain length specificity was C10 > C16 > C14 > C12 > C18 = C8 for Carnitine Palmitoyltransferase in heart mitochondrial outer membranes. It is concluded that the regulation of Carnitine Palmitoyltransferase of heart mitochondrial outer membranes differs from regulation of the liver enzyme in three characteristics — the heart enzyme (a) has greater sensitivity to malonyl-CoA inhibition, (b) is resistant to the effects of fasting and (c) has somewhat different acyl-CoA substrate specificity.