羟氨苄青霉素引起大疱性类天疱疮样疹

Lang, Florian, Gillian L. Busch, Markus Ritter, Harald Volkl, Siegfried Waldegger, Erich Gulbins, and Dieter Haussinger. Functional Significance of Cell Volume Regulatory Mechanisms. Physiol. Rev. ...

Functional Significance of Cell Volume Regulatory Mechanisms

Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.

Introduction Fundamentals of biochemical modeling Balance equations Rate laws Generalized mass-action kinetics Various enzyme kinetic rate laws Thermodynamic flow-force relationships Power-law approximation Steady states of biochemical networks General considerations Stable and unstable steady states Multiple steady states Metabolic oscillations Background Mathematical conditions for oscillations Glycolytic oscillations Models of intracellular calcium oscillations A simple three-variable model with only monomolecular and bimolecular reactions Possible physiological significance of oscillations Stoichiometric analysis Conservation relations Linear dependencies between the rows of the stoichiometry matrix Non-negative flux vectors Elementary flux modes Thermodynamic aspects A generalized Wegscheider condition Strictly detailed balanced subnetworks Onsager's reciprocity reactions for coupled enyme reactions Time hierarchy in metabolism Time constants The quasi-steady-state approximation The Rapid equilibrium approximation Modal analysis Metabolic control analysis Basic definitions A systematic approach Theorems of metabolic control analysis Summation theorems Connectivity theorems Calculation of control coefficients using the theorems Geometrical interpretation Control analysis of various systems General remarks Elasticity coefficients for specific rate laws Control coefficients for simple hypothetical pathways Unbranched chains A branched system Control of erythrocyte energy metabolism The reaction system Basic model Interplay of ATP production and ATP consumption Glycolytic energy metabolism and osmotic states A simple model of oxidative phosphorylation A three-step model of serine biosynthesis Time-dependent control coefficients Are control coefficients always parameter independent? Posing the problem A system without conserved moieties A system with a conserved moiety A system including dynamic channeling Normalized versus non-normalized coefficients Analysis in terms of variables other than steady-state concentrations and fluxes General analysis Concentration ratios and free-energy-differences as state variables Entropy production as response variable Control of transient times Control of oscillations A second-order approach A quantitative approach to metabolic regulations Co-response coefficients Fluctuations of internal variables versus parameter perturbations Internal response coefficients Rephrasing the basic equations of metabolic control analysis in terms of co-response coefficients and internal response coefficients Control within and between subsystems Modular approach Overall elasticities Overall control coefficients Flux control insusceptibility Control exerted by elementary steps in enzyme catalysis Control analysis of metabolic channeling Comparison of metabolic control analysis and power-law formalism Computational aspects Application of optimization methods and the interrelation with evolution Optimization of the catalytic properties of single enzymes Basic assumptions Optimal values of elementary rate constants Optimal Michaelis constants Optimization of multienzyme systems Maximization of steady-state flux Influence of osmotic constraints and minimization of intermediate concentrations Minimization of transient times Optimal stoichiometries.

The Regulation of Cellular Systems

Heterotrophic organisms generally face a trade-off between rate and yield of adenosine triphosphate (ATP) production. This trade-off may result in an evolutionary dilemma, because cells with a higher rate but lower yield of ATP production may gain a selective advantage when competing for shared energy resources. Using an analysis of model simulations and biochemical observations, we show that ATP production with a low rate and high yield can be viewed as a form of cooperative resource use and may evolve in spatially structured environments. Furthermore, we argue that the high ATP yield of respiration may have facilitated the evolutionary transition from unicellular to undifferentiated multicellular organisms.

https://science.sciencemag.org/content/sci/292/5516/504.full.pdf

Cooperation and Competition in the Evolution of ATP-Producing Pathways

The yeast nuclear gene ATP4, encoding the ATP synthase subunit 4, was disrupted by insertion into the middle of it the selective marker URA3. Transformation of the Saccharomyces cerevisiae strain D273-10B/A/U produced a mutant unable to grow on glycerol medium. The ATP4 gene is unique since subunit 4 was not present in mutant mitochondria; the hypothetical truncated subunit 4 was never detected. ATPase was rendered oligomycin-insensitive and the F1 sector of this mutant appeared loosely bound to the membrane. Analysis of mitochondrially translated hydrophobic subunits of F0 revealed that subunits 8 and 9 were present, unlike subunit 6. This indicated a structural relationship between subunits 4 and 6 during biogenesis of F0. It therefore appears that subunit 4 (also called subunit b in beef heart and Escherichia coli ATP synthases) plays at least a structural role in the assembly of the whole complex. Disruption of the ATP4 gene also had a dramatic effect on the assembly of other mitochondrial complexes. Thus, the cytochrome oxidase activity of the mutant strain was about five times lower than that of the wild type. In addition, a high percentage of spontaneous rho- mutants was detected.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1989.tb15098.x

The role of subunit 4, a nuclear-encoded protein of the F0 sector of yeast mitochondrial ATP synthase, in the assembly of the whole complex.

