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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids. The activity of this mitochondrial complex is regulated by the continuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions. The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component. Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes. The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases. The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site. The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex. One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1. These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes. When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is accomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group. PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2. During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms. Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes.
Prog Nucleic Acid Res Mol Biol 2001
PMID:Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. 1164 66

In the present study, we have characterized the dihydrolipoamide dehydrogenase (DLDH) of Strepto-coccus pneumoniae and its role during pneumococcal infection. We have also demonstrated that a lack of DLDH results in a deficiency in alpha-galactoside metabolism and galactose transport. DLDH is an enzyme that is classically involved in the three-step conversion of 2-oxo acids to their respective acyl-CoA derivatives, but DLDH has also been shown to have other functions. The dldh gene was virtually identical in three pneumococcal strains examined. Besides the functional domains and motifs associated with this enzyme, analysis of the pneumococcal dldh gene sequence revealed the presence of an N-terminal lipoyl domain. DLDH-negative bacteria totally lacked DLDH activity, indicating that this gene encodes the only DLDH in S. pneumoniae. These DLDH-negative bacteria grew normally in vitro but were avirulent in sepsis and lung infection models in mice, indicating that DLDH activity is necessary for the survival of pneumococci within the host. The lack of virulence was not associated with a loss of 2-oxo acid dehydrogenase activity, as the wild-type pneumococcal strains did not contain activity of any of the known 2-oxo acid enzyme complexes. Instead, studies of carbohydrate utilization demonstrated that the DLDH-negative bacteria were impaired for alpha-galactoside and galactose metabolism. The DLDH mutants lost their ability to oxidize or grow with galactose or melibiose as sole carbon source and showed reduced oxidation and growth on raffinose or stachyose. The bacteria had an 85% reduction in alpha-galactosidase activity and showed virtually no transport of galactose into the cells, which can explain these phenotypic changes. The DLDH-negative bacteria produced only 50% of normal capsular polysaccharide, a phenotype that may be associated with impaired carbohydrate metabolism.
Mol Microbiol 2002 Apr
PMID:Characterization of the dihydrolipoamide dehydrogenase from Streptococcus pneumoniae and its role in pneumococcal infection. 1197 81

Branched-chain alpha-keto acid dehydrogenase complex (BCKADH) contains decarboxylase (E1), dihydrolipoyl transacylase (E2), and dihydrolipoyl dehydrogenase (E3) as catalytic components. BCKADH purified from rainbow trout (Oncorhynchus mykiss) liver was comparable with mammalian BCKADH in various enzymatic characteristics, but less efficient in catalyzing the overall reaction. The trout E2 subunit was larger than the mammalian subunit and rather similar to the chicken one in relative molecular mass on SDS-PAGE, whereas the E1 component was similar between trout and mammalian both in relative molecular mass of its alpha and beta subunits and in the catalytic activity. Trout E2 cDNA cloning and nucleotide sequencing revealed that the mature trout E2 subunit consists of 435 residues, and possesses 14 additional residues compared with mammalian E2. Eleven of these are localized in two interdomain segments as two sequences with two and nine residues, respectively. Trout E2 was inferior to rat E2 in the capacity for binding the E1 component, similar to chicken E2. Thus, it appears that non-mammalian BCKADH E2 is distinct from that in mammals in the structure of interdomain segments, resulting in reduction of overall activity of the enzyme complex.
Comp Biochem Physiol B Biochem Mol Biol 2002 Jun
PMID:Characterization of rainbow trout branched-chain alpha-keto acid dehydrogenase complex: inter-domain segments of the E2 component affect the overall activity. 1203 70

Ferredoxin NADP(H) oxidoreductases (FNR) are flavoenzymes that catalyze the electron transfer between NADP(H) and a wide range of compounds including ferredoxins and bacterial flavodoxins. FNRs are classified into two major groups: plant- and vertebrate-type. Plant-type FNRs are implicated in photosynthesis and nitrogen fixation in plastids and photosynthetic bacteria, and were recently implicated in cell protection against reactive oxygen species (ROS). Vertebrate-type FNRs are mitochondrial enzymes implicated in steroid hormone biosynthesis in mammals and in Fe(+) uptake and metabolism in yeasts. We have cloned and sequenced a cDNA coding for the vertebrate-type Schistosoma mansoni FNR. Gel diaphorase activity and western blot assays demonstrated that SmFNR represented the major diaphorase activity of adult worms. An active recombinant SmFNR was expressed in Escherichia coli that made the bacteria tolerant to oxygen peroxide, cumene hydroperoxide and the superoxide-generating herbicide, methyl viologen (MV).
Mol Biochem Parasitol
PMID:Schistosoma mansoni ferredoxin NADP(H) oxidoreductase and its role in detoxification. 1238 48

