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PubMed1981

Substrate specificity of the pyruvate dehydrogenase complex from Escherichia coli.

The investigation of the substrate specificity of the pyruvate dehydrogenase complex from Escherichia coli allows a description of the binding region of pyruvate. Substrate analogs with electronegative substitutions in the methyl group show a strong competitive inhibition of the overall reaction of the pyruvate dehydrogenase complex. The most efficient inhibitor is fluoropyruvate which has a more than 100-fold higher affinity for the enzyme than pyruvate (Ki = 1.4 x 10(-6) M) does. The affinity of alpha-keto acids decreases with increasing chain length. Branched chain alpha-keto acids are even less effective inhibitors (Ki = approximately 0.02 M). alpha-Ketobutyrate is the only alpha-keto acid which is able to substitute for pyruvate as a substrate in the overall reaction of the enzyme complex. The Km value (3 mM) is 10-fold greater than that for pyruvate. The steady state kinetics of the overall reaction of alpha-ketobutyrate exhibits the same cooperativity (nh = 1.9) as seen with pyruvate. Small modifications of the carbonyl or the carboxyl group of pyruvate prevent binding completely. Binding of pyruvate to the pyruvate dehydrogenase complex may thus require interaction with two independent electrophilic centers. The acceptance of the methyl group seems not so much due to lipophilic interactions as to a steric effect. The experiments were carried out with an enzyme which was purified by a modified procedure which is faster and more convenient than previous methods. The procedure is applicable up to 0.5 liter of crude extract.

Binding Sites↗

PubMed1980

Bovine kidney pyruvate dehydrogenase complex. Limited proteolysis and molecular structure of the lipoate acetyltransferase component.

1. Bovine kidney pyruvate dehydrogenase multienzyme complex is inactivated by elastase in a similar manner as described earlier for papain. The core component, lipoate acetyltransferase, is cleaved by elastase into an active fragment (Mr 26000) and a fragment with apparent Mr of 45000 as analyzed by dodecylsulfate gel electrophoresis. Due to the fragmentation of the core, the enzyme complex is disassembled into its component enzymes which retain their complete enzymatic activities as assayed separately. 2. A different mechanism was found for the inactivation of pyruvate dehydrogenase complex with trypsin and some other proteases (chymotrypsin, clostripain). In these cases, the pyruvate dehydrogenase component is inactivated rapidly by limited proteolysis. More slowly, the enzyme complex is disassembled simultaneously with fragmentation of the lipoate acetyltransferase which again results in an active fragment of Mr 26000 and another fragment of apparent Mr 45000. Upon prolonged proteolysis, the latter fragment is cleaved further to give products of Mr 36000 or lower. 3. The enzyme-bound lipoyl residues of the pyruvate dehydrogenase complex have been labelled covalently by incubation with [2-14C]pyruvate. After treatment of this [14C]acetyl-enzyme with papain, elastase, or trypsin, radioactivity was associated exclusively with the 45000-Mr and 36000-Mr fragments but not with the active 26000-Mr fragment. 4. It is concluded that the bovine kidney lipoate acetyltransferase core is composed of 60 subunits each consisting of two dissimilar folding domains. One of these contains the intersubunit binding sites as well as the active center for transacylation whereas the other possesses the enzyme-bound lipoyl residues.

Acetyltransferases↗

PubMedDate not supplied

[Isolation and characterization of a membrane-bound pyruvate dehydrogenase complex from the phototrophic bacterium Rhodospirillum rubrum (author's transl)].

