pyruvate dehydrogenase

In patients with PDHC deficiency, the levels of pyruvate, lactate, and alanine are increased in blood and urine. No rights are granted to use HHMIs or BioInteractives names or logos independent from this Resource or in any derivative works. dehydrogenase: exon skipping, insertion of duplicate sequence, and missense PDP1c exhibits a random mechanism of dephosphorylation (with relative rates of site 2 > site 3 > site 1), indicating a lack of site-site dependence for dephosphorylation. This conversion is essential to begin the series of chemical reactions that produce energy for cells. An NMR method could identify ThDP-bound covalent intermediates stable under acidic conditions (LThDP, HEThDP, 2-acetylThDP) from the chemical shifts of their C6H proton resonances (54, 55). 1, bottom left), and the protonated 4-aminopyrimidinium (APH+) form, detected by CD and solid state NMR (48,50). The relative catalytic activity of the PDK isoforms towards PDH varies such that PDK2 and PDK4 exhibit the highest activity. Ganetzky R, McCormick EM, Falk MJ. The focus of this review is to present recent developments on structural aspects, as well as on structure-based catalytic mechanisms of the PDCs, illustrated with Escherichia coli PDC (PDCec) as the simplest form and human (mammalian) PDC (PDCh) as a highly evolved form of the complex for its regulation. 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"authorname:rleclair", "cssscreen:vatech", "licenseversion:40", "cssprint:vatech" ], https://med.libretexts.org/@app/auth/3/login?returnto=https%3A%2F%2Fmed.libretexts.org%2FBookshelves%2FBasic_Science%2FCell_Biology_Genetics_and_Biochemistry_for_Pre-Clinical_Students%2F04%253A_Fuel_for_now%2F4.01%253A_Glycolysis_and_the_Pyruvate_Dehydrogenase_Complex_(PDC), \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}}}\) \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{#1}}} \)\(\newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\) \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\) \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\) \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\) \( \newcommand{\Span}{\mathrm{span}}\) \(\newcommand{\id}{\mathrm{id}}\) \( 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The crystal structures of all four PDKs (either alone or in association with L2, ADP, or ATP) have been reported (87,93). Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. When glucose is high, glucokinase is released into the cytosol to phosphorylate glucose. Hydrogen deuterium exchange-MS analysis of the interaction loci of 3-lip E2ec and E3ec. Glucokinase also has a high \(V_{max}\) and is therefore not rapidly saturated. These loops are ordered on ThDP binding and disordered in its absence. Recent findings suggest a role of post-translational modifications in regulation of PDCh, including activation of PDK1 by tyrosine phosphorylation (85) and inhibition of PDP1 and E1h by lysine acetylation (86), that control PDC activity in cancer cells. Detailed structures of individual components of PDCh (31,35) and PDCec (36,39) have been determined by x-ray crystallography (Fig. 5th Ed. The animation is appropriate for teaching advanced high school or college-level students the in-depth actions of pyruvate dehydrogenase. This regulation is achieved via a combination of three major mechanisms: (1) reversible phosphorylation/dephosphorylation, (2) modifications of the activities of the regulatory components by the redox state and acetyl-CoA/CoA ratio, and (3) transcriptional regulation of the regulatory components. 1, top right). In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, In the liver, this enzyme will phosphorylate glucose only when glucose concentrations are high such as in the fed state. New York: McGraw Hill Education, 2018, 7278, 8589. Grey, Kindred, Figure 4.4 Regulation of glucokinase by glucokinase regulatory protein. Reactivation is achieved by the action of PDH phosphatase. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). This skewed X-inactivation causes the chromosome with the mutated PDHA1 gene to be expressed in more than half of cells. The PDC is also regulated through covalent modification. The genes involved in pyruvate dehydrogenase deficiency each provide instructions for making a protein that is a component of a group of proteins called the pyruvate dehydrogenase complex. (h) The formation of acetyl-CoA from [13C-C2]pyruvate could be monitored via NMR methods (55), also affirming the result in step g. As shown in Fig. E3 is shared by PDC as well as alpha-ketoglutarate and branched-chain 2-ketoacid dehydrogenase complexes and the glycine cleavage enzyme. Under fasted conditions, when glucagon is high, this leads to the phosphorylation and inactivation of PFK2;when the enzyme is phosphorylated, it functions as a phosphatase and is referred to as fructose 2,6-bisphosphatase (FBP2) (figure 4.5). To use the sharing features on this page, please enable JavaScript. As a library, NLM provides access to scientific literature. Hence, PDH converts pyruvate to acetyl-coA, No proton wire pathway was identified for E1h. It is the 31, PDB code 1NI4). Mol Genet Metab. 