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PubMed2001

Glucose and pyruvate metabolism during mouse gonadal sex differentiation.

In the mouse, gonadal sex differentiation starts around E12 and meiosis begins in the ovary shortly after E13. In the search for metabolic changes that might be correlated to gonadal sex differentiation and/or possibly the onset of meiosis, we investigated the metabolism of glucose and pyruvate in the developing mouse ovary before (E11.5-E12.5), during (E14.5-16.5), and after meiosis (E18.5), and in fetal testes without meiosis. Gonads were cultured with 14C-labeled glucose (0.02 and 5.58 mM) and 14C-pyruvate (0.17 mM). The oxidation expressed as 14CO2 production and the organification expressed as retention of 14C in the tissues were measured and correlated to the protein content of the gonads. Using 0.02 mM glucose, a decline in oxidation and organification was found in ovaries as well as in testes, which is probably related to starvation. Using 5.58 mM glucose, a continuous decline in oxidation was seen only in the testis. Organification of 0.17 mM pyruvate increased at E12.5 and E14.5 in the ovary but not in the testis. This was in despite of an exponential increase of protein content in the testes compared to only a moderate increase in the ovary. The CO2 production from 5.58 mM glucose was equal to that from 0.17 mM pyruvate in gonads of both sexes. In conclusion, an increased metabolism of 5.58 mM glucose and 0.17 mM pyruvate in the ovaries as compared to the testes is related to sex differences during gonadal formation and onset of meiosis in the ovaries. J. Exp. Zool. 288:130-138, 2001.

Animals↗
PubMed1979

Quinine protects pyruvate-kinase deficient red cells from dehydration.

Pyruvate kinase deficient red blood cells have an abnormal tendency to lose ATP when exposed to low pO2 or cyanide, whereas normal red cells do not. Once energy is depleted, all red cells take up calcium and subsequently lose intracellular potassium and water. It has been shown previously that quinine will inhibit the potassium and water flux seen in energy depleted normal cells. The present study indicates that quinine protects cyanide treated pyruvate kinase deficient erythrocytes from water and potassium loss. Quinine does not prevent ATP depletion or calcium uptake. By six hours, cyanide treated pyruvate kinase deficient cells have lost an average of 486 gm of water per kilogram cell solids and 140 mmoles of potassium per kilogram of cell solids, while cells treated with both quinine and cyanide have lost only 106 gm of water per kilogram of cell solids and 77 mmoles of potassium per kilogram of cell solids. These data support the concept that the membrane lesion in pyruvate kinase deficiency is secondary to ATP depletion and is a manifestation of the Gardos effect. Quinine may have therapeutic potential in the treatment of pyruvate kinase deficiency hemolytic anemia.

Adenosine Triphosphate↗
PubMed1979

Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease).

Autopsy examination confirmed the diagnosis of subacute necrotizing encephalomyelopathy (SNE) in a 7-month-old male infant who underwent several metabolic studies before death. Intermittent lactic acidemia and fumaric aciduria, an extreme hyperglycemic response to an intravenous bolus of alanine, and an elevated total body flux rate of glucose (58.4 mumoles . kg-1 . min-1) suggested a disturbance in the oxidative decarboxylation of pyruvate. Enzymological studies of postmortem samples revealed low nonactivated pyruvate dehydrogenase activity in liver (19.4%) and brain (53.8%). The lowest brain pyruvate dehydrogenase activities were noted in the midbrain and pontine regions. Supramaximal activation of the hepatic pyruvate dehydrogenase complex (135% of control values) occurred in vitro. Spontaneous reactivation following in vitro inactivation of the complex with adenosine triphosphate was significantly less (p less than 0.02) in the patient's samples compared to controls. The biochemical defect was not apparent in fibroblasts. These enzymological observations point to an in vivo defect in the activation mechanism of the pyruvate dehydrogenase complex as the biochemical disturbance in SNE. The findings suggest that dichloroacetate may be beneficial in treating SNE.

