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In mammalian tissues, two types of regulation of the pyruvate dehydrogenase complex have been described: end product inhibition by acetyl CoA and NADH: and the interconversion of an inactive phosphorylated form and an active nonphosphorylated form by an ATP requiring kinase and a specific phosphatase. This article is largely concerned with the latter type of regulation of the complex in adipose tissue by insulin (and other hormones) and in heart muscle by lipid fuels. Effectors of the two interconverting enzymes include pyruvate and ADP which inhibit the kinase, acetoin which activates the kinase and Ca2+ and Mg2+ which both activate the phosphatase and inhibit the kinase. Evidence is presented that all components of the pyruvate dehydrogenase complex including the phosphatase and kinase are located within the inner mitochondrial membrane. Direct measurements of the matrix concentration of substrates and effectors is not possible by techniques presently available. This is the key problem in the identification of the mechansims involved in the alterations in pyruvate dehydrogenase activity observed in adipose tissue and muscle. A number of indirect approaches have been used and these are reviewed. Most hopeful is the recent finding in this laboratory that in both adipose tissue and heart muscle, differences in activity of pyruvate dehydrogenase in the intact tissue persist during preparation and subsequent incubation of mitochondria.
Mol Cell Biochem 1975 Oct 31
PMID:Regulation of mammalian pyruvate dehydrogenase. 17 57

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/1) 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 mumol/1. 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.
Clin Sci Mol Med 1976 Nov
PMID:Regulation of the human pyruvate dehydrogenase complex. 18 26

In recent years it has become apparent that an increasing number of proteins can be phosphorylated at several different sites. In this article protein multisite phosphorylation is discussed with reference to the enzymes glycogen synthase, pyruvate dehydrogenase, and phosphorylase kinase. Each of these enzymes contains three or more different phosphorylation sites on one or more subunits. Activation and inactivation of the enzymes appear to correlate quite well with phosphorylation of a few key sites on the protein. The other phosphorylation sites may influence other kinetic properties of the enzymes or regulate the rates of dephosphorylation of the key sites by the appropriate phosphatase. Thus, multisite phosphorylation may represent an important mechanism for regulating several functions of complex proteins.
Mol Cell Endocrinol 1979 Dec
PMID:Regulatory functions of protein multisite phosphorylation. 23 Jan 3

When rat hearts were perfused with a medium containing 10 microM fura-2/AM for 1 hr at 37 degrees C a significant amount of the derived fura-2 could be detected in subsequently isolated mitochondria. This procedure allowed the measurement of matrix free Ca2+ concentration ([Ca2+]m) of mitochondria rapidly isolated from whole hearts by a method which avoids artefactual redistribution of Ca2+. [Ca2+]m in mitochondria prepared from control hearts and incubated with respiratory substrates and EGTA was found to be 172 +/- 23 nM (mean +/- S.E.M.). When hearts were subjected to either increased mechanical work or treatment with 1 microM L-epinephrine (for 2 mins) [Ca2+]m increased to 916 +/- 138 nM and 727 +/- 65 nM respectively. The presence of ruthenium red (2.5 microM) in the perfusion medium prior to and during inotropic intervention diminished these increases in [Ca2+]m(to 316 +/- 28 nM and 218 +/- 18 nM respectively) but did not affect control values. Addition of Na+ ions to incubated mitochondria to enhance mitochondrial Ca2+ egress diminished these increases in [Ca2+]m due to pre-treatment with positive inotropes (compared to controls). These changes in [Ca2+]m were broadly parallelled by changes in the active non-phosphorylated form of pyruvate dehydrogenase (PDH) under all circumstances. These results provide further evidence that the activation of PDH by positive inotropes is accomplished by, and at least in part due to, raised mitochondrial matrix free [Ca2+] and that such increases can be maintained in isolated and suitably incubated mitochondria.
J Mol Cell Cardiol 1992 Jul
PMID:The loading of fura-2 into mitochondria in the intact perfused rat heart and its use to estimate matrix Ca2+ under various conditions. 138 55

