Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1(-/-) mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed. Many of the enzymes that are induced in Gstz1(-/-) mice are regulated by antioxidant response elements that respond to oxidative stress via the Keap1/Nrf2 pathway. It is significant that diminished glutathione concentrations were also observed in the liver of Gstz1(-/-) mice, which supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress. Elevated GST activities in the livers of Gstz1(-/-) mice suggest that GSTZ1-1 deficiency may alter the metabolism of some drugs and xenobiotics. Gstz1(-/-) mice given acetaminophen demonstrated increased hepatotoxicity compared with wild-type mice. This toxicity may be attributed to the increased GST activity or the decreased hepatic concentrations of glutathione, or both. Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity.
Mol Pharmacol 2006 Feb
PMID:Deficiency of glutathione transferase zeta causes oxidative stress and activation of antioxidant response pathways. 1627 72

The A3243G mutation in the mitochondrial gene for human mitochondrial (mt) tRNA(Leu(UUR)), responsible for decoding of UUR codons, is associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We previously demonstrated that this mutation causes defects in 5-taurinomethyluridine (taum(5)U) modification at the anticodon first (wobble) position of the mutant mt tRNA(Leu(UUR)), leading to a UUG decoding deficiency and entraining severe respiratory defects. In addition, we previously identified a heteroplasmic mutation, G12300A, in the other mt leucine tRNA gene, mt tRNA(Leu(CUN)), which functions as a suppressor of the A3243G respiratory defect in cybrid cells containing A3243G mutant mtDNA. Although the G12300A mutation converts the anticodon sequence of mt tRNA(Leu(CUN)) from UAG to UAA, this tRNA carrying an unmodified wobble uridine still cannot decode the UUG codon. Mass spectrometric analysis of the suppressor mt tRNA(Leu(CUN)) carrying the G12300A mutation from the phenotypically revertant cells revealed that the wobble uridine acquires de novo taum(5)U modification. In vitro translation confirmed the functionality of the suppressor tRNA for decoding UUG codons. These results demonstrate that the acquisition of the wobble modification in another isoacceptor tRNA is critical for suppressing the MELAS mutation, and they highlight the primary role of the UUG decoding deficiency in the molecular pathogenesis of MELAS syndrome.
Hum Mol Genet 2006 Mar 15
PMID:Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect. 1644 7

Metabolic complications of severe malaria are some of the most important and potentially treatable manifestations of this deadly disease. The commonest metabolic complications (lactic acidosis and hypoglycaemia) arise from increased host anaerobic metabolism probably due to a mismatch between tissue oxygen supply and requirement. Optimising treatments for these complications should be guided by detailed understanding of their underlying pathophysiology, and may help to reduce the intolerably high case fatality rate of severe malaria.
Curr Mol Med 2006 Mar
PMID:Severe malaria: metabolic complications. 1651 7

Maternally inherited diabetes and deafness and mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes result from the 3243A>G mitochondrial point mutation. Current methods to detect the presence of the mutation have limited sensitivity and may lead to potential misclassification of patients with low levels of heteroplasmy. Here, we describe development and validation of a rapid real-time polymerase chain reaction (PCR) method for detection and quantification of levels of heteroplasmy in a single assay. Standard curve analysis indicated that the sensitivity of detection was less than 0.1%. Time from sample loading to data analysis was 110 minutes. We tested 293 samples including 23 known positives, 40 known negatives, and 230 samples from patients clinically classified as having type 2 diabetes. All positive samples were correctly detected, and of those samples previously quantified, heteroplasmy levels determined using the real-time assay correlated well (r(2) = 0.88 and 0.93) with results from fluorescently labeled PCR-restriction fragment length polymorphism and pyrosequencing methods. Screening of 230 patients classified as having type 2 diabetes revealed one patient with 0.6% heteroplasmy who had previously tested negative by PCR-restriction fragment length polymorphism. Real-time PCR provides rapid simultaneous detection and quantification of the 3243A>G mutation to a detection limit of less than 0.1%, without post-PCR manipulation.
J Mol Diagn 2006 May
PMID:Rapid and sensitive real-time polymerase chain reaction method for detection and quantification of 3243A>G mitochondrial point mutation. 1664 9

