Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied a PDH deficient patient who is clinically responsive to thiamine. High Km and low Vmax values for the TPP were identified in the patient's cultured cells. Immunoblot analysis detected trace amount of mutant E1 alpha polypeptide which was 3.5 KD larger than normal in size. Four-nucleotide deletion in the E1 alpha gene causes a reading frame shift, producing an abnormal polypeptide with additional 31 amino acids at C-terminus of the E1 alpha subunit. The tryptophan (codon 383) and lysine (385) residues near the C-terminus might play a crucial role in the binding of TPP to the E1.
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PMID:Thiamine responsive pyruvate dehydrogenase deficiency. 129 18

We report the molecular characterization of a case of a functional PDH-E1 (E1 subunit of pyruvate dehydrogenase) deficiency, a cause of severe congenital lactic acidosis. Residual PDH-E1 activity was reduced to 10% of normal values, although the subunit appeared to be quantitatively and qualitatively normal at the protein level as determined by Western blotting. The sequence of PDH-E1 alpha mRNA and the corresponding genomic DNA revealed an in-frame 21-bp insertion between codons 305 and 306 of the normal E1 alpha cDNA. The mutational insert commences with a novel GAT codon and is a nearly perfect tandem duplication of the wild type DNA sequence. A serine phosphorylation site regulating the activity of the PDH complex is altered by this insertion, which in all likelihood is responsible for the functional enzymatic deficiency leading to lactic acidosis.
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PMID:Pyruvate dehydrogenase (PDH) deficiency caused by a 21-base pair insertion mutation in the E1 alpha subunit. 155 69

We have cloned cDNAs encoding human and rat liver BCKDH E1 alpha subunits and deduced the primary structure of the mature protein. The sequences of the cDNA and protein are highly conserved between the two species. Significant sequence similarity has also been found between human BCKDH and PDH E1 alpha subunits. We have studied the molecular basis of MSUD by determining the enzyme activity and levels of BCKDH protein and mRNA, and by enzymatic amplification and sequencing of BCKDH E1 alpha-specific mRNA, from an MSUD patient and his parents. Different mutant alleles were identified in the two parents. The patient was a compound heterozygote, inheriting an allele encoding an abnormal E1 alpha from the father and an allele containing a defect in regulation from the mother. Our results demonstrate that a case of MSUD was caused by structural and regulatory mutations involving the E1 alpha subunit.
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PMID:cDNA cloning of the E1 alpha subunit of the branched-chain alpha-keto acid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease. 263 44

Prolactin is an important regulator of prostate citrate production. In rats this regulatory effect of prolactin is specific for lateral prostate, and has no effect on either ventral or dorsal prostate. The mechanisms by which prolactin regulates prostate citrate production have not been elucidated. Two key regulatory enzymes involved in citrate synthesis by prostate epithelial cells are mitochondrial aspartate aminotransferase (mAAT) which provides oxalacetate, and PDH E1 alpha (pyruvate dehydrogenase) which provides acetyl CoA for citrate synthesis. Our previous studies demonstrated that prolactin regulates mAAT. However, an increase in citrate synthesis would require an increase in both oxalacetate and acetyl CoA. Therefore, we investigated the possibility that prolactin might also regulate PDH E1 alpha in LP epithelial cells. The present studies demonstrate that prolactin administration (1 mg/rat) to rats resulted in an increased level of E1 alpha in LP epithelial cells within 6 hr, but had no effect on the E1 alpha level of VP epithelial cells. In vitro studies demonstrated that exposure of freshly prepared LP epithelial cells to prolactin (0.1-1.0 microgram/ml) resulted in increased levels of E1 alpha. Prolactin had no effect on either VP or DP epithelial cells. The stimulatory effect of prolactin on E1 alpha was inhibited by actinomycin and cycloheximide, thereby indicating that prolactin stimulated the biosynthesis of E1 alpha. The studies reveal that prolactin specifically stimulates E1 alpha levels of LP epithelial cells, whereas testosterone specifically stimulates E1 alpha levels of VP epithelial cells. At this time, we propose that the effects of prolactin and testosterone involve increased expression of the E1 alpha gene of LP and VP epithelial cells, respectively.
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PMID:Prolactin specifically increases pyruvate dehydrogenase E1 alpha in rat lateral prostate epithelial cells. 771 83

Expression of the PDA1 gene encoding the E1 alpha subunit of the pyruvate dehydrogenase complex (PDH complex) and activity of the complex were investigated in cells grown under several conditions. Comparable amounts of PDA1 mRNA and E1 alpha subunit were detected in cells from batch and chemostat cultures grown on various carbon sources, showing constitutive expression of PDA1 at the transcriptional and translational levels. Induction of the regulatory GCN4 mechanism upon histidine starvation, using the anti-metabolite 3-amino-1,2,4-triazole, increased the levels of PDA1 mRNA by approximately 40%. However, a corresponding increase of E1 alpha concentration or activity of the PDH complex could not be detected. Hence, expression of the PDA1 gene is only regulated to a small extent, if at all, by the GCN4 mechanism. Contrary to the constant levels of PDA1 mRNA and E1 alpha subunit in both batch and chemostat cultures, the specific activity of the PDH complex varied with the culture conditions. The activity of the PDH complex in chemostat cultures was approximately two-threefold higher than in batch cultures grown on the same carbon sources. Overproduction of the E1 alpha subunit in batch cultures resulted in a two-threefold increase in the activity of the PDH complex. Taken together, these results indicate that the activity of the PDH complex is mainly regulated by post-translational modification of the E1 alpha subunit. Expression of PDA1 and activity of the PDH complex were also detected in cultures grown under conditions where no physiological significance of the PDH complex was expected, i.e. during anaerobic growth on glucose or aerobic growth on ethanol. Apparently, the switch from oxidative growth to fermentation occurs without much effect on the PDH complex. These observations suggest that the PDH complex has an alternative function besides sugar catabolism.
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PMID:Regulation of the PDA1 gene encoding the E1 alpha subunit of the pyruvate dehydrogenase complex from Saccharomyces cerevisiae. 826 28

