Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a previous report, mitochondria were proposed as a subcellular structure where recognition sites for peripheral benzodiazepine ligands are located in adrenal glands. The present study examines the subcellular distribution of specific binding sites for PK 11195 in eight tissues and compares the relative densities of these binding sites in mitochondrial-enriched fractions with the relative activities of two mitochondrial marker enzymes. In all eight tissues examined, PK 11195 binding sites were found to subfractionate in a manner nearly identical to that of the mitochondrial enzyme succinate dehydrogenase. The subcellular distribution patterns of specific PK 11195 binding sites were unrelated to the distribution patterns of marker enzymes for plasma membranes, lysosomes, or endoplasmic reticulum. Scatchard analyses of mitochondrial fractions from all eight tissues demonstrated a greater than 100-fold difference in the densities of PK 11195 binding sites, the extremes being 140 and 1 pmol/mg of protein in adrenal and brain tissues, respectively. There was no correlation between the relative density of PK 11195 binding sites and the specific activities of succinate dehydrogenase and cytochrome c oxidase. These results suggest that the density of peripheral-type benzodiazepine receptors in mitochondria is tissue dependent and apparently regulated independently of the mechanisms by which these two mitochondrial enzymes are expressed or function. The photoaffinity probe PK 14105 was used to photolabel the peripheral-type benzodiazepine binding sites of mitochondrial fractions prepared from the eight tissues. In all preparations, a 17,000-Da polypeptide is specifically labeled as determined by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels. Thus, it appears that the protein recognition site for isoquinoline carboxamides of peripheral-type benzodiazepine receptor complexes is similar in all mitochondrial preparations.
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PMID:Molecular characterization and mitochondrial density of a recognition site for peripheral-type benzodiazepine ligands. 284 47

Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 approximately 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP+, so respiratory inhibition may underlie their reported neurotoxicity.
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PMID:Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 861 71

The neurotoxic agent MPP+ is an artificial substance producing a syndrome very similar to that of idiopathic Parkinson's disease. There are also naturally occuring neurotoxic substances under discussion like the group of isoquinoline and beta-carboline alkaloids. All these substances are more or less powerfull inhibitors of complex I of the mitochondrial oxidative phosphorylation. This study examined the effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a putative in vivo condensation product of chloralhydrate and tryptamine, on the oxidative phosphorylation system compared to MPP+. Similar to MPP+, TaClo inhibits only the electron transfer from complex I towards ubiquinone. Demonstrating a 10-times more effective inhibition than MPP+, complex I activity is fully inhibited by 800 microM TaClo in brain homogenates and submitochondrial particles. By extending the preincubation time from 5 to 30 min complex I is already inhibited by 400 microM TaClo. Other derivates of TaClo as N-methyl-TaClo demonstrate an even greater inhibitory effect on complex I and especially on complex II activities.
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PMID:1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, a new inhibitor of complex I. 882 Oct 63