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malfunction
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deletion of the E1a or E3 subunit genes of Plasmodium yoelii PDH causes no defect in blood stage development, mosquito stage development or early liver stage development. However, the gene deletions completely block the ability of the e1alpha- and e3-deficient parasites to form exo-erythrocytic merozoites during late liver stage development, thus preventing the initiation of a blood stage infection
physiological function
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Plasmodium pyruvate dehydrogenase activity is only essential for the parasites progression from liver infection to blood infection. The sole role of PDH is to provide acetyl-CoA for FAS II. PDH subunits E1a and E3 subunits are not essential for either blood stage or mosquito stage development but are essential for late liver stage development
physiological function
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pyruvate dehydrogenase is the rate-limiting enzyme coupling cytosolic glycolysis to mitochondrial citric acid cycle, and plays a critical role in maintaining homeostasis of brain glucose metabolism
physiological function
a hybrid complex consisting of E1p (thiamine diphosphate-dependent pyruvate dehydrogenase, AceE), E2 (dihydrolipoamide acetyltransferase, AceF), E3 (dihydrolipoamide dehydrogenase, Lpd), and E1o (thiamine diphosphate-dependent 2-oxoglutarate dehydrogenase, OdhA) contains six copies of E2 in its core. E2 forms a stable complex with E3 (E2-E3 subcomplex) in vitro, hypothetically comprised of two E2 trimers and four E3 dimers. E1o exists mainly as a hexamer in solution and is ready to form an active ODH complex when mixed with the E2-E3 subcomplex. In vitro, there is E1p- and E1o-dependent inhibition of ODH and PDH, respectively, actively supporting the formation of the hybrid complex, in which both E1p and E1o associate with a single E2-E3
physiological function
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addition of excess pure E3 from Enterococcus faecalis may substitute for loss of Lactococcus lactis E3 during purification
physiological function
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all the substrates, pyruvate, CoA and NAD+, exhibit cooperative klnetics towards the native enzyme complex. the calculated Hill coefficient for pyruvate is 1.34
physiological function
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complete cross-reactivity is found with antibodies directed against the pyruvate dehydrogenase complex from Escherichia coli and electron micrographs of both enzyme complexes reveal identical structures
physiological function
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dihydrolipoyl transacetylase subunit consists of 24 apparently identical polypeptide chains organized into a cube-like structure, and has the potential to bind 24 pyruvate dehydrogenase dimers in the absence of flavoprotein and 24 flavoprotein dimers in the absence of the pyruvate dehydrogenase subunit. The transacetylase can accommodate a total of only about 12 pyruvate dehydrogenase dimers and six flavoprotein dimers and this stoichiometry, which is the same as that of the native pyruvate dehydrogenase complex, produces maximum activity. Steric hindrance between the relatively bulky pyruvate dehydrogenase and flavoprotein molecules prevents the transacetylase from binding 24 molecules of each ligand
physiological function
disintegration of the pyruvate dehydrogenase complex core via double truncations (eight residues from E2 and seven residues from E3 binding protein PdhX) leads to the formation of highly active (approximately 70% of wild-type) unordered clusters or agglomerates and inactive nonagglomerated species (hexamer/trimer). After additional deletion of N-terminal swinging arms, the C-terminal truncations also cause the formation of agglomerates of minimized E2/E3 binding protein complexes
physiological function
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in T37i murine preadipocytes differentiated into brown adipocytes, the flux through the TCA cycle is enhanced and regulated by pyruvate dehydrogenase (PDH) activity. PDH plays an important role in directing glucose carbons towards oxidation
physiological function
knockdown of the expression of the subunit 1 of the E2 dihydrolipoyllysine-residue acetyltransferase gene to 17 % of that in the wild-type has only a slight effect on plant growth whereas knockout of subunit 2 leads to an embryo-lethal phenotype. The nearly null mutation of subunit 3 does not cause any developmental abnormality
physiological function