The pyruvate dehydrogenase complex (PDC) plays changing roles during the aerobic-anaerobic transition in the life cycle of the parasitic nematode, Ascaris suum. However, the dihydrolipoyl dehydrogenase (E3) subunit appears to be identical in all stages, despite the fact that the PDC is less sensitive to NADH inhibition in anaerobic muscle. Therefore, we have cloned cDNAs encoding E3 and a novel anaerobic-specific E3-binding protein (E3BP) that lacks the terminal lipoyl domain found in E3BPs from yeast and mammals, and functionally expressed E3 and E3 mutants designed to have decreased dimer stability on the assumption that the binding of E3 to an anaerobic-specific E3BP might stabilize the E3 dimer interface and decrease E3 sensitivity to NADH inhibition. As predicted, the mutants exhibited decreased thermal stability, increased sensitivity to NADH and the binding of E3(Y18F) to the E3-depleted core of the pig heart PDC increased E3 activity and decreased E3 sensitivity to NADH inhibition. However, although the free A. suum E3 was less sensitive to NADH inhibition than the pig heart E3, both E3s were significantly more sensitive to NADH inhibition when assayed with dihydrolipoamide than their corresponding PDCs assayed with pyruvate. More importantly, the binding of rE3 to its core complex had little effect on its apparent K(m) for NAD(+), K(i) for NADH inhibition, or the NADH/NAD(+) ratio yielding 50% inhibition. These data suggest that although binding to the core stabilizes the E3 dimer interface, it does not play a significant role in reducing the sensitivity of the A. suum PDC to NADH inhibition during anaerobiosis.
Mol Biochem Parasitol
PMID:Role of dihydrolipoyl dehydrogenase (E3) and a novel E3-binding protein in the NADH sensitivity of the pyruvate dehydrogenase complex from anaerobic mitochondria of the parasitic nematode, Ascaris suum. 1246 81

High levels of neuropeptide Y (NPY) are found in basal ganglia where it is co-localised with somatostatin (SOM) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH/d) in a population of striatal GABA containing interneurones. Although alterations occur in the levels of various neuropeptides in basal ganglia in Parkinson's disease (PD), it is not known whether NPY is affected. Using in situ hybridisation immunohistochemistry, we have examined the distribution of NPY mRNA in the caudate nucleus, putamen and nucleus accumbens of normal individuals and patients with PD. NPY mRNA was weakly expressed in the caudate nucleus, putamen and nucleus accumbens in normal individuals with a scattered labelling of neurones. However, there was no regional localisation within any brain area and no obvious differences between brain regions. In PD, the number of NPY mRNA-expressing cells was increased as was the density of the silver grains overlying each positive cell. The increase was more pronounced in the nucleus accumbens and in the ventral part of the caudate nucleus. The increase in NPY mRNA expression observed in patients with PD may reflect the loss of dopaminergic tone on striatal NPY containing interneurones, although a role for chronic L-DOPA therapy cannot be ruled out.
Brain Res Mol Brain Res 2003 Feb 20
PMID:Increased neuropeptide Y mRNA expression in striatum in Parkinson's disease. 1259 Nov 54

The funicular distribution of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd)-exhibiting axons was examined in the white matter of the rabbit spinal cord by using horizontal, parasaggital, and transverse sections. Four morphologically distinct kinds of NADPHd-exhibiting axons (2.5-3.5 microm in diameter) were identified in the sulcomarginal fasciculus as a part of the ventral column in the cervical and upper thoracic segments and in the long propriospinal bundle of the ventral column in Th3-L3 segments. Varicose NADPHd-exhibiting axons of the sympathetic preganglionic neurons, characterized by widely spaced varicosities, were found in the ventral column of Th2-L3 segments. A third kind of NADPHd-positive ultrafine axons, 0.3-0.5 microm in diameter with numerous varicosities mostly spherical in shape, was identified in large number within Lissauer's tract. The last group of NADPHd-exhibiting axons (1.0-1.5 microm in diameter) occurred in the Lissauer tract. Most of these axons were traceable for considerable distances and generated varicosities varying in shape from spherical to elliptical forms. The majority of NADPHd-exhibiting axons identified in the cuneate and gracile fascicles were concentrated in the deep portion of the dorsal column. An extremely reduced number of NADPHd-exhibiting axons, confirmed by a computer-assisted image-processing system, was found in the dorsal half of the gracile fascicle. Axonal NADPHd positivity could not be detected in a wide area of the lateral column consistent with the location of the dorsal spinoccrebellar tract. Numerous, mostly thin NADPHd-positive axonal profiles were detected in the dorsolateral funiculus in all the segments studied and in a juxtagriscal portion of the lateral column as far as the cervical and lumbar enlargements. A massive occurrence of axonal NADPHd positivity was detected in the juxtagriseal layer of the ventral column all along the rostrocaudal axis of the spinal cord. The prominent NADPHd-exhibiting bundles containing thick, smooth, nonvaricose axons were identified in the mediobasal and central portion of the ventral column. First, the sulcomarginal fasciculus was found in the basal and medial portion of the ventral column in all cervical and upper thoracic segments. Second, more caudally, a long propriospinal bundle displaying prominent NADPHd positivity was localized in the central portion of the ventral column throughout the Th3-L3 segments.
Cell Mol Neurobiol 2003 Feb
PMID:Localization and distribution patterns of nicotinamide adenine dinucleotide phosphate diaphorase exhibiting axons in the white matter of the spinal cord of the rabbit. 1270 84