The amino acid sequences of four thiamine pyrophosphate-requiring enzymes were aligned with the published amino acid sequence of the transketolase of Hansenula polymorpha. Sequences of the combined alpha and beta subunits of the E1 enzyme of the pyruvate dehydrogenase complexes of Homo sapiens and Bacillus stearothermophilus aligned well with the transketolase while the E1 of the pyruvate dehydrogenase complex of Escherichia coli aligned easily provided a non-aligning segment of 77 amino acids was omitted. The non-acetylating pyruvate decarboxylase of Saccharomyces cerevisiae could only be aligned if the sequence was cut in two with the C-terminus corresponding to the N-terminus of the other TPP-dependent enzymes. Using the published 2.5 A resolution of the X-ray crystal structure of Saccharomyces cerevisiae transketolase as a template we show that a hydrophobic region of the beta-subunit of the PDH E1 alpha beta enzymes likely contains a binding site for the thiazolium ring of TPP and key motifs are retained in common by all the TPP-dependent enzymes considered, which are essential for catalysis.
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PMID:The relationships between transketolase, yeast pyruvate decarboxylase and pyruvate dehydrogenase of the pyruvate dehydrogenase complex. 834 39

Human PDH complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. In an investigation at the level of the gene into ten cases of PDH complex (E1) deficiency, we found that all had mutations in the coding sequence of the X-linked E1 alpha gene while the E1 beta coding sequence was normal. Six of these patients (three males, three females) had missense mutations resulting in a changed amino acid residue in the E1 alpha subunit at positions amino acid 148 (in two siblings), 170, 202, 234 and 263 of the mature protein. Two of the females had one normal E1 alpha gene and one with a deletion at the sites of tandem repeats of AGTAAGA and TAT respectively. The two remaining females also had one normal E1 alpha gene and one with an insertion. Both insertions, one of 2 bp and one of 4 bp, occurred in DNA hotspots normally associated with deletions. Only two of these ten mutations have been reported in other patients previously. In the five cases (including the two siblings) where parent DNA was available, only in one case could the same mutation be found in the patient as well as the maternal genomic DNA.
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PMID:Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. 850 6

Transfection of PDH E1 alpha cDNAs into human normal (3781) and PDH-deficient (4787) lymphoblast cell lines was performed to study the expression of different E1 alpha cDNAs. Transfection of normal human E1 alpha cDNA into a severely PDH-deficient cell line with 10% residual activity resulted in a fivefold increase in residual PDH complex activity. Transfection of the normal cDNA into the normal cell line did not affect the residual enzyme activity. Transfection of three known human PDH E1 alpha mutations (A875T, C787G, and a 13-bp insertion at nucleotide 981) into the normal cell line resulted in a decrease of PDH complex activity. Expression of these same mutations in the deficient cell line resulted in an increase of PDH complex activity, with the C787G mutation causing the greatest increase in enzyme activity. The increase in activity seen with A875T expressed in the mutant cell line suggested that interallelic complementation had occurred.
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PMID:Expression of normal and mutant pyruvate dehydrogenase complex E1 alpha cDNAs in cultured human lymphoblasts. 944 11

We have characterized a novel mutation in a male patient that affects the coding sequence of PDH-E1 alpha gene and changes arginine-141 to a leucine. This nucleotide substitution was found in about 75% of the studied DNA (fibroblasts, liver and muscle), a scenario that would indicate a case of E1 alpha mosaicism in a male patient. When the mutant E1 alpha protein was expressed in human skin fibroblasts with zero endogenous pyruvate dehydrogenase complex activity and E1 alpha protein expression, no significant restoration of activity was recorded, in contrast to the wild-type cDNA. even though both wild-type and mutant protein levels were comparable. We concluded that the R141L mutation is a severe one and that it must have occurred in one of the E1 alpha alleles during early embryogenesis.
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PMID:A case of PDH-E1 alpha mosaicism in a male patient with severe metabolic lactic acidosis. 1175 83

We identified a new Y243S mutation in the X-linked E1 alpha-PDH gene in a patient with pyruvate dehydrogenase complex (PDHc) deficiency. The activity in cultured fibroblasts was very low even in the presence of high thiamine pyrophosphate (TPP) concentrations, indicating that the defect could be due to decreased affinity of PDHc for TPP.
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PMID:A novel Y243S mutation in the pyruvate dehydrogenase El alpha gene subunit: correlation with thiamine pyrophosphate interaction. 1222 66


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