High levels of fatty acids decrease the extent of mechanical recovery of hearts reperfused following a transient period of severe ischemia. Glucose oxidation rates during reperfusion are low under these conditions, which can result in a decreased recovery of mechanical function. Stimulation of glucose oxidation with the carnitine palmitoyl transferase I inhibitor, Etomoxir, or by directly stimulating pyruvate dehydrogenase activity with dichloroacetate (DCA) results in an improvement in mechanical function during reperfusion of previously ischemic hearts. Addition of DCA (1 mM) to hearts perfused with 11 mM glucose and 1.2 mM palmitate results in an increase in contribution of glucose oxidation to overall ATP production from 6 to 23%, with a parallel decrease in that of fatty acid oxidation from 90 to 69%. In aerobic hearts, endogenous myocardial triglycerides are an important source of fatty acids for beta-oxidation. Using hearts in which the myocardial triglycerides were pre-labeled, the contribution of both endogenous and exogenous fatty acid oxidation to myocardial ATP production was determined in hearts perfused with 11 mM glucose, 1.2 mM palmitate and 500 microU/ml insulin. In hearts reperfused following a 30 min period of global no flow ischemia, 91.9% of ATP production was derived from endogenous and exogenous fatty acid oxidation, compared to 87.7% in aerobic hearts. This demonstrates that fatty acid oxidation quickly recovers following a transient period of severe ischemia. Furthermore, therapy aimed at overcoming fatty acid inhibition of glucose oxidation during reperfusion of ischemic hearts appears to be beneficial to recovery of mechanical function.
Mol Cell Biochem 1992 Oct 21
PMID:The relative contribution of glucose and fatty acids to ATP production in hearts reperfused following ischemia. 148 Jan 39

The pyruvate dehydrogenase complex of the adult parasitic nematode Ascaris suum functions in the reducing environment present in their anaerobic mitochondria. These organelles use fumarate and enoyl CoAs as terminal electron acceptors instead of oxygen. A lambda gt11 cDNA library was constructed from RNA isolated from adult ascarid muscle. Partial clones for the pyruvate dehydrogenase alpha subunit were isolated by screening the lambda gt11 library with a specific antiserum. Full-length clones (type I) were identified in a cDNA library prepared from RNA isolated from early embryos. During the hybridization screening, a second type of cDNA clone (type II) was identified. The nucleotide sequences of both clones are presented. The predicted amino acid sequences of the mature proteins are 91% identical to one another and about 55% identical to the predicted sequences of the alpha subunit of human pyruvate dehydrogenase. Northern blots were used to examine the expression of both mRNAs in various larval stages and in tissues of the adult. Type I sequences are found mainly in adult muscle. Type II sequences are abundant in third-stage larvae as well as in adult muscle.
Mol Biochem Parasitol 1992 Mar
PMID:Characterization of cDNA clones for the alpha subunit of pyruvate dehydrogenase from Ascaris suum. 156 36

Homogenates prepared from the temporal cortex and hippocampus of individuals who had histopathologically confirmed Alzheimer's disease exhibited reduced in vitro cyclic AMP-dependent phosphorylation of synapsin I, neuronal phosphoprotein. One specific phosphorylation site (site 1) was affected while two other sites, which are phosphorylated by calcium/calmodulin kinase II, exhibited no such differences. Other phosphoproteins such as pyruvate dehydrogenase, did not show these differences. The reductions were not observed in either cerebellum or thalamus of Alzheimer's disease brain. Analysis by immunoblots indicated that the reductions were not caused by a decrease in absolute amounts of the protein. The reduced AD synapsin I phosphorylation was not overcome by the addition of purified cyclic AMP-dependent protein kinase. No differences were detected in total cyclic AMP-dependent protein kinase activity between the control and Alzheimer samples. However, dephosphorylation of the synapsin I prior to the in vitro phosphorylation reversed the differences observed between the control and AD homogenates. Thus, the reduced in vitro phosphorylation of the synapsin I in the Alzheimer homogenate reflects a reduced phosphorylatability of the protein due to either an increased phosphate content or some other alteration of the phosphorylation site.
Brain Res Mol Brain Res 1991 Jan
PMID:Reduced in vitro phosphorylation of synapsin I (site 1) in Alzheimer's disease postmortem tissues. 185 67

