Regulation of the Human Pyruvate Dehydrogenase Complex

1976 ◽  
Vol 51 (5) ◽  
pp. 445-452 ◽  
Author(s):  
D. Stansbie
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Human Heart ◽  
Pyruvate Dehydrogenase Complex ◽  
Human Adipose Tissue ◽  
Terminal Phosphate Group ◽  
Mammalian Tissues ◽  
High Level ◽  
Pyruvate Dehydrogenase Phosphatase ◽  
Thiamin Pyrophosphate ◽  
Dehydrogenase Complex

1. The pyruvate dehydrogenase complex from human heart has been partially purified and shown to be regulated by a phosphorylation-dephosphorylation cycle similar to that previously found for other mammalian tissues. 2. Incubation of the complex with ATP (2 mmol/l) led to its inactivation associated with the concomitant incorporation into the protein of 32P from the terminal phosphate group of the ATP. Pyruvate, ADP, thiamin pyrophosphate and dichloroacetate diminished the rate of inactivation by ATP. 3. Pyruvate dehydrogenase phosphatase from human heart requires Mg2+ for activity and is sensitive to Ca2+ at concentrations of a few μmol/l. Similar ionic requirements of the skeletal muscle phosphatase have been demonstrated in a crude tissue extract. 4. The activity of pyruvate dehydrogenase in human adipose tissue was less than 10% of typical values in rats. This could be due to the high level of dietary fat consumed by humans, which is known to repress the enzyme activity in rats.

Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites

2001 ◽  
Vol 358 (1) ◽  
pp. 69-77 ◽  
Author(s):  
Elena KOLOBOVA ◽  
Alina TUGANOVA ◽  
Igor BOULATNIKOV ◽  
Kirill M. POPOV
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Phosphorylation Site ◽  
Enzymic Activity ◽  
Mammalian Tissues ◽  
Activity State ◽  
The Individual ◽  
Pyruvate Dehydrogenase Phosphatase ◽  
Thiamin Pyrophosphate ◽  
Dehydrogenase Complex

The enzymic activity of the mammalian pyruvate dehydrogenase complex is regulated by the phosphorylation of three serine residues (sites 1, 2 and 3) located on the E1 component of the complex. Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (PDK1, PDK2, PDK3 and PDK4) differ in their abilities to phosphorylate the enzyme. PDK1 can phosphorylate all three sites, whereas PDK2, PDK3 and PDK4 each phosphorylate only site 1 and site 2. Although PDK2 phosphorylates site 1 and 2, it incorporates less phosphate in site 2 than PDK3 or PDK4. As a result, the amount of phosphate incorporated by each isoenzyme decreases in the order PDK1>PDK3PDK4>PDK2. Significantly, binding of the coenzyme thiamin pyrophosphate to pyruvate dehydrogenase alters the rates and stoichiometries of phosphorylation of the individual sites. First, the rate of phosphorylation of site 1 by all isoenzymes of kinase is decreased. Secondly, thiamin pyrophosphate markedly decreases the amount of phosphate that PDK1 incorporates in sites 2 and 3 and that PDK2 incorporates in site 2. In contrast, the coenzyme does not significantly affect the total amount of phosphate incorporated in site 2 by PDK3 and PDK4, but instead decreases the rate of phosphorylation of this site. Furthermore, pyruvate dehydrogenase complex phosphorylated by the individual isoenzymes of kinase is reactivated at different rates by pyruvate dehydrogenase phosphatase. Both isoenzymes of phosphatase (PDP1 and PDP2) readily reactivate the complex phosphorylated by PDK2. When pyruvate dehydrogenase is phosphorylated by other isoenzymes, the rates of reactivation decrease in the order PDK4PDK3> PDK1. Taken together, results reported here strongly suggest that the major determinants of the activity state of pyruvate dehydrogenase in mammalian tissues include the phosphorylation site specificity of isoenzymes of kinase in addition to the absolute amounts of kinase and phosphatase protein expressed in mitochondria.

scholarly journals Metabolism of 1-aminoethylphosphinate generates acetylphosphinate, a potent inhibitor of pyruvate dehydrogenase

1987 ◽  
Vol 248 (2) ◽  
pp. 351-358 ◽  
Author(s):  
B Laber ◽  
N Amrhein
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Potent Inhibitor ◽  
Pyruvate Dehydrogenase Complex ◽  
Anthocyanin Synthesis ◽  
Anaerobic Conditions ◽  
First Order ◽  
Saturation Kinetics ◽  
Thiamin Pyrophosphate ◽  
Dehydrogenase Complex

The alanine analogue 1-aminoethylphosphinate [H3C-CH(NH2)-PO2H2] effectively inhibited anthocyanin synthesis in buckwheat hypocotyls and caused an increase in the concentrations of alanine and alanine-derived metabolites. Aminotransferase inhibitors partially alleviated the effects of the analogue. 1-Aminoethylphosphinate did not affect the growth of Klebsiella pneumoniae under anaerobic conditions, but under aerobic conditions it inhibited growth and caused the massive excretion of pyruvate. The analogue inhibited the pyruvate dehydrogenase complex in vitro in the presence of an aminotransferase activity. The transamination product of 1-aminoethylphosphinate, acetylphosphinate (H3C-CO-PO2H2), was found to inhibit the pyruvate dehydrogenase complex in a time-dependent reaction that followed first-order and saturation kinetics and required the presence of thiamin pyrophosphate.

