Summary
The mitochondrial succinate dehydrogenase (E.C. 1.3.3.99) is subjected to apparently complicated regulatory mechanism. Yet, systematic analysis of the mechanism reveals the simplicity of the control. There are two stable forms of the enzyme; the non-active form stabilized as 1:1 complex with oxaloacetate and the active form stabilized by binding of activating ligands. This model quantitatively describes either the equilibrium level of active enzyme or the kinetics of activation-deactivation, in the presence of various concentrations of opposing effectors. The site where the regulatory ligands interact with the enzyme is not the substrate bonding site. The marked differences of dissociation constants of the same ligand from the two sites clearly distinguish between them.
This model is fully developed for simple cases where the activating ligands are dicarboxylic acids or monovalent anions. On the other hand with activators such as ATP or CoQH2, quantitation is still not at hand. This stems from the difficulties in maintaining determined, measurable, concentrations of the ligand in equilibrium with the membranal enzyme.
While in active form the histidyl flavin moity of the enzyme is reduced by physiological substrate (succinate; CoQH2). The non-active form is not reduced by these compounds, only strong reductants with low redox potential reduce the non-active enzyme. It is suggested that deactivation is a simple modulation of the redox potential of the flavin form E′ ≃ 0 mV in the active enzyme to E′ < −190 mV. The switch from one state to another might be achieved by distortion of the planar form of oxidized flavin to the bend configuration of the reduced flavin. Thus, in the active enzyme such distortion will destabilize the oxidized state of the flavin, shifting the redox potential to the higher value. The binding of oxaloacetate to the regulatory sites releases the distorting forces by relaxing the conformation of the enzyme. Consequently, the flavin assumes its planar form with the low redox potential. This assumption is supported by the spectral shifts of the flavin associated with the activation deactivation transition.
The suicidal oxidation of malate to oxaloacetate, carried by the succinate dehydrogenase, plays an important role in modulating the enzyme activity in the mitochondria. This mechanism might supply oxaloacetate for deactivation in spite of the negligible concentration of free oxaloacetate in the matrix. The oxidation of malate by the enzyme is controlled by the redox potential at the immediate vicinity of the enzyme, and is imposed by the redox level of the membranal quinone.
Finally, the modulation of succinate dehydrogenase activity is closely associated with regulation of NADH oxidation through the mutual inhibition between oxidases (Gutman, M. in Bioenergetics of Membranes, L. Packer et al., ed. Elsevier 1977, p. 165). The consequence of these interactions is the selection for the main electron donnor for the respiratory chain, during mixed substrate respiration, according to the metabolic demands from the mitochondria.
Similar content being viewed by others
Abbreviations
- SDH:
-
succinate dehydrogenase (succinate: acceptor oxidoreductase (E.C. 1.3.99.1));
- OAA:
-
oxaloacetate
- Act:
-
activator
- EA, EA :
-
active and non active forms of the enzyme, respectively
- K'eq:
-
apparent equilibrium constant
- K'd:
-
apparent dissociation constant
- KAct, KOAA :
-
dissociation constant of the respective ligand from the enzyme
- K'a, k'd:
-
the apparent rate constants of activation and deactivation, respectively
- ka, kd:
-
the true rate constant of activation and deactivation respectively
- ETP, ETPII :
-
non phosphorylating and phosphorylating submitochondrial particles
- PMS:
-
phenazine methosulfate
- DCIP:
-
dichlorophenol indophenol
- CoQ:
-
ubiquinone
- TIFA:
-
Thenotriflouvoacetone
- NEM:
-
N methyl Maleimide
References
Kearney, E. B., Singer, T. P. and Zastrow, N., 1955. Arch. Biochem. Biophys., 55, 580–581.
Kearney, E. B., 1957. J. Biol. Chem., 229, 363–375.
Kimura, T., Hauber, J. and Singer, T. P., 1963. Biochem. Biophys. Res. Commun., 11, 83–87.
Kimura, T., Hauber, J. and Singer, T. P., 1967. J. Biol. Chem., 242, 4987–4993.
