Regulation of the pyruvate dehydrogenase complex

2006 ◽  
Vol 34 (2) ◽  
pp. 217-222 ◽  
Author(s):  
M.S. Patel ◽  
L.G. Korotchkina
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Redox State ◽  
Pyruvate Dehydrogenase Complex ◽  
Energy Status ◽  
Short Term ◽  
Disease States ◽  
Glucose Homoeostasis ◽  
Specific Distribution ◽  
Dehydrogenase Complex

The PDC (pyruvate dehydrogenase complex) plays a central role in the maintenance of glucose homoeostasis in mammals. The carbon flux through the PDC is meticulously controlled by elaborate mechanisms involving post-translational (short-term) phosphorylation/dephosphorylation and transcriptional (long-term) controls. The former regulatory mechanism involving multiple phosphorylation sites and tissue-specific distribution of the dedicated kinases and phosphatases is not only dependent on the interactions among the catalytic and regulatory components of the complex but also sensitive to the intramitochondrial redox state and metabolite levels as indicators of the energy status. Furthermore, differential transcriptional controls of the regulatory components of PDC further add to the complexity needed for long-term tuning of PDC activity for the maintenance of glucose homoeostasis during normal and disease states.

scholarly journals PDK2: An Underappreciated Regulator of Liver Metabolism

Livers ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 82-97
Author(s):  
Benjamin L. Woolbright ◽  
Robert A. Harris
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Mammalian Cells ◽  
Drug Targets ◽  
Pyruvate Dehydrogenase Complex ◽  
Liver Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Flexibility ◽  
Fed State ◽  
Disease States ◽  
Dehydrogenase Complex

Pyruvate metabolism is critical for all mammalian cells. The pyruvate dehydrogenase complex couples the pyruvate formed as the primary product of glycolysis to the formation of acetyl-CoA required as the primary substrate of the citric acid cycle. Dysregulation of this coupling contributes to alterations in metabolic flexibility in obesity, diabetes, cancer, and more. The pyruvate dehydrogenase kinase family of isozymes phosphorylate and inactive the pyruvate dehydrogenase complex in the mitochondria. This function makes them critical mediators of mitochondrial metabolism and drug targets in a number of disease states. The liver expresses multiple PDKs, predominantly PDK1 and PDK2 in the fed state and PDK1, PDK2, and PDK4 in the starved and diabetic states. PDK4 undergoes substantial transcriptional regulation in response to a diverse array of stimuli in most tissues. PDK2 has received less attention than PDK4 potentially due to the dramatic changes in transcriptional gene regulation. However, PDK2 is more responsive than the other PDKs to feedforward and feedback regulation by substrates and products of the pyruvate dehydrogenase complex. Although underappreciated, this makes PDK2 particularly important for the minute-to-minute fine control of the pyruvate dehydrogenase complex and a major contributor to metabolic flexibility. The purpose of this review is to characterize the underappreciated role of PDK2 in liver metabolism. We will focus on known biological actions and physiological roles as well as what roles PDK2 may play in disease states. We will also define current inhibitors and address their potential as therapeutic agents in the future.

Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation

2003 ◽  
Vol 31 (6) ◽  
pp. 1143-1151 ◽  
Author(s):  
M.J. Holness ◽  
M.C. Sugden
Keyword(s):  
Fatty Acid ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Tricarboxylic Acid Cycle ◽  
Pyruvate Dehydrogenase Complex ◽  
Oxidative Decarboxylation ◽  
Acid Cycle ◽  
Essential Component ◽  
Glucose Homoeostasis ◽  
Dehydrogenase Complex

PDC (pyruvate dehydrogenase complex) catalyses the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle. Regulation of PDC determines and reflects substrate preference and is critical to the ‘glucose–fatty acid cycle’, a concept of reciprocal regulation of lipid and glucose oxidation to maintain glucose homoeostasis developed by Philip Randle. Mammalian PDC activity is inactivated by phosphorylation by the PDKs (pyruvate dehydrogenase kinases). PDK inhibition by pyruvate facilitates PDC activation, favouring glucose oxidation and malonyl-CoA formation: the latter suppresses LCFA (long-chain fatty acid) oxidation. PDK activation by the high mitochondrial acetyl-CoA/CoA and NADH/NAD+ concentration ratios that reflect high rates of LCFA oxidation causes blockade of glucose oxidation. Complementing glucose homoeostasis in health, fuel allostasis, i.e. adaptation to maintain homoeostasis, is an essential component of the response to chronic changes in glycaemia and lipidaemia in insulin resistance. We develop the concept that the PDKs act as tissue homoeostats and suggest that long-term modulation of expression of individual PDKs, particularly PDK4, is an essential component of allostasis to maintain homoeostasis. We also describe the intracellular signals that govern the expression of the various PDK isoforms, including the roles of the peroxisome proliferator-activated receptors and lipids, as effectors within the context of allostasis.

scholarly journals Variation in the organization and subunit composition of the mammalian pyruvate dehydrogenase complex E2/E3BP core assembly