2012 6-5). The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. However, many females with one altered copy of this gene have pyruvate dehydrogenase deficiency similar to affected males because the X chromosome with the normal copy of the PDHA1 gene is turned off through a process called X-inactivation. FOIA Glycerol 3-phosphate can diffuse across the mitochondrial membrane where it will donate electrons to membrane bound FAD (bound to succinate dehydrogenase) (figure 4.7). The bovine phosphatase is the most extensively studied. Additionally, there are two isoforms of the subunit of E1h that are encoded by separate genes in most mammals (19, 20). WebThe pyruvate dehydrogenase complex (PDC) 3 catalyzes the oxidative decarboxylation of pyruvate with the formation of acetyl-CoA, CO 2 and NADH (H +) ( 1 , 2 , 3 ). It was concluded that: (a) the rate of formation of the first CC bond is affected when the inner loop is disordered and (b) loop dynamics controls covalent catalysis with ThDP (55). Additionally, PFK2 can be regulated by covalent modification such as phosphorylation. It also requires the cofactors TPP, lipoic acid, and flavin adenine dinucleotide (FAD). CC BY 4.0. Although it is unclear how mutations in each of these genes affect the complex, reduced functioning of one component of the complex appears to impair the activity of the whole complex. Monomers in the dimeric PDK are in a head-to-head orientation with the primary interaction between the C-terminal domains. This complex catalyzes multiple reactions with its three types of enzymes. Overall PDC reactions, E2 and E3BP domain structures, and stepwise E1 reactions. Phosphorylation of the complex will decrease activity of the enzyme. In icosahedral PDCh, the E2h-E3BP core provides the binding sites for E1h through the subunit-binding domain of the E2h. PDPr was not found to have any native phosphatase activity and, despite the homology of PDPr to the enzyme dimethylglycine dehydrogenase, no enzymatic activity towards dimethylglycine or related molecules was found. Flux through the PDC is tightly regulated to maintain glucose homeostasis during both the fed and fasting states. 6-5). The first enzyme of the PDC complex is pyruvate dehydrogenase (E1). 1, bottom, all rate constants could be assessed for PDCec with these methods. The E2h-E3BP core provides the binding sites for E3h through the E3BD of E3BP. By continuing you agree to the use of cookies. The transfer of electrons from the dihydrolipoyl moieties of E2 to FAD and then to NAD+ is carried out by E3. The site is secure. The first regulatory step in glycolysis is the phosphorylation of glucose by hexo or glucokinase. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle. the contents by NLM or the National Institutes of Health. Lieberman M, Peet A. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. This arrangement is consistent with a hand-on-hand movement of PDK to serve many E1s in the complex (16). Both patients had abnormal neuromuscular development and lactic acidosis. In contrast, hexokinase has a lower \(K_m\) and a high affinity for glucose (figure 4.3). Upon binding of PDK3 to L2, the crossover configuration of the C-terminal tails results in an open conformation promoting the widening of the active-site cleft, causing disordering of the ATP lid and accelerating the release of trapped ADP (88, 89, 91). Crystal structures of E1 and E3 from E. coli and human. Anaudio descriptive versionof the film is available via our media player. Secondly, the presence of PDPr confers spermine sensitivity to the phosphatase. The energy produced through this process is much less than through aerobic oxidation and therefore less favorable (figure 4.1). PDC links the degradation of intracellular glycogen and extracellular glucose via glycolysis, as well as the oxidation of extracellular pyruvate and lactate, to the energy requirements of the cell. The E1 is a thiamin diphosphate (ThDP)-dependent enzyme and catalyzes two consecutive steps (refer to Fig. Following glucose phosphorylation to glucose 