Model for action of local anaesthetics with cytochrome oxidase

Casanovas, Anna; Labat, Christian; Courrière, Philippe; Oustrin, J

doi:10.1016/0006-2952(85)90168-6

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…Many of these inhibitors have in common either a polar headgroup and/or a free amine group. It is usually the neutral form of the compound that is most effective; protonation of the amines for example can decrease the inhibition [3,31]. It is attractive to postulate that the inhibitor site is close to the cytochrome c-binding site with the lipid-soluble tail binding to a hydrophobic patch and the polar residue(s) interfering with cytochrome c binding [3].…”

Section: Discussionmentioning

confidence: 99%

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (β-galactosylsphingosine)

Cooper

Markus

Seetulsingh

et al. 1993

Biochemical Journal

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1. Psychosine (beta-galactosylsphingosine) is the toxic agent in Krabbe's disease (globoid cells leukodystrophy). It inhibits purified bovine heart mitochondrial cytochrome c oxidase; there is a rapid phase of inhibition (complete within 10-15 s) and a slower phase (complete within 10-15 min). Both phases are also seen in rat liver mitochondria. IC50 is about 200 microM psychosine in the purified enzyme and less than 20 microM in mitochondria. Psychosine inhibition is due to binding to cytochrome oxidase, not cytochrome c. 2. Bovine heart submitochondrial particles show inhibition similar to rat liver mitochondria. However, although proteoliposomes containing bovine heart cytochrome oxidase show an identical fast phase, they have no noticeable slow phase of inhibition. Addition of phospholipid liposomes to submitochondrial particles relieved the majority of psychosine inhibition, consistent with the removal of those molecules binding in the slow phase. Psychosine can inhibit cytochrome oxidase molecules facing in either direction in proteoliposomes and submitochondrial particles, suggesting that it can rapidly interact with both sides of a membrane when added externally. 3. At high ionic strength, the presence of psychosine decreases the Vmax. of cytochrome oxidase with little effect on the Km for cytochrome c. This non-competitive inhibition suggests that the psychosine-enzyme complex is kinetically inactive and not labile over the time course of the assay. Psychosine does not inhibit the reduction of haem a or haem a3 by artificial electron donors, but does inhibit the reduction of haem a by cytochrome c.

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Section: Discussionmentioning

confidence: 99%

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (β-galactosylsphingosine)

Cooper

Markus

Seetulsingh

et al. 1993

Biochemical Journal

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“…Since neither the positively charged amines nor the negatively charged carboxylates were observed to inhibit cytochrome c oxidase, it may be that the inhibitor-binding site is uncharged. Similarly Casanovas et al (1985b) concluded from their studies on the inhibition of cytochrome c oxidase by amine local anaesthetics that it is the neutral form of the anaesthetic that is the most potent and is responsible for enzyme inhibition. The inhibitor-binding site on cytochrome c oxidase probably contains a polar region that can interact with the oxygen atom of the inhibitor.…”

Section: Inhibition With Detergent-solubilized Enzymementioning

confidence: 99%

“…Singer (1982) also observed a similar relative increase in Ki' to that shown in Table 1 when the enzyme was incorporated into liposomes. It has been postulated (Casanovas et al, 1985b) that the neutral forms of the amine local anaesthetics interact with the cytochrome c oxidase boundary lipid. It has been established that there is lipid adjacent to the low-affinity substrate-binding site (Bisson et al, 1980).…”

Section: Inhibition With Detergent-solubilized Enzymementioning

confidence: 99%

The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity

Hasinoff

Davey

1989

Biochemical Journal

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The inhibition of the membrane-bound enzyme cytochrome c oxidase by aliphatic n-alcohols and other neutral organic compounds was studied as a model for anaesthetic action and drug toxicity. The n-alcohols (C1 to C14) displayed a variation in inhibition constant of over 500,000-fold. The inhibition constants correlated well with the number of carbon atoms in the n-alcohols and also their n-octanol/water partition coefficients. General anaesthetic potency is known to be similarly well correlated with octanol/water partition coefficients. The free-energy change for transferring a methylene group of the n-alcohol to the more hydrophobic environment bound to the enzyme is similar to that for transferring a methylene group from water to pure alcohol. These results are consistent with the n-alcohols inhibiting by binding to an octanol-like environment on the enzyme or the protein/phospholipid interface. Neither negatively charged carboxylates nor positively charged amine analogues were observed to cause any inhibition, indicating that this postulated binding site may be uncharged. Inhibition of cytochrome c oxidase by n-alcohols was also demonstrated in both bovine heart and rat liver sonicated submitochondrial fragments.

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“…A decrease in the rate of synthesis of choline and ethanolamine glycerophospholipids occurs in aged brain (Gaiti et al, 1982a,b) enhancing the cholesterol-to-phospholipid molar ratio (Sun and Sun, 1979). Although the bulk of dry matter of inner mitochondria1 membrane is protein (Harmon et al, 1974), a direct relationship exists between amount of negatively charged phospholipids and catalytic activity of cytochrome oxidase (Vik and Capaldi, 1977;Fry and Green, 1980;Casanovas et al, 1985). During aging the decrease in the cytochrome oxidase activity (Abu-Erreish and Sanadi, 1978;Benzi, 1979;Benzi et al, 1980) may be induced by both decrease in the number of cytochrome aa3 molecules (Curti et al, 1990) and/or changes in membrane lipid composition (Sun and Sun, 1979).…”

Section: Discussionmentioning

confidence: 96%

Age‐related acute depletion of cerebral glutathione by peroxidative stress

Benzi

Curti

Marzatico

et al. 1991

J of Neuroscience Research

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Cyclohexene-1-one and cycloheptene-1-one cause a severe age-related depletion of reduced glutathione (GSH) in the forebrain of 5- or 15- or 25-month-old rats. Chronic pretreatment with phosphatidylcholine partially inhibits the GSH depletion in old forebrains by the prooxidants tested, suggesting that in aged animals alterations in mitochondrial inner membrane phospholipid composition and/or cytochrome oxidase activity might play a role in oxygen free-radical production.

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Model for action of local anaesthetics with cytochrome oxidase

Cited by 11 publications

References 36 publications

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (β-galactosylsphingosine)

Kinetics of inhibition of purified and mitochondrial cytochrome c oxidase by psychosine (β-galactosylsphingosine)

The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity

Age‐related acute depletion of cerebral glutathione by peroxidative stress

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