The inhibition of mitochondrial Pi transport by SH-reagents was investigated together with incorporation of SH-reagents into mitochondrial membranes. The reactivity of the Pi carrier SH-group is influenced by several factors during the preincubation with the SH-reagent. By using more or less permeant maleimide derivatives, ethylmaleimide and N-(N-acetyl-4-sulfamoyl-phenyl) maleimide (ASPM), different reactivities can be attributed to accessibility variations. Differences in reactivity become apparent only on short-term incubations with SH-reagents, which allow measurements of reaction rates. The following results were obtained:



1
The reaction rate of ASPM with the Pi carrier is about three-times slower than that of ethylmaleimide.

2
With increasing pH the reactivity of the Pi carrier decreases with ASPM but increases with ethylmaleimide.

3
Pi protects partially against inhibition both by ethylmaleimide and ASPM with a Km between 2 and 10 mM, slightly competitive with the SH-reagent. For protection Pi must be allowed to be taken up by the mitochondria indicating that endogenous Pi protects better than exogenous Pi.

4
The incorporation of ethylmaleimide and ASPM into mitochondria shows smaller differences than inhibition of Pi transport. On titration with SH-reagents the inhibitor of the Pi carrier begins when 11 out of a total of 20 μmol SH-groups/g protein have been reacted. Inhibition is then complete when 15 μmol/g protein have been titrated. Thus 2–4 μmol SH-reagent cause the Pi carrier to pass from an active to an inactive form. This number probably includes more SH-groups than can be attributed to the Pi carrier.

5
The SH-reactivity of the Pi carrier is strongly influenced by uncouplers, ionophores and respiratory inhibitors. The strongest increase of reactivity is obtained with valinomycin, less with uncoupler and none with nigericin. The protective effect of Pi is then completely abolished. On the other hand, valinomycin plus uncoupler does not increase the sensitivity to SH-reagents.

6
Succinate and other respiratory substrates decrease reactivity and increase protection by Pi, whereas malonate increases inhibition. This shows that the removal of endogenous Pi by exchange with a nonrespiring dicarboxylate reverses the protective effect of Pi.





The variability of SH-reactivity is interpreted in terms of accessibility of ASPM. The protection of the Pi carrier is mainly based on reorientation of the carrier inside and outside the membrane. A carrier model is derived from the data in which an equilibrium exists between a protonized immobile form (CH+) of the carrier and a dissociated mobile form (C). Only the CH+ form can bind with mono-anionic Pi− and gives the mobile Pi-carrier complex. Thus the Pi-carrier complex will distribute with ΔpH across the membrane opposite to Pi. The protection by Pi is mainly due to endogenous Pi moving Pi-carrier complex inside, the activation by H+ mainly due to moving empty carrier outside. The model is in accordance with an electroneutral Pi transport. It explains the majority of data, in particular the stimulation by H+ and by valinomycin and also the preferential protection by endogenous Pi.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1974.tb03323.x

Analysis of the reactivity of SH-reagents with the mitochondrial phosphate carrier.

We investigated the effects of 2,6-diisopropylphenol on oxidative phosphorylation of isolated rat liver mitochondria. Diisopropylphenol strongly inhibits state-3 and uncoupled respiratory rates, when glutamate and malate are the substrates, as a direct consequence of the limitation of electron transfer at the level of complex I. In addition, diisopropylphenol acts as an uncoupler in non-phosphorylating mitochondria, which leads to an increase in respiratory rate and a large decrease in proton-motive force. However, such effects cannot be due to the classical protonophoric property of this drug, since addition of ADP plus oligomycin before diisopropylphenol avoids this increase in proton permeability, and in phosphorylating mitochondria, the ATP/O ratio is not significantly affected by diisopropylphenol addition. In the absence of added ADP, diisopropylphenol modifies some mitochondrial ATPases in such a way that they become insensitive to oligomycin and unable to couple proton movement to ATP synthesis or hydrolysis. However, these modified enzymes can catalyse passive proton permeability, which leads to uncoupling. Addition of ADP before diisopropylphenol prevents these changes. We propose that ADP induces a change in conformation of ATPase, which leads to insensitivity of this complex towards diisopropylphenol. In conclusion, we show that diisopropylphenol has two main effects on rat liver mitochondria: inhibition of the respiratory chain at the level of complex I level and modification of ATPase such that, in the absence of phosphorylation, it catalyses a H+ leak, which becomes negligible when oxidative phosphorylation is functional.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1996.0280t.x

Bernard Guerin

Papers

The role of subunit 4, a nuclear-encoded protein of the F0 sector of yeast mitochondrial ATP synthase, in the assembly of the whole complex.

Analysis of the reactivity of SH-reagents with the mitochondrial phosphate carrier.

Mechanisms of Inhibition and Uncoupling of Respiration in Isolated Rat Liver Mitochondria by the General Anesthetic 2,6‐Diisopropylphenol

Phosphate transport and ATP synthesis in yeast mitochondria: effect of a new inhibitor: the tribenzylphosphate.

A Mitochondrial Pyruvate Dehydrogenase Bypass in the YeastSaccharomyces cerevisiae