The pyruvate dehydrogenase complex occupies a unique position in the anaerobic mitochondrial metabolism of the parasitic nematode Ascaris suum. This paper describes cDNA clones for the beta subunit of the pyruvate dehydrogenase component of this complex. A cDNA library has been constructed in lambda gt11 from poly(A)+ RNA isolated from adult ascarid body wall muscle. The library was screened with antiserum prepared against the beta subunit of pyruvate dehydrogenase. Full-length clones of 1.2 kb have been characterized. The first 15 amino acids determined from the purified protein match exactly those predicted from the cDNA sequence. The deduced protein sequence contains a 26-amino-acid presequence that has characteristics of mitochondrial targeting sequences. The mature protein is predicted to contain 334 amino acids and is 62% identical to the predicted sequence of the corresponding human subunit. Full-length in vitro transcripts have been translated in vitro to yield a 39-kDa polypeptide consistent with the open reading frame present in the cDNA sequence. The 90 nucleotides at the 3' end of the cDNA sequence have the potential to form a cruciform structure that may play a role in the synthesis of the enzyme.
Mol Biochem Parasitol 1991 Mar
PMID:Characterization of cDNA clones for the beta subunit of pyruvate dehydrogenase from Ascaris suum. 205 42

Two gene loci for the E1 alpha subunit of the pyruvate dehydrogenase (PDH) complex have been mapped in the mouse by in situ hybridization. One locus maps to the X chromosome in the region F3-F4, the other to chromosome 19, in band B close to the centromere. This arrangement is exactly comparable to the situation in man where there is an X-linked PDH E1 alpha locus and an autosomal locus on chromosome 4. Comparison of the regional localization of the human and mouse X-linked PDH E1 alpha genes provides further information concerning sites of rearrangement of segments of the X chromosome during mammalian evolution. The human autosomal PDH E1 alpha gene is a "processed" gene, which lacks the introns that are present in the X-linked gene. It codes for a testis-specific E1 alpha subunit that is only expressed after the onset of spermatogenesis. The comparative mapping results in the mouse suggest that the genetic organization and pattern of expression of the two PDH E1 alpha genes is the same in the two species.
Somat Cell Mol Genet 1990 Sep
PMID:Pyruvate dehydrogenase E1 alpha subunit genes in the mouse: mapping and comparison with human homologs. 212 29

The recovery of both contractile performance and metabolic response of rat heart following 1 h of ischemia after equilibration with glucose + insulin (glucose-ischemia) or with pyruvate (pyruvate-ischemia), was tested in normoxic reperfusion in the presence of glucose + insulin, pyruvate, lactate or acetate. In glucose-ischemia only the reperfusion with pyruvate results in a complete recovery of the contractile force (left ventricular pressure, LVP) (170%) and good recovery of high energy phosphate compounds. Lower LVP and tissue energy charge were found in glucose reperfusion and even less in lactate and acetate reperfusion. Disappearance of the IMP accumulated during ischemia is evident only in the pyruvate reperfusion indicating a higher metabolic recovery. On the contrary in pyruvate-ischemia all types of reperfusion tested were effective in reactivating the contractile force (although acetate to a lesser extent); the contractile activity was accompanied by a good recovery of phosphocreatine, ATP, energy charge and by the decrease of IMP. Large decreases of adenine nucleotides and NADP and lower decreases of NAD are observed during ischemia/reperfusion in both systems. Pyruvate-ischemia is quite similar to, if not worse than glucose-ischemia, for all the metabolic parameters considered, but not worse for the possibility of recovery. Some specific effect of pyruvate should be exerted during the ischemic phase. The mechanism of pyruvate protection is discussed in relationship to: (i) the possible activation of pyruvate dehydrogenase, (ii) the activation of NADPH-dependent peroxide scavenging systems, (iii) the direct scavenging action of pyruvate on H2O2.
J Mol Cell Cardiol 1990 Feb
PMID:The protective action of pyruvate on recovery of ischemic rat heart: comparison with other oxidizable substrates. 218 87


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