The pyruvate dehydrogenase complex from the photosynthetic bacterium Rhodospirillum rubrum was associated with the membrane fraction both in heterotrophically and photosynthetically grown cells. The complex was separated from the membranes and partially purified by precipitation with MgSO4 and gelfiltration through Sepharose 4B. The purified complex had a specific activity of 1.5-2mumol/min-mg protein and contained the following partial activities: pyruvate dehydrogenase (EC 1.2.4.1), dihydrolipoamide transacetylase (EC 2.3.1.12) and dihydrolipoamide dehydrogenase (EC 1.6.4.3). Contrary to other bacterial pyruvate dehydrogenase complexes, the enzyme complex from R. rubrum revealed no cooperatively between pyruvate binding sites. The kinetic constants (Km) for the overall reaction were (in mM): 0.14 (pyruvate), 0.07 (NAD) and 0.025 (coenzyme A). The Km for thiamine pyrophosphate was dependent on the nature and the concentration of the divalent metal ion (Mn or Mg) present in the reaction mixture, the values ranging from 0.5 to 3 micrometer. NADH was a potent inhibitor (Ki=5 micrometer) of the enzyme complex and the dihydrolipo amide dehydrogenase. The inhibition was competitive with respect to NAD. In addition to its rapid inhibitory effect, NADH also inactivated the enzyme. Cysteine partially protected the enzyme complex against NADH-inactivation. Acetyl-coenzyme A also inhibited the overall reaction (Ki=40 micrometer). The inhibition was dependent on the concentration of coenzyme A, but independent of the concentration of pyruvate. Sugar phosphates, phosphoenolpyruvate, citric acid cycle intermediates and nucleosidephosphates (1 mM) had no pronounced effect on the overall reaction.

Acetyl Coenzyme A↗

PubMed1996

Alcaligenes eutrophus possesses a second pyruvate dehydrogenase (E1).

Two gene loci, which hybridized with pdhA, the structural gene of the E1 component of the Alcaligenes eutrophus pyruvate dehydrogenase complex [Hein, S. & Steinbüchel, A. (1994) J. Bacteriol. 176, 4394-4408], were identified on two nonrelated A. eutrophus chromosomal BamHI fragments by using a pdhA-specific DNA probe. These data indicated that A. eutrophus possesses, beside PdhA, two additional distinct pyruvate dehydrogenases (E1). A 6.8-kbp genomic BamHI fragment of A. eutrophus was cloned, and sequence analysis of a 3.896-kbp region revealed the structural gene pdhE (2.694 kbp) for a second pyruvate dehydrogenase (E1), which was not clustered with structural genes for other components of 2-oxo acid dehydrogenase complexes. The A. eutrophus pdhE gene product (898 amino acid residues) exhibited significant similarities to the E1 components of the pyruvate dehydrogenase complexes of A. eutrophus, Neisseria meningitidis, Escherichia coli and Azotobacter vinelandii, which are also composed of only one type of subunit. Heterologous expression of pdhE in the aceEF deletion mutant E. coli YYC202 was demonstrated by spectrometric detection of enzyme activities and by phenotypic complementation to acetate prototrophy. These complementation studies indicated that the E1 component of the A. eutrophus pyruvate dehydrogenase complex can be replaced by a functionally active pdhE gene product.

Alcaligenes↗

PubMed1988

The dihydrolipoyltransacetylase component of the pyruvate dehydrogenase complex from Azotobacter vinelandii. Molecular cloning and sequence analysis.

The gene encoding the dihydrolipoyltransacetylase component (E2) of the pyruvate dehydrogenase complex from Azotobacter vinelandii has been cloned in Escherichia coli. A plasmid containing a 2.8-kbp insert of A. vinelandii chromosomal DNA was obtained and its nucleotide sequence determined. The gene comprises 1911 base pairs, 637 codons excluding the initiation codon GUG and stop codon UGA. It is preceded by the gene encoding the pyruvate dehydrogenase component (E1) of pyruvate dehydrogenase complex and by an intercistronic region of 11 base pairs containing a good ribosome binding site. The gene is followed downstream by a strong terminating sequence. The relative molecular mass (64913), amino acid composition and N-terminal sequence are in good agreement with information obtained from studies on the purified enzyme. Approximately the first half of the gene codes for the lipoyl domain. Three very homologous sequences are present, which are translated in three almost identical units, alternated with non-homologous regions which are very rich in alanyl and prolyl residues. The N-terminus of the catalytic domain is sited at residue 381. Between the lipoyl domain and the catalytic domain, a region of about 50 residues is found containing many charged amino acid residues. This region is characterized as a hinge region and is involved in the binding of the pyruvate dehydrogenase and lipoamide dehydrogenase components. The homology with the dihydrolipoyltransacetylase from E. coli is high: 50% amino acid residues are identical.

Acetyltransferases↗

PubMed1980

Isolation and properties of pyruvate dehydrogenase complex mutants of Pseudomonas aeruginosa PAO.