The 3243A>G mutation in the MTTL1 (tRNA(Leu)) gene and the 8344A>G mutation in the MTTK (tRNA(Lys)) gene are the most common mutations found in mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes and myoclonic epilepsy associated with ragged-red fibers, respectively. These mitochondrial DNA mutations are usually detected by conventional polymerase chain reaction followed by restriction enzyme digestion and gel electrophoresis. We developed a LightCycler real-time polymerase chain reaction assay to detect these two mutations based on fluorescence resonance energy transfer technology and melting curve analysis. Primers and fluorescence-labeled hybridization probes were designed so that the sensor probe spans the mutation site. The observed melting temperatures differed in the mutant and wild-type DNA by 9 degrees C for the MTTL1 gene and 6 degrees C for the MTTK gene. This method correctly identified all 10 samples that were 3243A>G mutation-positive, all 4 samples that were 8344A>G mutation-positive, and all 30 samples that were negative for both mutations, as previously identified by traditional gel-based methods. This LightCycler assay is a rapid and reliable technique for molecular diagnosis of these mitochondrial gene mutations.
J Mol Diagn 2006 May
PMID:Detection of common disease-causing mutations in mitochondrial DNA (mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes MTTL1 3243 A>G and myoclonic epilepsy associated with ragged-red fibers MTTK 8344A>G) by real-time polymerase chain reaction. 1664 16

The clinical presentation and the biochemical and molecular genetic findings are described in a 13 year old Chinese boy with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The diagnosis was initially suspected because of the characteristic clinical features and the strong family history of convulsions. Using polymerase chain reaction-restriction enzyme analysis, the heteroplasmic nt3243 A-->G mutation in mtDNA of peripheral blood leucocytes and a muscle sample was demonstrated. The oligosymptomatic relatives were then screened by this method and the degree of heteroplasmy was analysed. This appears to be the first report of a MELAS family in Hong Kong with this described mutation. Molecular genetic techniques are advantageous in the diagnosis of MELAS.
Clin Mol Pathol 1995 Oct
PMID:Diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in a Chinese family by PCR/restriction enzyme analysis. 1669 23

The pyruvate dehydrogenase complex (PDC) is integral to metabolism and energetics. Congenital PDC deficiency leads to lactic acidosis, neurological degeneration and early death. An investigational compound for such defects is dichloroacetate (DCA), which activates the PDC (inhibiting reversible phosphorylation of the E1alpha subunit) and decreases its turnover. Here, primary human fibroblast cultures from five healthy subjects and six patients with mutations in the PDC-E1 component were grown in media+/-DCA, exposed to media containing (13)C-labeled glucose, and studied (as cell extracts) by nuclear magnetic resonance (NMR) spectroscopy. Computer modeling of NMR-derived (13)C-glutamate isotopomeric patterns estimated relative carbon flow through TCA cycle-associated pathways and characterized effects of PDC deficiency on metabolism and energetics. Rates of glucose consumption (GCR) and lactate production (LPR) were measured. With the exception of one patient cell line expressing an unusual splicing mutation, PDC-deficient cells had significantly higher GCR, LPR and label-derived acetyl-CoA, indicative of increased glycolysis vs. controls. In all cells, DCA caused a major shift (40% decrease) from anaplerotic-related pathways (e.g., pyruvate carboxylase) toward flux through PDC. Ignoring the patient with the splicing mutation, DCA decreased average glycolysis (29%) in patient cells, but had no significant effect on control cells, and did not change LPR or the nucleoside triphosphate to diphosphate ratio (NTP/NDP) in either cell type. Maintenance of NTP despite reduced glycolysis indicates that DCA improves metabolic efficiency by increasing glucose oxidation. This study demonstrates that NMR spectroscopy provides insight into biochemical consequences of PDC deficiency and the mechanism of putative therapeutic agents.
Mol Genet Metab
PMID:Magnetic resonance spectroscopic investigation of mitochondrial fuel metabolism and energetics in cultured human fibroblasts: effects of pyruvate dehydrogenase complex deficiency and dichloroacetate. 1676 24