mitochondrial proteins, Pkp2 (Ygl059wp) and Ppp2 (Ycr079wp), are engaged in the regulation of the pyruvate dehydrogenase complex by affecting the phosphorylation state of subunit Pda1. Ppp2 is almost exclusively localized in the mitochondrial matrix and associated with the complex. Cells lacking Ppp2 but also cells with a non-functional pyruvate dehydrogenase complex due to deletion of Pda1 possess similar sensitivity toward rapamycin
physiological function
residues in the lipoyl-lysine beta-turn region of the unlipoylated subunit E2p lipoyl domain undergo significant changes in both chemical shift and transverse relaxation time in the presence of subunit E1p but not E1o. Residue Gly11, in a prominent surface loop between beta-strands 1 and 2 in the E2p lipoyl domain, also undergoes a significant change in chemical shift. Addition of pyruvate to the mixture of unlipoylated E2p lipoyl domain and E1p causes larger changes in chemical shift and the appearance of multiple cross-peaks for certain residues. Residues in both beta-strands 4 and 5, together with those in the prominent surface loop and the following beta-strand 2, interact with E1p. The values of transverse relaxation time across the polypeptide chain backbone are lower than in the presence of E1p alone. The lipoylated domain E2p exhibits significant changes in chemical shift and decreases in the overall transverse relaxation times in the presence of E1p, the residues principally affected being restricted to the half of the domain that contains the lipoyl-lysine (Lys41) residue
physiological function
the active centers of the alpha2beta2 E1 component are not equivalent. In the activated active site, pyruvate is rapidly bound and decarboxylated with apparent forward rate constants of covalent pyruvate binding of 2 per s and decarboxylation of the formed 2-lactylthiamine intermediate of 5 per s. In the dormant site, these steps are as slow as 0.03 per s
physiological function
the activity of PDC is regulated by different isozymes of pyruvate dehydrogenase kinase PDK in different tissues. Isoform PDK1 is the principal isozyme regulating hepatic PDC. PDK2 is largely responsible for inactivation of PDC in tissues of muscle origin and brown adipose tissue (BAT). PDK3 is the principal kinase regulating pyruvate dehydrogenase activity in kidney and brain. In a well-fed state, the tissue levels of PDK4 protein are fairly low. In most tissues tested, PDK4 ablation has little effect on the overall rates of inactivation of PDC in kinase reaction
physiological function
the inner loop of the E1 component, i.e. residues 401-413, sequesters the active center from carboligase side reactions, assists the interaction between the E1 and the E2 components, thereby affecting the overall reaction rate of the entire multienzyme complex, and controls substrate access to the active center. Formation of the pre-decarboxylation intermediate is specifically affected by loop movement
physiological function
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the time course for acetylation can be analyzed in terms of two kinetic processes. At long times 10 nmol of acetyl groups is incorporated per mg of enzyme complex. The slower process is much too slow to be of catalytic significance. The rate constant for the faster process is not dependent on enzyme concentration and reaches a limiting value of 40-65 per s at high pyruvate concentrations. The minimum molar turnover number of the enzyme complex is 420 per s (17.5 per s per pyruvate decarboxylase). The acetylated lipoic acids are deacetylated by coenzyme A at a rate much faster than that of acetylation. Complete deacetylation is obtained only if the deacetylation is carried out within seconds of the acetylation
physiological function
there are at least two loci of interaction between the E1 and E2 subunits: the thiamin diphosphate-bound substrate on E1 and the lipoylamide of E2, as reflected by the ability to reductively acetylate the latter and amino terminal residues 1-45 of E1 with regions of E2
physiological function
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within the complex, the E1 enzyme pyruvate dehydrogenase (PDH) is the main regulatory site and is subject to inhibitory phosphorylation. Total PDH content does not change significantly during hibernation in any tissue but phospho-PDH content increases in all. Heart PDH shows increased phosphorylation at the three sites S232, S293, S300 by 8.1-, 10.6- and 2.1fold, respectively. Liver also shows elevated phospho-S300 (2.5fold) and phospho-S293 (4.7fold) content. Phosphorylation of S232 and S293 increases significantly in brain and lung but only S232 phosphorylation increases in kidney and skeletal muscle
physiological function