6-phosphate, the glucose 6-phosphate can be used for glycogen synthesis or the pentose phosphate pathway. The LibreTexts libraries arePowered by NICE CXone Expertand are supported by the Department of Education Open Textbook Pilot Project, the UC Davis Office of the Provost, the UC Davis Library, the California State University Affordable Learning Solutions Program, and Merlot. Pyruvate, a product of glycolysis (first animation), is the source of carbon and electrons for aerobic respiration. Pyruvate dehydrogenase kinase inactivates PDH by phosphorylation with ATP (Fig. The activity of E1 is regulated by phosphatases (activators) and kinases (inhibitors). PDP1 (orthologue of PDPcat) is activated by Ca2+ but not by spermine. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 6: Bioenergetics and Oxidative Phosphorylation: Section V, VI, Chapter 8: Introduction to Metabolism and Glycolysis, Chapter 9: TCA Cycle and Pyruvate Dehydrogenase Complex: Section IIA, IIB, Chapter 11: Glycogen Metabolism: Section V, VI, Chapter 16: Fatty Acid Ketone Body and TAG Metabolism: Section II, IV, V, Chapter 23: Metabolic Effect of Insulin and Glucagon, Chapter 25: Diabetes Mellitus. Site 1 phosphorylation by all PDKs is inactivating, with PDK2 being the most active kinase on this site. Figure 4.3 Comparison of glucokinase and hexokinase kinetics. Both PDP1c and PDP2c are able to dephosphorylate all three phosphorylation sites on E1h. PDH regulation in mammals effectively integrates the intermediary metabolism of glucose, amino acids, and lipids under a variety of nutritional and physiological states. However, it has been observed that PDH-E1 protein content is 25% lower in skeletal muscle of women than men and that PDK4 mRNA is higher in female skeletal muscle (Kiens, unpublished observations). WebPyruvate dehydrogenase complex ( PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. CC BY 4.0. Isolated dihydrolipoyl dehydrogenase (lipoamide dehydrogenase) deficiency has been reported in which patients presented lactic acidosis and ketosis with neurologic abnormality. We also acknowledge previous National Science Foundation support under grant numbers 1246120, 1525057, and 1413739. C, Mine M, Marsac C, Saudubray JM, Brivet M. Molecular characterization of 82 Louis Hue, Luc Bertrand, in The Scientist's Guide to Cardiac Metabolism, 2016. The role of the regulatory subunit of PDP is unclear. Pyruvate dehydrogenase (PDH) is a convergence point in the regulation of the metabolic finetuning between glucose and FA oxidation. Overall the complex catalyzes five reactions, with the overall reaction being: Pyruvate + CoA + NAD + acetyl-CoA + CO 2 https://archive.org/details/4.8_20210924. With substitutions at Arg-129 more strongly affecting the binding of E3ec and substitutions at Arg-150 strongly affecting the E1ec binding to E2ec, the studies suggested that E1ec and E3ec bind to nonidentical but overlapping loci of PSBD (76). This complex converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. In addition, other proteins included in the complex ensure its proper function. This spares the limited glucose supply for preferential use by neuronal tissues including the brain. Figure 3. See our, URL of this page: https://medlineplus.gov/genetics/condition/pyruvate-dehydrogenase-deficiency/. WebPyruvate dehydrogenase kinase (also pyruvate dehydrogenase complex kinase, PDC kinase, or PDK; EC 2.7.11.2) is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP . There are six genes that encode components of this pathway (PDHA1, PDHB, DLD, DLAT, PDHX, PDP1) that are associated with PDC deficiencies. Figure 4.7: Glycerol 3-phosphate shuttle. Structure of Pyruvate dehydrogenase phosphatase regulatory subunit epitope presented by H2-Dd The PDC occupies a key position in the oxidation of glucose by linking the glycolytic pathway to the oxidative pathway of the tricarboxylic acid cycle. Pyruvate carboxylase deficiency represents not only a defect in gluconeogenesis, but also a Krebs cycle defect. The PDC is regulated by covalent modification through the action of a specific kinase and phosphatase; the kinase and phosphatase are regulated by changes in NADH, acetyl-CoA, pyruvate, and insulin. Three catalytic components work sequentially, catalyzing the oxidative decarboxylation of pyruvate with the formation of acetyl-CoA, CO2, and NADH (H+). Covalent Regulation, Enzyme Catalysis, Protein-Protein Interaction, Pyruvate Dehydrogenase Complex (PDC), Pyruvate Dehydrogenase Kinase (PDC Kinase), A trial of research from lipoic acid to -keto acid dehydrogenase complexes, Domains, motifs, and linkers in 2-oxo acid dehydrogenase multienzyme complexes: a paradigm in the design of a multifunctional protein, Molecular biology and biochemistry of pyruvate dehydrogenase complexes, The biochemistry of the pyruvate dehydrogenase complex, Korotchkina L. G., Sidhu S., Patel M. S. (2006), Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase, Harris R. A., Bowker-Kinley M. M., Huang B., Wu P. (2002), Regulation of the activity of the pyruvate dehydrogenase complex, Regulation of pyruvate dehydrogenase complex, Mammalian -keto acid dehydrogenase complexes: gene regulation and genetic defects, Imbard A., Boutron A., Vequaud C., Zater M., de Lonlay P., Ogier de Baulny H., Barnerias C., Min M., Marsac C., Saudubray J.