2011 ◽  
Vol 437 (3) ◽  
pp. 565-574 ◽  
Author(s):  
Swetha Vijayakrishnan ◽  
Philip Callow ◽  
Margaret A. Nutley ◽  
Donna P. McGow ◽  
David Gilbert ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Catalytic Efficiency ◽  
Fine Tuning ◽  
Subunit Composition ◽  
Glucose Homoeostasis ◽  
Multiple Copies ◽  
Accessory Subunit ◽  
Cross Bridges ◽  
Dehydrogenase Complex

Crucial to glucose homoeostasis in humans, the hPDC (human pyruvate dehydrogenase complex) is a massive molecular machine comprising multiple copies of three distinct enzymes (E1–E3) and an accessory subunit, E3BP (E3-binding protein). Its icosahedral E2/E3BP 60-meric ‘core’ provides the central structural and mechanistic framework ensuring favourable E1 and E3 positioning and enzyme co-operativity. Current core models indicate either a 48E2+12E3BP or a 40E2+20E3BP subunit composition. In the present study, we demonstrate clear differences in subunit content and organization between the recombinant hPDC core (rhPDC; 40E2+20E3BP), generated under defined conditions where E3BP is produced in excess, and its native bovine (48E2+12E3BP) counterpart. The results of the present study provide a rational basis for resolving apparent differences between previous models, both obtained using rhE2/E3BP core assemblies where no account was taken of relative E2 and E3BP expression levels. Mathematical modelling predicts that an ‘average’ 48E2+12E3BP core arrangement allows maximum flexibility in assembly, while providing the appropriate balance of bound E1 and E3 enzymes for optimal catalytic efficiency and regulatory fine-tuning. We also show that the rhE2/E3BP and bovine E2/E3BP cores bind E3s with a 2:1 stoichiometry, and propose that mammalian PDC comprises a heterogeneous population of assemblies incorporating a network of E3 (and possibly E1) cross-bridges above the core surface.

scholarly journals Short-term regulation of the mammalian pyruvate dehydrogenase complex.

2005 ◽  
Vol 52 (4) ◽  
pp. 759-764 ◽  
Author(s):  
Sławomir Strumiło
Keyword(s):  
Kinetic Parameters ◽  
Pyruvate Dehydrogenase ◽  
Divalent Cations ◽  
Pyruvate Dehydrogenase Complex ◽  
Lag Phase ◽  
Thiamine Diphosphate ◽  
Strong Decrease ◽  
Reversible Phosphorylation ◽  
Short Term ◽  
Dehydrogenase Complex

In this minireview the main mechanism of control of mammalian pyruvate dehydrogenase complex (PDHC) activity by phosphorylation-dephosphorylation is presented in the first place. The information recently obtained in several laboratories includes new data about isoforms of the PDH converting enzymes (kinase and phosphatase) and their action in view of short-term regulation of PDHC. Moreover, interesting influence of exogenous thiamine diphosphate (TDP) and some divalent cations, especially Mn(2+), on the kinetic parameters of PDHC saturated with endogenous tightly bound TDP, is discussed. This influence causes a shortening of the lag-phase of the catalyzed reaction and a strong decrease of the K(m) value of PDHC mainly for pyruvate. There are weighty arguments that the effects have an allosteric nature. Thus, besides reversible phosphorylation, also direct manifold increase of mammalian PDHC affinity for the substrate by cofactors seems an important aspect of its regulation.

Molecular architecture of the pyruvate dehydrogenase complex: bridging the gap

2006 ◽  
Vol 34 (5) ◽  
pp. 815-818 ◽  
Author(s):  
M. Smolle ◽  
J.G. Lindsay
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Sites ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Decarboxylase ◽  
Molecular Architecture ◽  
Glucose Homoeostasis ◽  
Bulk Medium ◽  
Substrate Channelling ◽  
Rapid Transfer ◽  
Dehydrogenase Complex

The PDC (pyruvate dehydrogenase complex) is a high-molecular-mass (4–11 MDa) complex of critical importance for glucose homoeostasis in mammals. Its multi-enzyme structure allows for substrate channelling and active-site coupling: sequential catalytic reactions proceed through the rapid transfer of intermediates between individual components and without diffusion into the bulk medium due to its ‘swinging arm’ that is able to visit all PDC active sites. Optimal positioning of individual components within this multi-subunit complex further affects the efficiency of the overall reaction and stability of its intermediates. Mammalian PDC comprises a 60-meric pentagonal dodecahedral dihydrolipoamide (E2) core attached to which are 30 pyruvate decarboxylase (E1) heterotetramers and six dihydrolipoamide (E3) homodimers at maximal occupancy. Stable E3 integration is mediated by an accessory E3-binding protein associated with the E2 core. Association of the peripheral E1 and E3 enzymes with the PDC core has been studied intensively in recent years and has yielded some interesting and substantial differences when compared with prokaryotic PDCs.

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