Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two mutant alleles of the gene encoding electron transfer flavoprotein-ubiquinone oxidoreductase were identified and characterized in fibroblasts from a patient with glutaric acidemia type II. One of these alleles is a C-T transition in the donor site of an intron that causes skipping of a 222 bp exon. Included in the missing 74 amino acids is C561, which is predicted to be one of the four cysteine ligands of the 4Fe4S cluster. This mutant allele does not encode a stable ETF-QO in human fibroblasts but, when expressed in Saccharomyces cerevisiae, the mutant ETF-QO is relatively stable and properly targeted to and processed by mitochondria. The mutant protein lacks ubiquinone reductase activity, but does accept electrons from ETF in the catalyzed disproportionation of ETF semiquinone. These data suggest that in the normal protein the flavin center accepts electrons from ETF and that the 4Fe4S cluster reduces ubiquinone. Deleting the 74 amino acids also alters the association between the protein and membrane such that the mutant ETF-QO cannot be extracted from the membrane using the same conditions used for wild type ETF-QO. A site directed mutant that contains only the single amino acid substitution, C561A, exhibits the same catalytic behavior as the deletion mutant, supporting the hypothesis regarding the specific functions of the two redox centers. It is, however, solubilized by the same conditions as wild type ETF-QO.
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PMID:Characterization of a mutation that abolishes quinone reduction by electron transfer flavoprotein-ubiquinone oxidoreductase. 775 62

We describe a 22-year-old male who developed severe hypoglycemia and lethargy during an acute illness at 4 months of age and subsequently grew and developed normally. At age 4 years he developed recurrent vomiting with mild hyperammonemia and dehydration requiring frequent hospitalizations. Glutaric aciduria Type II was suspected based upon biochemical findings and managed with cornstarch, carnitine and riboflavin supplements. He did not experience metabolic crises between ages 4-12 years. He experienced recurrent vomiting, mild hyperammonemia, and generalized weakness associated with acute illnesses and growth spurts. At age 18 years, he developed exercise intolerance and proximal muscle weakness leading to the identification of multiple acyl-CoA dehydrogenase and complex II/III deficiencies in both skeletal muscle and liver. Subsequent molecular characterization of the ETFDH gene revealed novel heterozygous mutations, p.G274X:c.820 G > T (exon 7) and p.P534L: c.1601 C > T (exon 12), the latter within the iron sulfur-cluster and predicted to affect ubiquinone reductase activity of ETFDH and the docking of ETF to ETFDH. Our case supports the concept of a structural interaction between ETFDH and other enzyme partners, and suggests that the conformational change upon ETF binding to ETFDH may play a key role in linking ETFDH to II/III super-complex formation.
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PMID:Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle. 2108 98