Alanine↗
PubMed1994

Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy.

OBJECTIVE: To evaluate the use of the lactate: pyruvate ratio as a test for the detection of zidovudine myopathy. METHODS: Twenty consecutive human immunodeficiency virus-infected patients with muscle involvement and 20 without muscle involvement were studied prospectively. Blood lactate and pyruvate levels and serum creatine kinase levels were tested, muscle involvement was assessed both clinically and electrophysiologically, and muscle biopsy was performed in patients with myopathy. RESULTS: Nine patients had biopsy-proven zidovudine myopathy. All 9 had a high lactate:pyruvate ratio, with elevations on 2 of 2 determinations in 6 patients and on 1 of 2 in 3 patients. Two of 11 patients with other myopathies and 2 of 20 patients without myopathy had a high lactate:pyruvate ratio on 1 of 2 determinations. CONCLUSION: The lactate:pyruvate ratio, when determined repeatedly, is a sensitive test for detecting mitochondrial muscular toxicity of zidovudine.

Adult↗
PubMed2004

Process strategies to enhance pyruvate production with recombinant Escherichia coli: from repetitive fed-batch to in situ product recovery with fully integrated electrodialysis.

Using the pyruvate production strain Escherichia coli YYC202 ldhA::Kan different process alternatives are studied with the aim of preventing potential product inhibition by appropriate product separation. This strain is completely blocked in its ability to convert pyruvate into acetyl-CoA or acetate, resulting in acetate auxotrophy during growth in glucose minimal medium. Continuous experiments with cell retention, repetitive fed-batch, and an in situ product recovery (ISPR) process with fully integrated electrodialysis were tested. Although the continuous approach achieved a high volumetric productivity (QP) of 110 g L(-1) d(-1), this approach was not pursued because of long-term production strain instabilities. The highest pyruvate/glucose molar yield of up to 1.78 mol mol(-1) together with high QP 145 g L(-1) d(-1) and high pyruvate titers was achieved by the repetitive fed-batch approach. To separate pyruvate from fermentation broth a fully integrated continuous process was developed. In this process electrodialysis was used as a separation unit. Under optimum conditions a (calculated) final pyruvate titer of >900 mmol L(-1) (79 g L(-1)) was achieved.

Bioreactors↗
PubMed2001

Dynamics of pyruvate metabolism in Lactococcus lactis.

The pyruvate metabolism in the lactic acid bacterium Lactococcus lactis was studied in anaerobic cultures under transient conditions. During growth of L. lactis in continuous culture at high dilution rate, homolactic product formation was observed, i.e., lactate was produced as the major end product. At a lower dilution rate, the pyruvate metabolism shifted towards mixed acid-product formation where formate, acetate, and ethanol were produced in addition to lactate. The regulation of the shift in pyruvate metabolism was investigated by monitoring the dynamic behavior of L. lactis in continuous cultures subjected to step changes in dilution rate. Both shift-up and shift-down experiments were carried out, and these experiments showed that the enzyme pyruvate formate-lyase (PFL) plays a key role in the regulation of the shift. Pyruvate formate-lyase in vivo activity was regulated both at the level of gene expression and by allosteric modulation of the enzyme. A simple mathematical model was proposed to estimate the relative significance of the regulatory mechanisms involved.

Acetates↗
PubMed1989

Antimitochondrial autoantibodies in primary biliary cirrhosis recognize cross-reactive epitope(s) on protein X and dihydrolipoamide acetyltransferase of pyruvate dehydrogenase complex.