-M., Brivet M. (2011), Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. E1h in this review refers to PDHA1 protein expressed in somatic cells. 2002 Feb;110(2):187-91. doi: 10.1007/s00439-001-0665-3. The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. This response to glucose scarcity may be crucial for glucose conservation. Sapcariu et al., "Pro-inflammatory macrophages sustain pyruvate oxidation through pyruvate dehydrogenase for the synthesis of Itaconate and to enable cytokine expression," The CC BY 4.0. The reverse reaction, which is part of gluconeogensis, is catalyzed by glucose 6-phosphatase. https://archive.org/details/4.7_20210924. As NADH oxidation takes place in the mitochondria, and the membrane is not permeable to NADH, two shuttles are used to move cytosolic NADH into the mitochondria. No direct interaction of the N-terminal region of E1ec with the E2ec core domain was evident. All other steps in glycolysis are reversible (as indicated by the arrows) and are also used in gluconeogenesis. In milder cases, random samples of blood or urine may show normal amounts of lactate. sharing sensitive information, make sure youre on a federal These approaches and their outcomes are summarized in this section and refer to steps in Fig. PFK1 is also inhibited by citrate and ATP; levels of these compounds are indicative of a high energy state, suggesting there are sufficient oxidation productions and glucose is diverted to storage pathways. Left, the homodimeric assembly from E. coli (reproduced from Ref. 2021. https://archive.org/details/4.5-new. Although the overall structures are similar for E3ec and E3h, their binding mode to the E2 core is different, and will be discussed below. In the structure of E1ec in complex with C2-phosphonolactylthiamin diphosphate (PLThDP), a stable analog of the pre-decarboxylation intermediate LThDP, two disordered loops had become ordered and completed the active center: the inner (residues 401413) and outer loop (residues 541557) (38). Figure 9.4 A comparison between hexokinase I and glucokinase. Grey, Kindred, Figure 4.2 Regulatory step committed by hexo or glucokinase 2021. https://archive.org/details/4.2_20210924. Studies of E1h variants with only a single functional site for phosphorylation (with the other two phosphorylation sites converted to alanine) revealed that each of the three sites could be phosphorylated independently, resulting in E1h inactivation in each case (66, 67). Here, we show that In mammals, PDC plays the role of a gatekeeper in the metabolism of pyruvate to maintain glucose homeostasis during the fed and fasting states. It is Ca2+-activated with Ca2+ causing a reduction in the K0.5 for Mg2+. (2002), Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor- ligands, glucocorticoids, and insulin, Kwon H. S., Huang B., Unterman T. G., Harris R. A. See text for more details. The two lipoyl-binding pockets are located on the outer surface of the PDK dimer in the opposite direction, suggesting that PDK may bind to two different lipoyl domains on PDC at a time. The E1 component is a tetramer containing a 41-kDa and 36-kDa subunit. Each PDK monomer has two domains of about equal size, the N-terminal domain and the C-terminal domain, and these two domains are connected by a flexible, poorly ordered loop. The E1 enzyme performs one part of this chemical reaction. (2004), Protein kinase B- inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors, Reed L. J., Debusk B. G., Gunsalus I. C., Hornberger C. S., Jr. (1951), Crystalline -lipoic acid: a catalytic agent associated with pyruvate dehydrogenase, Hitosugi T., Fan J., Chuang T.-W., Lythgoe K., Wang X., Xie J., Ge Q., Gu T.-L., Polakiewicz R. D., Roesel J. L., Chen G. Z., Boggon T. J., Lonial S., Fu H., Khuri F. R., Kang S., Chen J. Elevation of substrate (pyruvate) will enhance flux through this enzyme as will the indication of low energy states as triggered by high NAD+ levels.