Four independent ace mutants of Pseudomonas aeruginosa PAO lacking the activity of the pyruvate dehydrogenase complex have been isolated. They resembled ace mutants of Escherichia coli and Salmonella typhimurium in requiring acetate as an essential supplement for aerobic growth on glucose, succinate or lactate and in their ability to utilize acetate as sole carbon and energy source. Assays for the individual components of the pyruvate dehydrogenase complex indicated that they lacked the pyruvate dehydrogenase component (El) or the pyruvate dehydrogenase and dihydrolipoamide acetyltransferase components (E1 and E2) but not the lipoamide dehydrogenase component (E3). Genetic studies with plasmid R68.45-mediated conjugation and phage F116L-mediated transduction indicated that the ace mutations are located at approximately 15 min in the P. aeruginosa PAO linkage map.

Acetates↗

PubMed1983

Elementary steps in the reaction of the pyruvate dehydrogenase complex from pig heart. Kinetics of thiamine diphosphate binding to the complex.

In the progress curve of the reaction of the pyruvate dehydrogenase complex, a lag phase was observed when the concentration of thiamin diphosphate was lower than usual (about 0.2-1 mM) in the enzyme assay. The length of the lag phase was dependent on thiamin diphosphate concentration, ranging from 0.2 min to 2 min as the thiamin diphosphate concentration varied from 800 nM to 22 nM. The lag phase was also observed in the elementary steps catalyzed by the pyruvate dehydrogenase component. A Km value of 107 nM was found for thiamin diphosphate with respect to the steady-state reaction rate following the lag phase. The pre-steady-state kinetic data indicate that the resulting lag phase was the consequence of a slow holoenzyme formation from apoenzyme and thiamin diphosphate. The thiamin diphosphate can bind to the pyruvate dehydrogenase complex in the absence of pyruvate, but the presence of 2 mM pyruvate increases the rate constant of binding from 1.4 X 10(4) M-1 S-1 to 1.3 X 10(5) M-1 S-1 and decreases the rate constant of dissociation from 2.3 X 10(-2) S-1 to 4.1 X 10(-3) S-1. On the other hand, the effect of pyruvate on the thiamin diphosphate binding revealed the existence of a thiamin-diphosphate-independent pyruvate-binding site in the pyruvate dehydrogenase complex. Direct evidence was also obtained with fluorescence techniques for the existence of this binding site and the dissociation constant of pyruvate was found to be 0.38 mM. On the basis of these data we have proposed a random mechanism for the binding of pyruvate and thiamin diphosphate to the complex. Binding of substrates to the enzyme complex caused an increase in the fluorescence of the dansylaziridine-labelled pyruvate dehydrogenase complex, showing that binding of substrates to the complex is accompanied by structural changes.

Animals↗

PubMed1985

Pyruvate and acetate oxidation by leukocytes in vitro. Activation of the pyruvate dehydrogenase complex by uncoupling of oxidative phosphorylation.

Pyruvate oxidation by normal intact leukocytes has been systematically studied to define optimal conditions for detection of enzymatic defects in this process. Leukocytes were isolated by dextran sedimentation and lymphocytes by Ficoll centrifugation. Cells were incubated for 2 h with [1-14C]-pyruvate, [2-14C]-pyruvate or [1-14C]-acetate as substrate. The specific oxidative capacity of lymphocytes was almost three times higher than that of granulocytes from the same blood. Oxidation of both pyruvate and acetate was highly dependent on the substrate concentration in the medium reaching a plateau between 0.5 and 1.0 mmol/l. Addition of succinate (1 mmol/l) stimulated oxidation of [1-14C]-pyruvate by 30%. Uncoupling of phosphorylation by addition of carbonyl cyanide chlorophenylhydrazone (CCCP) (0.1 mumol/l) increased oxidation of [1-14C]-pyruvate by 200% and of [1-14C]-acetate by 70%. Addition of CCCP plus succinate caused further stimulation of pyruvate oxidation (+40%), but not of acetate oxidation. It is therefore concluded that: (1) Lymphocytes are better than mixed leukocytes for oxidative studies. (2) Unlabelled substrate should be added at optimal concentrations. (3) The pyruvate dehydrogenase complex is normally only partially active in lymphocytes. (4) Stimulation of oxidation by CCCP greatly enhances the flux through the PDH step thus facilitating the detection of defects in pyruvate oxidation.

Acetates↗

PubMed1991

Demonstration of an unstable variant of pyruvate dehydrogenase protein (E1) in cultured fibroblasts from a patient with congenital lactic acidemia.