scholarly journals Inhibition of pyruvate dehydrogenase complex by moniliformin

1986 ◽  
Vol 233 (3) ◽  
pp. 719-723 ◽  
Author(s):  
P S Gathercole ◽  
P G Thiel ◽  
J H S Hofmeyr
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Inhibitory Action ◽  
Pyruvate Dehydrogenase Complex ◽  
Time Dependent ◽  
Enzyme Complex ◽  
First Order ◽  
Saturation Kinetics ◽  
Thiamin Pyrophosphate ◽  
Inhibition Reaction ◽  
Dehydrogenase Complex

The mechanism for the inhibition of pyruvate dehydrogenase complex from bovine heart by moniliformin was investigated. Thiamin pyrophosphate proved to be necessary for the inhibitory action of moniliformin. The inhibition reaction was shown to be time-dependent and to follow first-order and saturation kinetics. Pyruvate protected the pyruvate dehydrogenase complex against moniliformin inactivation. Extensive dialysis of the moniliformin-inactivated complex only partially reversed inactivation. Moniliformin seems to act by inhibition of the pyruvate dehydrogenase component of the enzyme complex and not by acting on the dihydrolipoamide transacetylase or dehydrogenase components, as shown by monitoring the effect of moniliformin on each component individually. On the basis of these results, a suicide inactivator mechanism for moniliformin on pyruvate dehydrogenase is proposed.

scholarly journals Abnormal Lipid Droplets Accumulation Induced Cognitive Deficits in Obstructive Sleep Apnea Syndrome Mice via JNK/SREBP/ACC Pathway but Not Through PDP1/PDC Pathway

2021 ◽  
Author(s):  
Dongze Li ◽  
Yan Yu ◽  
Na Xu ◽  
Wanting Li ◽  
Yanyan Hou ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Pyruvate Dehydrogenase ◽  
Intermittent Hypoxia ◽  
Lipid Droplets ◽  
Salvia Miltiorrhiza ◽  
Pyruvate Dehydrogenase Complex ◽  
Acetyl Coa ◽  
Obstructive Sleep ◽  
Pyruvate Dehydrogenase Phosphatase ◽  
Dehydrogenase Complex

Abstract The mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Here, our study found that 12 weeks CIH treatment induced lipid droplets (LDs) accumulation in hippocampal neurocytes of C57BL/6 mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in neurocytes. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Therefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. Together, lipid metabolic disorders contributed to neurocytes damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.

scholarly journals Inhibition of pyruvate:ferredoxin oxidoreductase from Trichomonas vaginalis by pyruvate and its analogues. Comparison with the pyruvate decarboxylase component of the pyruvate dehydrogenase complex

1990 ◽  
Vol 268 (1) ◽  
pp. 69-75 ◽  
Author(s):  
K P Williams ◽  
P F Leadlay ◽  
P N Lowe
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site ◽  
Trichomonas Vaginalis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Decarboxylase ◽  
Oxidative Decarboxylation ◽  
Oxidoreductase Activity ◽  
Pyruvate:Ferredoxin Oxidoreductase ◽  
Thiamin Pyrophosphate ◽  
Dehydrogenase Complex

Pyruvate:ferredoxin oxidoreductase and the pyruvate dehydrogenase multi-enzyme complex both catalyse the CoA-dependent oxidative decarboxylation of pyruvate but differ in size, subunit composition and mechanism. Comparison of the pyruvate:ferredoxin oxidoreductase from the protozoon Trichomonas vaginalis and the pyruvate dehydrogenase component of the Escherichia coli pyruvate dehydrogenase complex shows that both are inactivated by incubation with pyruvate under aerobic conditions in the absence of co-substrates. However, only the former is irreversibly inhibited by incubation with hydroxypyruvate, and only the latter by incubation with bromopyruvate. Pyruvate:ferredoxin oxidoreductase activity is potently, but reversibly, inhibited by addition of bromopyruvate in the presence of CoA, and it is suggested that the mechanism involves formation of an adduct between CoA and bromopyruvate in the active site of the enzyme. It is proposed that both enzymes are inactivated by pyruvate through a mechanism involving oxidation of an enzyme-bound thiamin pyrophosphate/substrate adduct to form a tightly bound inhibitory species, possibly thiamin thiazolone pyrophosphate as hypothesized by Sumegi & Alkonyi.

scholarly journals Abnormal Lipid Droplets Accumulation Induced Cognitive Deficits in Obstructive Sleep Apnea Syndrome Mice via JNK/SREBP/ACC Pathway but Not Through PDP1/PDC Pathway

2021 ◽  
Author(s):  
Dongze Li ◽  
Yan Yu ◽  
Na Xu ◽  
Wanting Li ◽  
Yanyan Hou ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Pyruvate Dehydrogenase ◽  
Intermittent Hypoxia ◽  
Lipid Droplets ◽  
Active Component ◽  
Salvia Miltiorrhiza ◽  
Pyruvate Dehydrogenase Complex ◽  
Acetyl Coa ◽  
Pyruvate Dehydrogenase Phosphatase ◽  
Dehydrogenase Complex

Abstract IntroductionThe mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. MethodsWe assessed the CIH exposure influences of C57BL/6 mice on the activity of nerve, measured projects related to lipid metabolism, and treated with drugs SMND-309. ResultsOur study found that 12 weeks CIH treatment induced lipid droplets (LDs) accumulation in hippocampal neurocytes of mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in neurocytes. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice. ConclusionTherefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Together, lipid metabolic disorders contributed to neurocytes damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.

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