Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.1.8 (acyl-CoA dehydrogenase)
 785 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies demonstrated that during cisplatin-induced acute renal failure, there is a significant reduction in proximal tubule fatty acid oxidation. We now report on the effects of peroxisome proliferator-activated receptor-alpha (PPAR alpha) ligand Wy-14643 (WY) on the abnormalities of medium chain fatty acid oxidation and pyruvate dehydrogenase complex (PDC) activity in kidney tissue of cisplatin-treated mice. Cisplatin causes a significant reduction in mRNA levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD). PPAR alpha ligand WY ameliorated cisplatin-induced acute renal failure and prevented cisplatin-induced reduction of mRNA levels and enzyme activity of MCAD. In contrast, in cisplatin-treated PPAR alpha null mice, WY did not protect kidney function and did not reverse cisplatin-induced decreased expression of MCAD. Cisplatin inhibited renal PDC activity before the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPAR alpha agonist WY. Cisplatin also induced increased mRNA and protein levels of pyruvate dehydrogenase kinase-4 (PDK4), and PPAR alpha ligand WY prevented cisplatin-induced increased expression of PDK4 protein levels in wild-type mice. We conclude that PPAR alpha agonists have therapeutic potential for cisplatin-induced acute renal failure. Use of PPAR alpha ligands prevents acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes, MCAD-mediated fatty acid oxidation and PDC activity.
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PMID:PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity. 1461 80

The aim of this study was to illustrate the difficulties in establishing a diagnosis of mitochondrial respiratory chain (MRC) disorders based on clinical grounds in combination with intermediate activities of the MRC enzyme complexes. We reviewed retrospectively all medical and laboratory records of patients initially considered likely to have MRC disorders on clinical grounds, and subsequently diagnosed with other disorders (n = 20; 11 males, 9 females). Data were retrieved from hospital records, referral letters, and results of enzymatic analysis at a reference laboratory. Clinical symptoms included developmental delay, epilepsy, hypotonia, movement disorder, spastic quadriplegia, tetany, microcephaly, visual problems, carpopedal spasms, dysmorphism, hearing loss, muscle weakness and rhabdomyolysis, and fulminant hepatitis. Blood and cerebrospinal fluid lactate levels were elevated in 13/20 and 9/20 respectively. One or more MRC complex activities (expressed as ratios relative to citrate synthase and/or complex II activity) were less than 50% of control mean activity in 11/20 patients (including patients with deficiencies of pyruvate dehydrogenase complex, pantothenate kinase, holocarboxylase synthetase, long-chain hydroxy acyl-CoA dehydrogenase, molybdenum co-factor, and neonatal haemochromatosis). One patient had a pattern suggestive of mitochondrial proliferation. We conclude that intermediate results of MRC enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses.
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PMID:Decreased activities of mitochondrial respiratory chain complexes in non-mitochondrial respiratory chain diseases. 1641 69

Accumulation of organic acids as well as their CoA and carnitine esters in tissues and body fluids is a common finding in organic acidurias, beta-oxidation defects, Reye syndrome, and Jamaican vomiting sickness. Pathomechanistic approaches for these disorders have been often focused on the effect of accumulating organic acids on mitochondrial energy metabolism, whereas little is known about the pathophysiologic role of short- and medium-chain acyl-CoAs and acylcarnitines. Therefore, we investigated the impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on central components of mitochondrial energy metabolism, namely alpha-ketoglutarate dehydrogenase complex, pyruvate dehydrogenase complex, and single enzyme complexes I-V of respiratory chain. Although at varying degree, all acyl-CoAs had an inhibitory effect on pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex activity. Effect sizes were critically dependent on chain length and number of functional groups. Unexpectedly, octanoyl-CoA was shown to inhibit complex III. The inhibition was noncompetitive regarding reduced ubiquinone and uncompetitive regarding cytochrome c. In addition, octanoyl-CoA caused a blue shift in the gamma band of the absorption spectrum of reduced complex III. This effect may play a role in the pathogenesis of medium-chain and multiple acyl-CoA dehydrogenase deficiency, Reye syndrome, and Jamaican vomiting sickness which are inherited and acquired conditions of intracellular accumulation of octanoyl-CoA.
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PMID:Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism. 1858 32