Antimitochondrial autoantibodies are characteristically present in sera of patients with primary biliary cirrhosis. The antimitochondrial autoantibodies recognize four major antigens from beef heart mitochondria at relative molecular weights of 74, 56, 52 and 48 kD. In the present study, we report that the 56 kD antigen is the protein X of pyruvate dehydrogenase complex and that it possesses cross-reactive antimitochondrial autoantibody epitope(s) with the 74 kD antigen, the acetyltransferase (E2) of the pyruvate dehydrogenase complex. This was demonstrated by comparing the specificities of primary biliary cirrhosis sera with a protein X-specific rabbit antiserum and by absorbing primary biliary cirrhosis sera with recombinant pyruvate dehydrogenase-E2 fusion protein. In the two-dimensional gel analysis, primary biliary cirrhosis sera and protein X-specific rabbit antiserum reacted to the same two isoelectric point polypeptides at 56 kD molecular weight. The absorption of primary biliary cirrhosis sera with the human recombinant pyruvate dehydrogenase-E2 removed reactivity toward both the 74 and 56 kD antigens. Furthermore, analysis of 82 antimitochondrial autoantibody-positive primary biliary cirrhosis sera by immunoblotting did not reveal any sera which reacted solely against either the 74 or 56 kD antigen. Finally, primary biliary cirrhosis sera recognized protein X from human, bovine and porcine sources but not protein X from rat or mouse origin. The identification of protein X as another major target of the autoimmune response in primary biliary cirrhosis suggests that the pyruvate dehydrogenase complex may have a central role in the induction of this enigmatic disease.

Acetyltransferases↗
PubMed1994

2,3,7,8-Tetrachlorodibenzo-p-dioxin induced alterations of pyruvate carboxylase levels and lactate dehydrogenase isozyme shifts in C57BL/6J male mice.

A dose-dependent reduction of hepatic pyruvate carboxylase levels and activity occurs in C57BL/6J male mice given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) i.p. in a corn oil carrier. The dose range was from 1 to 75 micrograms/kg body weight and the analysis was done 8 days postinjection. At the maximum TCDD level investigated, we found a 10-fold reduction in pyruvate carboxylase activity. Furthermore, TCDD at a dose of 1 microgram/kg body weight blocks corn oil induction of an increase in the amount of pyruvate carboxylase in liver protein extracts. At doses beyond those required to initiate a reduction in pyruvate carboxylase, lactate dehydrogenase isozyme patterns shift. This is accompanied by an increase in blood lactic acid levels. We propose that TCDD-mediated reduction in pyruvate carboxylase and lactate dehydrogenase isozyme shifts may represent a major component in TCDD toxicity.

Animals↗
PubMed1978

Localization of pyruvate kinase isozymes in bovine kidney and comparison of these patterns with those of lactate dehydrogenases and aldolases.

Electrophoretic and immunofluorescence analysis were used to study the distribution of pyruvate kinase isozymes in the bovine kidney. Electrophoretic analysis demonstrated the presence of large amounts of K4 plus small amounts of K-M hybrids in cortical, medullary, and papillary sections cut from the kidney. Nearly all of the K-L hybrids seen in whole kidney extracts were found in cortical sections. Immunofluorescence of frozen sections revealed the presence of type L subunits in the tubules but the complete absence of this subunit type in flomeruli. Glomeruli do contain large quantities of pyruvate kinase isozymes, probably K4 and K-M hybrids, that cross-react with antibodies produced against type M pyruvate kinase. Type L-containing forms of pyruvate kinase and aldolase type B both appear to be found in cell types thought to be capable of catalyzing of gluconeogenesis, while type K pyruvate kinase and type A aldolase are found in predominantly glycolytic cell types of the kidney. Lactate dehydrogenase isozymic patterns appear to be less closely correlated with glycolytic versus gluconeogenic functions of the kidney but may be determined more directly by other metabolic functions.

Animals↗
PubMed2003

Pyruvate: an in vivo marker of cestodal infestation of the human brain on proton MR spectroscopy.