The deficiency of pyruvate dehydrogenase enzyme complex causes congenital lactic acidemia and devastating neurologic abnormalities in newborns and children. In the majority of cases, the basic defect appears to be in the pyruvate dehydrogenase (E1) component, which consists of two subunits, alpha and beta. Whereas some patients are deficient of a single subunit, in other patients both subunits of E1 are missing. To find out why two proteins were deficient, we investigated the cultured fibroblasts of a female patient who had missing E1-alpha and E1-beta protein bands on Western blot. Radiolabeling-immunoprecipitation studies with 35S-methionine revealed that patient fibroblasts synthesized normal sized precursor E1-alpha and E1-beta proteins, which were presumably transported into mitochondria and processed into normal sized mature proteins. However, pulse-chase analysis showed that alpha- and beta-proteins were degraded rapidly compared to normal. Our findings proved that alpha- and beta-subunits were synthesized and processed normally but failed to form a stable structure for incorporation into the pyruvate dehydrogenase complex.

Cells, Cultured↗

PubMed1987

The effect of diet composition on weight gain and pyruvate dehydrogenase activity in heart muscle in the gold thioglucose obese mouse.

Pyruvate dehydrogenase complex activity is the major determinant of glucose oxidation in animal cells. Tissue glucose oxidation is reduced in obesity and states of insulin resistance and alternate fuels are utilized for energy and pyruvate dehydrogenase activity is reduced in cardiac muscle in obesity. The effect of four different diets (standard laboratory chow, high-carbohydrate, high-protein and high-fat) on weight gain, cardiac pyruvate dehydrogenase activity (PDHa) and serum insulin, glucose and free fatty acids was studied in the gold thioglucose obese mouse. All four diets produced significant weight gain in the gold thioglucose injected animal. Cardiac PDHa was influenced by both obesity and diet composition. The obese chow-fed animals had significantly reduced PDHa. On high-carbohydrate and high-protein feeding lean controls had a significant decrease in cardiac PDHa compared to chow-fed controls, but only in high-carbohydrate-fed animals was this further reduced by obesity. High-fat feeding produced a rapid and almost complete suppression of PDHa in both lean and obese animals. Serum insulin, glucose and free fatty acids were also affected by diet as well as obesity. The highest serum insulins were found in chow-fed obese animals whereas the highest serum glucoses were in high-carbohydrate-fed obese animals. Hyperinsulinaemia did not develop in the high-fat-fed obese animal, but the highest serum free fatty acids were found in high-fat feeding. It is concluded that both diet composition and obesity affect cardiac PDHa and therefore glucose utilization in this tissue. Insulin resistance in the acute stages of obesity development is also affected by diet composition.

Animals↗

PubMed1980

Bovine kidney pyruvate dehydrogenase complex. Isolation of the component enzymes after limited proteolysis with papain.

1. Bovine kidney pyruvate dehydrogenase multienzyme complex is inactivated rapidly by papain. However, none of the component activities of the complex is destroyed during inactivation of the overall reaction. 2. The core component, lipoate acetyltransferase, is cleaved by papain to give principal fragments with Mr 26,500 and 26,000 (as determined by dodecylsulfate gel electrophoresis). Much more slowly, the alpha chain of the pyruvate dehydrogenase component is attacked. 3. Fragmented lipoate acetyltransferase retains its complete enzymatic activity and remains of high molecular weight. It is unable, however, to bind the other component enzymes, pyruvate dehydrogenase and lipoamide dehydrogenase. Therefore, the multienzyme complex is disassembled when treated with papain. 4. A method is described which allows the rapid and convenient isolation of nicked lipoate acetyltransferase as well as unfragmented pyruvate dehydrogenase and lipoamide dehydrogenase from papain-treated complex under very mild conditions. The two uncleaved component enzymes have identical properties and similar specific activities as enzyme preparations obtained by other, more laborious procedures.

Acetyltransferases↗

PubMed1984

Properties and regional distribution of pyruvate dehydrogenase kinase in rat brain.