Wojtczak, L., Wojtczak, A. B. and Ernster, L., 1969. Biochim. Biophys. Acta., 191, 10–21.
Kearney, E. B., Ackrell, B. A. C. and Mayer, M., 1972. Biochem. Biophys. Res. Commun., 49, 1115–1120.
Kearney, E. B. and Ackrell, B. A. C., 1974. In: Dynamics of Energy Transducing Membranes., Ernster, L., Eastabrook, R. and Slater, E. C. ed., Elsevier, Amsterdam, p. 111.
Ackrell, B. A. C., Kearney, E. B. and Mayer, M., 1974. J. Biol. Chem., 249, 2021–2027.
Zeylemaker, W. P. and Slater, E. C., 1970. Biochem. Biophys. Acta., 132, 210–212.
Kenney, W. C., Mowery, P. C., Sang, R. L. and Singer, T. P., 1976. J. Biol. Chem. 251, 2369–2373.
Clealand, W. W., 1963. Biochim. Biophys. Acta., 67, 173–187.
Gutman, M., 1977. Biochemistry, 16, 3067–3073.
Zimakova, N. I., Shuetsov, Y. N. and Vinogradov, A. D., 1970. Biokhimiya., 35, 973–982.
Gutman, M., Kearney, E. B. and Singer, T. P., 1971. Biochem. Biophys. Res. Commun., 42, 1016–1023.
Gutman, M., Kearney, E. B. and Singer, T. P., 1971. Biochem. Biophys. Res. Commun., 44, 526–532.
Gutman, M., Kearney, E. B. and Singer, T. P., 1971. Biochemistry 10, 2726–2733.
Gutman, M., Kearney, E. B. and Singer, T. P., 1971. Biochemistry 10, 4763–4769.
La Noue, K. F., Nicklas, W. J. and Williamson, J. R., 1970. J. Biol. Chem. 245, 102–111.
Kearney, E. B., Ackrell, B. A. C., Mayer, M. and Singer, T. P., 1974. J. Biol. Chem. 249, 2016–2020.
Gutman, M., 1976. Biochemistry 15, 1324–1348.
Klasse, A. D. K. and Slater, E. C., 1972. Z. Naturforch., 27b, 1077–1078.
Salach, J. and Singer, T. P., 1974. J. Biol. Chem., 249, 3765–3767.
Ackrell, B. A. C., Kearney, E. B. and Edmondson, D., 1975. J. Biol. Chem. 250, 7114–7119.
Ackrell, B. A. C., Kearney, E. B. and Edmondson, D., 1976. In: Flavins and Flavoproteins., Singer, T. P. (ed.) Elsevier, Amsterdam, p. 522.
Gutman, M. and Silman, N., 1975. Mol. Cell. Bioc. 7, 177–185.
Gutman, M. and Silman, N., 1976. In: Flavins and Flavoproteins., Singer, T. P. (ed.) Elsevier, Amsterdam, p. 537.
Gutman, M. and Silman, N., 1975. Mol. Cell. Biochem., 7, 51–58.
Williamson, J. R., Smith, C. M., La Noue, K. F. and Bryla, J., 1972. In: Energy Metabolism and Regulation of Metabolic Processes in the Mitochondria., Mehlman and Hansen (eds.) Academic Press, New York, p. 185.
Dervartanian, D. V. and Veeger, C., 1965. Biochim. Biophys. Acta., 105, 424–436.
Thorn, M. B., 1962. Biochem. J., 85, 116–117.
Das, N. B., 1937. Biochem. J., 31, 1116.
Dervartanian, D. V. and Veeger, C., 1964. Biochim. Biophys. Acta., 92, 233–247.
Beinert, H., Ackrell, B. A. C., Kearney, E. B. and Singer T. P., 1974. Biochem. Biophys. Res. Commun., 58, 564–571.
Beinert, H., Ackrell, B. A. C., Kearney, E. B. and Singer, T. P., 1975. Eur. J. Biochem., 54, 185–194.