PURPOSE: To study intracranial cestodal cysts using in vivo proton magnetic resonance spectroscopy ((1)H MRS) in an effort to identify metabolite(s) that may help in recognizing the parasitic etiology and, perhaps, viability of such tapeworm cysts. Cestodal infestations of the human central nervous system (CNS)-cysticercosis and hydatidosis-are not rare. Identification of a scolex is considered diagnostic of cysticercosis on imaging. In its absence, however, the features are non-specific. MATERIALS AND METHODS: Three patients with intracranial hydatid cysts and 13 patients with intracranial cysticercal cysts (four intraventricular, seven parenchymal, and two subarachnoid racemose cysts) were studied on a 1.5-T MR system. In vivo (1)H MRS was performed by multivoxel two-dimensional hybrid chemical shift imaging technique (TE = 135 msec). In vitro (1)H NMR and mass spectroscopy (matrix assisted laser desorption/ionization [MALDI]) were performed on excised cysticercal and hydatid cyst fluid. MALDI spectra for pyruvate and succinate were also obtained. RESULTS: Alanine, pyruvate, and acetate were seen in all the three hydatid cysts. Lactate was seen in racemose cysticercal cysts. A large resonance at 2.4 ppm, confirmed as pyruvate at mass spectroscopy, was seen in 13 cestodal cysts. Pyruvate was not seen in one each of racemose, intraventricular, and parenchymal cysticercal cysts. CONCLUSION: Pyruvate is the predominant metabolite in cestodal cysts infesting the human CNS. It may be a marker of parasitic etiology and perhaps that of viability of such intracranial cysts.

Biomarkers↗
PubMed1980

Inhibitors of polyamine biosynthesis VII: Evaluation of pyruvate derivatives as inhibitors of S-adenosyl-L-methionine decarboxylase.

The mechanism of the enzymatic decarboxylation of S-adenosyl-L-methionine catalyzed by S-adenosyl-L-methionine decarboxylase and its inhibition by methylglyoxal bis(guanylhydrazone) were investigated. The results indicate that the carbonyl group of the pyruvate cofactor does not form an azomethine bond with an amino group of the enzyme protein. The substrate and/or product forms an azomethine bond with the pyruvate cofactor, which can be reduced efficiently with sodium cyanoborohydride. Methylglyoxal bis(guanylhydrazone) appears to interfere with the formation of the enzyme--substrate complex by competing with the substrate for binding with the active enzyme site. The dimethylaminoethylhydrazone, semicarbazone, and guanylhydrazone derivatives of pyruvic acid, ethyl pyruvate, pyruvic acid amide, and pyruvyl glycineamide were synthesized. None of these compounds had significant inhibitory activity on the enzymatic decarboxylation of S-adenosyl-L-methionine by S-adenosyl-L-methionine decarboxylase from rat liver in vitro. These results indicate that the structural requirements for binding of methylglyoxal bis(guanylhydrazone) to the enzyme are strict and that structural modifications of this compound result in a dramatic loss of activity.

Adenosylmethionine Decarboxylase↗
PubMed2001

Prenatal diagnosis of pyruvate dehydrogenase deficiency using magnetic resonance imaging.

INTRODUCTION: Pyruvate dehydrogenase deficiency is an inherited inborn error of metabolism associated with early neonatal death and long-term neurologic sequelae in survivors. Prenatal diagnosis currently relies on isolation of fetal cells for subsequent genetic and/or biochemical studies. Magnetic resonance imaging and magnetic resonance spectroscopy have been used on occasion for both postnatal diagnosis and management of pyruvate dehydrogenase deficiency. We illustrate a case in which these non-invasive modalities also prove useful for prenatal diagnosis of this condition. CASE: A 31-year-old multipara with a history of two prior infants affected with pyruvate dehydrogenase deficiency presented with a spontaneous dichorionic, diamniotic twin pregnancy. Magnetic resonance imaging and magnetic resonance spectroscopy were performed on both fetuses. Magnetic resonance imaging of the presenting (male) fetus demonstrated mild ventriculomegaly, increased extracerebrospinal fluid, and decreased cortical sulcation and gyration. The non-presenting (female) fetus was structurally normal. Magnetic resonance spectroscopy spectra were obtained for both fetuses, and were normal. The diagnosis of pyruvate dehydrogenase deficiency was made in the presenting fetus after delivery on the basis of subsequent mortality from severe lactic acidosis. CONCLUSION: Prenatal MR imaging of the fetal brain can be used for prenatal diagnosis in fetuses at risk for pyruvate dehydrogenase deficiency. Prenatal MR spectroscopy, although technically feasible, does not appear to have a role in the prenatal diagnosis of this condition.