A method is described to measure directly in rat brain the activity of pyruvate dehydrogenase kinase (PDHa kinase; EC 2.7.1.99), which catalyzes the inactivation of pyruvate dehydrogenase complex (PDHC, EC 1.2.4.1, EC 2.3.1.12, and EC 1.6.4.3). The activity showed the expected dependence on added ATP and divalent cation, and the expected inhibition by dichloroacetate, pyruvate, and thiamin pyrophosphate. These results, and the properties of pyruvate dehydrogenase phosphate phosphatase (EC 3.1.3.43), indicate that the mechanisms of control of phosphorylation of PDHC seem qualitatively similar in brain to those in other tissues. Regionally, PDHa kinase is more active in cerebral cortex and hippocampus, and less active in hypothalamus, pons and medulla, and olfactory bulbs. Indeed, the PDHa kinase activity in olfactory bulbs is uniquely low, and is more sensitive to inhibition by pyruvate and dichloroacetate than that in the cerebral cortex. Thus, there are significant quantitative differences in the enzymatic apparatus for controlling PDHC activity in different parts of the brain.

Adenosine Triphosphate↗

PubMed1999

Pyruvate dehydrogenase from Azotobacter vinelandii. Properties of the N-terminally truncated enzyme.

The pyruvate dehydrogenase multienzyme complex (PDHC) catalyses the oxidative decarboxylation of pyruvate and the subsequent acetylation of coenzyme A to acetyl-CoA. Previously, limited proteolysis experiments indicated that the N-terminal region of the homodimeric pyruvate dehydrogenase (E1p) from Azotobacter vinelandii could be involved in the binding of E1p to the core protein (E2p) [Hengeveld, A. F., Westphal, A. H. & de Kok, A. (1997) Eur J. Biochem. 250, 260-268]. To further investigate this hypothesis N-terminal deletion mutants of the E1p component of Azotobacter vinelandii pyruvate dehydrogenase complex were constructed and characterized. Up to nine N-terminal amino acids could be removed from E1p without effecting the properties of the enzyme. Truncation of up to 48 amino acids did not effect the expression or folding abilities of the enzyme, but the truncated enzymes could no longer interact with E2p. The 48 amino acid deletion mutant (E1pdelta48) is catalytically fully functional: it has a Vmax value identical to that of wild-type E1p, it can reductively acetylate the lipoamide group attached to the lipoyl domain of the core enzyme (E2p) and it forms a dimeric molecule. In contrast, the S0.5 for pyruvate is decreased. A heterodimer was constructed containing one subunit of wild-type E1p and one subunit of E1pdelta48. From the observation that the heterodimer was not able to bind to E2p, it is concluded that both N-terminal domains are needed for the binding of E1p to E2p. The interactions are thought to be mainly of an electrostatic nature involving negatively charged residues on the N-terminal domains of E1p and previously identified positively charged residues on the binding and catalytic domain of E2p.

Amino Acid Sequence↗

PubMed1989

The behaviour of pyruvate dehydrogenase in circulating lymphocytes from diabetic children.

The basal and total pyruvate dehydrogenase activities were assayed in circulating lymphocytes from children with juvenile diabetes at diagnosis and after five days of insulin therapy and from control subjects. In untreated diabetic children, basal and total pyruvate dehydrogenase activities were deeply decreased and both showed very similar values; whereas, in control subjects basal activity was about 30% lower than total activity. In diabetic patients treated with insulin (in vivo situation), both basal and total activity levels were equal or even higher than those of the control subjects. The incubation of lymphocytes from diabetic patients with insulin (5 microU/ml) (in vitro situation) stimulates, but less than in vivo, the basal and total pyruvate dehydrogenase activities.

Blood Glucose↗

PubMed1987

Catecholamine activation of pyruvate dehydrogenase in white adipose tissue of the rat in vivo.

Intraperitoneal injections of noradrenaline or adrenaline into rats increased the proportion of pyruvate dehydrogenase in the active state in white adipose tissue; this effect of catecholamines was also apparent in streptozotocin-diabetic rats, showing that it was not due to an increase in serum insulin concentration. The catecholamine-induced increase in pyruvate dehydrogenase of white adipose tissue in vivo was completely blocked by prior injection of either the beta-antagonist propranolol or the alpha 1-antagonist prazosin. Cervical dislocation of conscious rats increased pyruvate dehydrogenase activity of white adipose tissue, which was prevented by prior injection of propranolol. Adrenaline (30 nM) activated pyruvate dehydrogenase in white adipocytes in vitro; the maximum effect of adrenaline required activation of both alpha 1- and beta-receptors. The results show that catecholamines activate pyruvate dehydrogenase of white adipose tissue both in vivo and in vitro and that this effect is mediated by a combination of alpha 1- and beta-adrenergic receptors.