Mono ADP-ribosyltransferases (ADPRTs) are a class of functionally conserved enzymes present in prokaryotic and eukaryotic organisms. In bacteria, these enzymes often act as potent toxins and play an important role in pathogenesis. Here we report a profile-based computational approach that, assisted by secondary structure predictions, has allowed the identification of a previously undiscovered ADP-ribosyltransferase in Neisseria meningitidis (NarE). NarE shows structural homologies with E. coli heat-labile enterotoxin (LT) and cholera toxin (CT) and possesses ADP-ribosylating and NAD-glycohydrolase activities. As in the case of LT and CT, NarE catalyses the transfer of the ADP-ribose moiety to arginine residues. Despite the absence of a signal peptide, the protein is efficiently exported into the periplasm of Neisseria. The narE gene is present in 25 out of 43 strains analysed, is always present in ET-5 and Lineage 3 but absent in ET-37 and Cluster A4 hypervirulent lineages. When present, the gene is 100% conserved in sequence and is inserted upstream of and co-transcribed with the lipoamide dehydrogenase E3 gene. Possible roles in the pathogenesis of N. meningitidis are discussed.
Mol Microbiol 2003 Nov
PMID:NarE: a novel ADP-ribosyltransferase from Neisseria meningitidis. 1461 61

Toxicity to o-sec-butylphenyl methylcarbamate compound (BPMC) was analyzed in the rice brown planthopper, Nilaparvata lugens, using a differential proteomics approach of identifying proteins on two dimensional-polyacrylamide gel electrophoresis (2D-PAGE). Proteome analysis from BPMC-treated brown planthopper resulted in the modulation of 22 proteins at the expression level as compared to control samples on coomassie brilliant blue (CBB) stained gels. Out of total 22 proteins, 10 proteins showed elevated expression, eight proteins showed decreased expression and four proteins showed specific expression after insecticide treatment. The N-terminal sequences of seven out of 22 proteins were determined by a gas-phase protein sequencer. The internal amino acid sequences of the 15 proteins were determined by the sequence analyses of peptides obtained by Cleveland peptide mapping method and were compared with those of the known proteins available in public databases and the EST database of the brown planthopper in our laboratory to understand the nature of the proteins. Sequence analyses revealed that the expression of putative serine/threonine protein kinase, paramyosin, HSP 90, beta-tubulin, calreticulin, ATP synthase, actin and tropomyosin was elevated, and that of beta-mitochondrial processing peptidase, dihydrolipoamide dehydrogenase, enolase and acyl-coA dehydrogenase was reduced due to the exposure of BPMC. The differential expression of these proteins reflects the overall change in cellular structure and metabolism after insecticide treatment.
Insect Biochem Mol Biol 2004 May
PMID:Proteomic analysis of brown planthopper: application to the study of carbamate toxicity. 1511 Aug 63

The cytochrome b6f complex from the thermophilic cyanobacterium Mastigocladus laminosus and spinach chloroplasts has been purified as a dimeric species. It was found by electrospray ionization mass spectroscopy to contain eight and nine subunits, respectively, and dimeric masses of 217,070 and 286,454 Da. The subunits common to the complex from both sources are petA (cytochrome f), B (cytochrome b6), C (Rieske iron-sulfur protein), D (subunit IV), and small 3.2-4.2 kDa polypeptides petG,L,M, and N. The ninth polypeptide, the 35 kDa petH poly-peptide in the spinach complex, was identified as ferredoxin NADP reductase (FNR), which binds to the complex tightly at a stoichiometry of approx 0.9 (cyt f)-1. The spinach complex contains diaphorase activity diagnostic of FNR, and is active in facilitating ferredoxin-dependent electron transfer from NADPH to the cytochrome b6f complex. The purified cytochrome b6f complex contains stoichiometrically bound chlorophyll a and beta-carotene at a ratio of one per cytochrome f, and bound lipid, in which MGDG and PG are the most abundant species. The delipidated highly purified complexes are active immediately after preparation and for approx 1 wk if left on ice, transferring 300-350 electrons/cyt f/s. Both complexes are subject to proteolysis and associated loss of activity if left for extended periods (>1 wk) at room temperature. Addition of pure synthetic lipid to the delipidated M. laminosus complex (the "lipid augmentation" technique) allows rapid and ready formation of large (>0.2 mm) crystals suitable for x-ray diffraction analysis and structure determination, which diffract with good statistics to 3.0 A.
Methods Mol Biol 2004
PMID:Purification and crystallization of the cytochrome b6f complex in oxygenic photosynthesis. 1518 70


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