The ND1 subunit gene of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) is a hot spot for mutations causing Leber hereditary optic neuropathy and several mutations causing the mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). We have used Escherichia coli and Paracoccus denitrificans as model systems to study the effect of mutations 3946 and 3949, which change conserved residues in ND1 and cause MELAS. The vicinity of these mutations was also explored with a series of mutations in charged residues. The 3946 mutation results in E214K substitution in human ND1. Replacement of the equivalent residue in E. coli with lysine or glutamine detracted from enzyme assembly and the assembled enzyme was inactive. However, the equivalent E234Q mutant enzyme in P. denitrificans failed to assemble completely (or was rapidly degraded). Also the corresponding substitution with aspartate decreased the enzyme activity in P. denitrificans and E. coli. The 3949-equivalent substitution, Y229H in E. coli, lowered the catalytic activity by 30%. In addition, an activation of the enzyme during catalytic turnover was seen in this bacterial NDH-1, something that was even more pronounced in another mutant in the same loop, D213E. Several other mutations in this region decreased the enzyme activity. The studied MELAS mutations are situated in a matrix-side loop, which appears to be highly sensitive to structural perturbations. The results provide new information on the function of the region affected by the MELAS mutations 3946 and 3949 that is not obtainable from patient samples or current eukaryote models.
Hum Mol Genet 2006 Sep 01
PMID:The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I. 1684 71

Mitochondrial respiratory chain disorders are clinically and genetically heterogeneous. There are several mitochondrial DNA (mtDNA) point mutations responsible for common mitochondrial diseases such as mitochondrial encephalopathy, lactic acidosis, stroke-like events, myoclonic epilepsy and ragged red fibers, neuropathy, ataxia, retinitis pigmentosa, and Leber's hereditary optic neuropathy. As a result of the clinical overlap, it is usually necessary to analyze more than one mutation for a patient suspected of a mitochondrial disorder. Molecular diagnosis is often performed using polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) analysis of the most likely point mutations. However, this method is time-consuming and often produces problems associated with incomplete restriction enzyme digestion. In addition, PCR/RFLP analysis may not be able to detect a low percentage of heteroplasmy. For a more effective method of diagnosing mtDNA disorders, we have developed a multiplex PCR/ allele-specific oligonucleotide (ASO) dot blot hybridization method to simultaneously analyze 11 point mutations. The PCR products from a DNA sample containing a homoplasmic wild-type or mutant mtDNA sequence will hybridize to either the wild-type or the mutant ASO probe. The PCR products of a heteroplasmic DNA sample will hybridize to both wild-type and mutant ASO probes. This PCR/ASO method allows the detection of low percentage mutant heteroplasmy.
Methods Mol Biol 2006
PMID:Molecular analysis of mitochondrial DNA point mutations by polymerase chain reaction. 1691 59

Defects in NADH:ubiquinone oxidoreductase, the complex I of the mitochondrial respiratory chain represents the most frequent cause of mitochondrial diseases and is associated with a wide clinical spectrum varying from severe lactic acidosis in infants to muscle weakness in adults. Here, we report a patient with Leigh syndrome (LS), born to consanguineous parents, with severe complex I defect and a novel mutation in the NDUFS7 gene subunit. The homozygous mutation at nucleotide (nt) 434 G>A resulted in the modification of the arginine 145 to histidine in a highly conserved region of the protein. Parents were heterozygous carriers for this mutation. The mutation was absent from over than 100 healthy controls from the same ethnic origin. Identifying nuclear mutations as a cause of respiratory chain disorders will enhance the possibility of prenatal diagnosis and help us to understand how moleculardefects can lead to complex I deficiency.
Mol Genet Metab 2007 Apr
PMID:A novel mutation in the human complex I NDUFS7 subunit associated with Leigh syndrome. 1727 78


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