Acidosis, Lactic↗
PubMed1993

Role of flavin in acetoin production by two bacterial pyruvate oxidases.

Escherichia coli pyruvate oxidase (POXEC) requires FAD both for the oxidative decarboxylation of pyruvate to acetate and CO2 and for the formation of acetoin from pyruvate and acetaldehyde. Prior work has shown that the catalytic activity (kcat/Km) for POXEC in the oxidative reaction is stimulated approximately 450-fold by amphiphilic activators. This paper shows that the acetoin reaction does not respond to activation. The FAD requirement for acetoin formation can be replaced by 5-deaza-FAD and 6-hydroxy-FAD, FAD analogs which form kinetically stable oxidized and reduced enzyme species, respectively. As would be expected, the 5-deaza- and 6-hydroxy-FAD enzymes are not active in the oxidative reaction. A second flavin pyruvate oxidase from Pediococcus pseudomonas (POXPP), which catalyzes the oxidative decarboxylation of pyruvate to CO2 and acetyl phosphate, also requires FAD for acetoin formation. POXPP has an oxidative rate comparable to that of POXEC, but in comparison to POXEC, POXPP catalyzes acetoin formation at a much reduced rate. Again, as was found with the POXEC, an FAD analog incapable of undergoing facile oxidation-reduction reactions also could replace the FAD requirement in the POXPP acetoin reaction. The results indicate that the role for FAD in acetoin formation with both enzymes is based on a structural requirement and that FAD does not participate in a redox function in the acetoin reaction.

Acetoin↗
PubMed1996

Identification of novel alternatively spliced pyruvate carboxylase mRNAs with divergent 5'-untranslated regions which are expressed in a tissue-specific manner.

We have identified and characterized multiple mRNA transcripts of rat and human pyruvate carboxylases [EC 6.4.1.1] using rapid amplification of cDNA 5' ends-polymerase chain reaction (RACE-PCR). Five alternative forms of rat pyruvate carboxylase cDNAs have been identified in liver, kidney, brain, and adipose tissue and these are expressed in a tissue-specific manner. Two alternative forms of human pyruvate carboxylase cDNA have also been identified in liver. These pyruvate carboxylase cDNAs have a common coding region but differ in their 5' untranslated regions (5'UTRs), suggesting that they are generated by alternative splicing of the primary transcript. Southern blot analysis of restriction enzyme digested rat genomic DNA revealed that pyruvate carboxylase is encoded by a single copy gene.

Alternative Splicing↗
PubMed1997

The pkI gene encoding pyruvate kinase I links to the luxZ gene which enhances bioluminescence of the lux operon from Photobacterium leiognathi.

Partial 3'-end nucleotide sequence of the pkI gene (GenBank accession No. AF019143) from Photobacterium leiognathi ATCC 25521 has been determined, and the encoded pyruvate kinase I is deduced. Pyruvate kinase I is the key enzyme of glycolysis, which converts phosphoenol pyruvate to pyruvate. Alignment and comparison of pyruvate kinase Is from P. leiognathi, E. coli and Salmonella typhimurium show that they are homologous. Nucleotide sequence reveals that the pkI gene is linked to the luxZ gene that enhances bioluminescence of the lux operon from P. leiognathi. The gene order of the pkI and luxZ genes is-pk1-ter-->-R&R"-luxZ-ter"-->, whereas ter is transcriptional terminator for the pkI and related genes, and R&R" is the regulatory region and ter" is transcriptional terminator for the luxZ gene. It clearly elicits that the pkI gene and luxZ gene are divided to two operons. Functional analysis confirms that the potential hairpin loop omega T is the transcriptional terminator for the pkI and related genes. It infers that the pkI and related genes are simply linked to the luxZ gene in P. leiognathi genome.

