Uncouplers and Inhibitors2010

Uncouplers and Inhibitors2010 - Uncouplers and Inhibitors...

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Uncouplers and Inhibitors Much of our knowledge of mitochondrial function results from the study of toxic compounds. Specific inhibitors were used to distinguish the electron transport system from the phosphorylation system and helped to define the sequence of redox carriers along the respiratory chain. If the chain is blocked then all the intermediates on the substrate side of the block become more reduced, while all those on the oxygen side become more oxidised. It is easy to see what has happened because the oxidised and reduced carriers often differ in their spectral properties. If a variety of different inhibitors are available then many of the respiratory carriers can be placed in the correct order. There are six distinct types of poison which may affect mitochondrial function: 1) Respiratory chain inhibitors (e.g. cyanide, antimycin, rotenone & TTFA) block respiration in the presence of either ADP or uncouplers. 2) Phosphorylation inhibitors (e.g. oligomycin) abolish the burst of oxygen consumption after adding ADP, but have no effect on uncoupler-stimulated respiration. 3) Uncoupling agents (e.g. dinitrophenol, CCCP, FCCP) abolish the obligatory linkage between the respiratory chain and the phosphorylation system which is observed with intact mitochondria. 4) Transport inhibitors (e.g. atractyloside, bongkrekic acid, NEM) either prevent the export of ATP, or the import of raw materials across the the mitochondrial inner membrane. 5) Ionophores (e.g. valinomycin, nigericin) make the inner membrane permeable to compounds which are ordinarily unable to cross. 6) Krebs cycle inhibitors (e.g. arsenite, aminooxyacetate) which block one or more of the TCA cycle enzymes, or an ancillary reation. Some of the best-known compounds are listed below: Compound Mode of action and effects Amino- oxyacetate Ancillary enzyme inhibitor. Inhibits all transaminases by reacting covalently with their pyridoxal phosphate prosthetic group. Blocks the malate / aspartate cycle by inhibiting glutamate - oxaloacetate transaminase (GOT). Antimycin A Respiration inhibitor. Blocks the respiratory chain at complex 3 between cytochrome b and cytochrome c 1 . It therefore prevents the oxidation of both NADH and succinate, but has no effect on ascorbate + TMPD. Arsenite
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This note was uploaded on 11/19/2010 for the course BIO 361 taught by Professor Lake during the Fall '08 term at SUNY Stony Brook.

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Uncouplers and Inhibitors2010 - Uncouplers and Inhibitors...

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