Adipose Tissue↗

PubMed1993

Altered pyruvate dehydrogenase control and mitochondrial free Ca2+ in hearts of cardiomyopathic hamsters.

The fraction of total pyruvate dehydrogenase in the active, dephosphorylated form is much lower in the glucose-perfused isolated hearts of two myopathic strains of Syrian hamster (BIO 14.6 and TO-2) than in the hearts of healthy control animals (F1B). The myopathic hearts also develop significantly less pressure under these conditions. Experiments with isolated myocytes from the BIO 14.6 heart reveal that intramitochondrial free Ca2+ ([Ca2+]m), a positive effector of pyruvate dehydrogenase interconversion, rises much less in response to a protocol of increased frequency of electrical stimulation and adrenergic stimulation than does [Ca2+]m in cells from the healthy control animals (viz from 248 +/- 15 to 348 +/- 44 nM in BIO 14.6 vs. from 241 +/- 35 to 830 +/- 124 nM in F1B, at 4 Hz). As the concentration of Ca2+ that produces half-maximal activation of pyruvate dehydrogenase within mitochondria is 650 nM, this difference between strains is likely the mechanism of the altered enzyme interconversion. The lesser response of [Ca2+]m to electrical stimulation in the BIO 14.6 cells probably results mainly from smaller systolic transients in cytosolic free Ca2+ in response to excitation of single myocytes from the BIO 14.6 animal. Lowered values of [Ca2+]m within the range described would compromise not only pyruvate dehydrogenase activity, but also flux through the tricarboxylate cycle in the myopathic heart, owing to the sensitivity of 2-oxoglutarate dehydrogenase to Ca2+. This may explain the decreased activity of oxidative phosphorylation and performance of work in the myopathic heart.

Animals↗

PubMed1996

Stoichiometry of binding of mature and truncated forms of the dihydrolipoamide dehydrogenase-binding protein to the dihydrolipoamide acetyltransferase core of the pyruvate dehydrogenase complex from Saccharomyces cerevisiae.

The dihydrolipoamide dehydrogenase-binding protein (E3BP), a component of the Saccharomyces cerevisiae and mammalian pyruvate dehydrogenase (PDH) complexes, anchors an E3 homodimer inside each of the 12 pentagonal faces of the 60-mer dihydrolipoamide acetyltransferase (E2). To gain further insight into the number and localization of binding sites for E3BP on the 60-mer E2, truncated forms of the E3BP lacking the lipoyl and E3-binding domains were engineered by deletion mutagenesis. The recombinant proteins contained a polyhistidine extension on the amino terminus to facilitate purification to near-homogeneity. The stoichiometry of binding of the truncation mutants to a truncated form (inner core) of E2 (tE2, residues 181-454), lacking the lipoyl domain and the E1-binding domain, was determined. Mixtures containing tE2 and excess intact or truncated forms of E3BP were subjected to ultracentrifugation to separate the large complexes from unbound E3BP or tE3BP, and the complexes were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After staining with Coomassie brilliant blue and destaining, the gels were analyzed with a video area densitometer. The results showed that tE2 binds about 20 copies of intact E3BP-H, about 24 copies of tE3BP-H144 (residues 144-380), lacking the lipoyl domain, and about 31 copies of tE3BP-H218 (residues 218-380), lacking both the lipoyl and E3-binding domains. The results indicate that there apparently is a binding site for E3BP on each E2 subunit and that steric hindrance by segments of E3BP prevents full stoichiometric binding of E3BP to the pentagonal dodecahedron-like E2.

Acetyltransferases↗

PubMed1989

X-chromosome localization of the functional gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex.

The functional gene locus for the E1 alpha subunit of the human pyruvate dehydrogenase complex has been localized to the p22.1-22.2 region of the X chromosome by in situ hybridization and analysis of somatic cell hybrids with various human X-chromosome rearrangements. Another locus showing significant cross-hybridization with an E1 alpha cDNA probe was detected on chromosome 4, in the region q22. The X-chromosome localization of the pyruvate dehydrogenase E1 alpha subunit gene provides a number of possible explanations for the clinical and biochemical variability which is a major feature of human pyruvate dehydrogenase deficiency.

Animals↗