Amino Acid Sequence↗
PubMed1985

Evidence for calcium enhanced phosphorylation of pyruvate kinase by pancreatic islets.

Pancreatic islet cytosol contains a calcium-calmodulin dependent protein kinase that can mediate the phosphorylation of an endogenous protein that has an Mr of 57 000, as well as exogenous muscle pyruvate kinase (subunit Mr, 57 000). EGTA and trifluoperazine decreased the phosphorylation. Alkaline inactivation of pyruvate kinase made it a better substrate for the kinase. As in rat islet cytosol, rabbit islet cytosol catalyzed the phosphorylation of a 57 000 Mr protein in the presence of calcium and calmodulin. This phosphoprotein was immunoprecipitated with anti-pyruvate kinase antibody. This is consistent with the idea that the 57 000 Mr phosphoprotein in islet cytosol is the subunit of pyruvate kinase. The paper following this paper shows that the kinetic and immunologic properties of the islet pyruvate kinase indicate it is the M2 isoenzyme and that its phosphorylation does not affect its catalytic activity.

Animals↗
PubMed1986

Difference of 14C turnovers in brain and in transplanted glioma after intravenous injection of 14C-1-pyruvate into rats.

Carbon 14 from 14C-1-pyruvate injected intravenously into glioma-transplanted rats was incorporated into various compounds in the brain and in the tumor. In the brain the majority of activity was found in CO2 (60%), and minor activities were found in alanine, lactate (15%), glutamate, and aspartate, with decreasing order, 5 min after injection. In the tumor, at 5 min, the largest activity was in lactate (56%), and lower activities were found in CO2 (24%), alanine, glutamate, and aspartate. The total 14C concentration in the tumor was twice that in the brain at 5 min and 15 min. The result was in accordance with the prediction that in brain, where the mitochondrial function is active, 14C-1-pyruvate will be oxidized completely into 14CO2, and that in tumor, where the mitochondrial function is insufficient, 14C-1-pyruvate will be converted only into 14C-lactate and prevent further degradation. It may be assumed that this difference in the turnover of 14C of 14C-1-pyruvate between brain and tumor could constitute a basis for the 'hot' visualization of human brain tumor using cyclotron-produced 11C-1-pyruvate and positron-emission tomography.

Animals↗
PubMed1976

Pyruvate kinase isozymes in man. I. M type isozymes in adult and foetal tissues, electrofocusing and immunological studies.

Anti human M2 type and anti human L type pyruvate kinase sera allowed us to distinguish two groups of pyruvate kinase in man. Erythrocyte and liver (L type) enzymes on the one hand were inhibited by anti L and not all by anti M2 serum; pyruvate kinase from all the other tissues on the other hand were inhibited by anti M2 and not at all by anti L serum. This latter group represent the M type pyruvate kinase isozymes. The M type isozymes have been studied by electrofocusing in thin layer acrylamide-ampholine gel. In adult tissues 4 types of isozymes were found, designated, from acid to alkaline pH, as M2 (predominant form in spleen, leukocytes, lung...), M3, M4 and M1 (predominant form in muscle and brain). In foetal tissues an extra band M2, called M2f, more anodic than M2, was added to the previously described isozymes. Except in brain (in which the isozymes M2, M3, M4 and M1 were found), the most anodic bands (M2f, M2 and M3) were predominant in all the foetal tissues. The isozymes M2f and M2 seem therefore to be the original M type pyruvate kinase forms from which the other isozymes issue. The rate of each isozyme seems to depend on tissue factors characterizing the state of differentiation of some tissues, as indicated by the ability of adult muscle extracts to change the isozymes M2 and M3 into more cathodic forms.

Adult↗