during lactate consumption, component E1 subunit alpha Ser293 and Ser300 phosphorylation levels are 33% higher compared to the phase of glucose excess. At the same time, the relative phosphorylation level of Ser232 increases steadily throughout the cultivation (66% increase overall). The intracellular pyruvate accumulates only during the period of high lactate production, while acetyl-CoA shows nearly no accumulation
physiological function
high salt intake downregulates sirtuin SIRT3 level in brown adipose tissue, accompanied by decreased oxygen consumption rate, and causes a severe loss of brown adipose tissue characteristics. SIRT3 interacts with pyruvate dehydrogenase E1alpha (PDHA1) and deacetylates residue Lys83 both in vitro and in vivo under high salt intake. In parallel, high salt intake suppresses salt-induced kinase (Sik) 2 phosphorylation. Silencing Sik2 further diminishes SIRT3 activity and enhances acetylation of PDHA1 K83. Reconstruction of SIRT3 restores PDH activity and thermogenic markers expression in differentiated brown adipocytes from SIRT3 knockout mice
physiological function
in Corynebacterium glutamicum, the PDH-ODH hybrid complex consists of six copies of subunit E2 in its core. E2 forms a stable complex with E3 (E2-E3 subcomplex) in vitro, hypothetically comprised of two E2 trimers and four E3 dimers. E1o exists mainly as a hexamer in solution and is ready to form an active ODH complex when mixed with the E2-E3 subcomplex. Inhibition of ODH and PDH is E1p- and E1o-dependent, respectively, actively supporting the formation Iof the hybrid complex, in which both E1p and E1o associate with a single E2-E3
physiological function
mitochondrial PDC E1 contributes to polar auxin transport during organ development. MAB1 encodes a mitochondrial PDC E1beta subunit that can form both a homodimer and a heterodimer with alpha-subunit IAR4. The MAB1 mutation impairs MAB1 homodimerization, reduces the abundance of IAR4 and IAR4L, weakens PDC enzymatic activity, and diminishes mitochondrial respiration. Mutation leads to significant changes in metabolites including amino acids, and an accumulation of Ala. In MAB1 mutants and seedlings where the TCA cycle is pharmacologically blocked, reduced abundance of the PIN-FORMED (PIN) auxin efflux carriers is found
physiological function
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nitric oxide produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. Inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase in an NO-dependent and hypoxia-inducible factor Hif1alpha-independent manner, thereby promoting glutamine-based anaplerosis
physiological function
the pyruvate dehydrogenase complex PDC displays size versatility in an ionic strength-dependent manner. Yeast PDC is a salt-labile complex that dissociates into submegadalton individual components even under physiological ionic strength. The ionic strength can modulate its catalytic activity
physiological function
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in Corynebacterium glutamicum, the PDH-ODH hybrid complex consists of six copies of subunit E2 in its core. E2 forms a stable complex with E3 (E2-E3 subcomplex) in vitro, hypothetically comprised of two E2 trimers and four E3 dimers. E1o exists mainly as a hexamer in solution and is ready to form an active ODH complex when mixed with the E2-E3 subcomplex. Inhibition of ODH and PDH is E1p- and E1o-dependent, respectively, actively supporting the formation Iof the hybrid complex, in which both E1p and E1o associate with a single E2-E3
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physiological function
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the pyruvate dehydrogenase complex PDC displays size versatility in an ionic strength-dependent manner. Yeast PDC is a salt-labile complex that dissociates into submegadalton individual components even under physiological ionic strength. The ionic strength can modulate its catalytic activity
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physiological function
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a hybrid complex consisting of E1p (thiamine diphosphate-dependent pyruvate dehydrogenase, AceE), E2 (dihydrolipoamide acetyltransferase, AceF), E3 (dihydrolipoamide dehydrogenase, Lpd), and E1o (thiamine diphosphate-dependent 2-oxoglutarate dehydrogenase, OdhA) contains six copies of E2 in its core. E2 forms a stable complex with E3 (E2-E3 subcomplex) in vitro, hypothetically comprised of two E2 trimers and four E3 dimers. E1o exists mainly as a hexamer in solution and is ready to form an active ODH complex when mixed with the E2-E3 subcomplex. In vitro, there is E1p- and E1o-dependent inhibition of ODH and PDH, respectively, actively supporting the formation of the hybrid complex, in which both E1p and E1o associate with a single E2-E3
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