Van Voorst, J. D. W., Veeger, C. and Dervartanian, D. V., 1967. Biochim. Biophys. Acta., 146, 376–379.
Priegnitz, A., Brezhevskaya, O. R. and Wojtczak, L., 1973. Biochem. Biophys. Res. Commun., 51, 1034–1041.
Ackrell, B. A. C., Kearney, E. B. and Singer, T. P., 1972. J. Biol. Chem., 252, 1582–1588.
Vinogradov, A. D., Winter, D. B. and King, T. E., 1972. Biochem. Biophys. Res. Commun., 49, 441–444.
Vinogradov, A. D., Gavrikova, E. V. and Zuersky, V. V., 1976. Eur. J. Biochem., 63, 365–371.
Singer, T. P., Kearney, E. B. and Gutman, M., 1972. In: Biochemical Regulatory Mechanisms in Eukaryotic Cells., Kun, E. and Grisolia, S. (eds.) J. Wiley, New York, p. 271.
Gilles, R., Hogue, P. and Kearney, E. B., 1971. Life Sciences 10, 1421–1427.
Kearney, E. B., Mayer, M. and Singer, T. P., 1972. Biochem. Biophys. Res. Commun., 46, 531–537.
Coles, C. J., Tisdale, H. D., Kenney, W. C. and Singer, T. P., 1974. J. Biol. Chem., 249, 381–385.
Kenney, W. C., 1975. J. Biol. Chem., 250, 3089–3094.
Kean, E. A., Gutman, M. and Singer, T. P., 1971. J. Biol. Chem. 246, 2346–2353.
Mowery, P. C., Steenkamp, D. J., Ackrell, B. A. C., Singer, T. P. and White, G. A., 1977. Arch. Biochem. Biophys., 178, 495–506.
Susheela, L. and Ramasamra, T., 1972. Biochem. Biophys. Res. Commun., 46, 2087–2092.
Susheela, L. and Ramasamra, T., 1971. Biochim. Biophys. Acta., 242, 532–540.
Gregolin, C. and Scalella, P., 1965. Biochim. Biophys. Acta., 90, 187–190.
Singer, T. P., Gutman, M. and Kearney, E. B., 1972. In: Biochemistry and Biophysics of Mitochondrial Membrane, Academic Press, New York, p. 41.
Cerletti, P. and Manzacchi, A., 1973. Acta. Vitaminologica et Enzymologica, 27, 5–22.
Oestreicher, G., Hague, P. and Singer, T. P., 1973. Plant Physiol., 52, 622–626.
Klingenberg, M. and Rottenberg, H., 1977. Eur. J. Biochem. 73, 125–130.
Ohnishi, T., Salerno, J. C., Winter, D. B., Lim, J., Yu, C. A., Ya, L. and King, T. E., 1976. J. Biol. Chem., 251, 2094–2104.
Ohnishi, T., Lim, J., Winter, D. B. and King, T. E., 1976. J. Biol. Chem., 251, 2105–2109.
Edmondson, D. E. and Singer, T. P., 1973. J. Biol. Chem., 248, 8144–8149.
Patek, D. R. and Evisell, W. R., 1972. Arch. Biochem. Biophys., 150, 347–354.
Kierkegaard, P., Norrestram, P., Werner, P. E., Csoregh, I., Von-Glehn, M., Karlsson, R., Leijonmarck, M., Ronnquist, O., Stensland, B., Tillberg, O. and Torbjornsson, L., 1971. In: Flavins and Flavoproteins., Kamin, H. (ed.). University Park Press, Baltimore 1971, p. 1.
Urban, M. and Klingenberg, M., 1969. Eur. J. Biochem., 9, 519–525.
Gutman, M. and Silman, N., 1972. FEBS Lett., 26, 207–210.
Davis, K. A. and Hatafi, Y., 1971. Biochemistry 10, 2509–2516.
Singer, T. P., Kearney, E. B. and Ackrell, B. A. C., 1973. In: Mechanisms in Bioenergetics, Academic Press, New York, p. 485.
La None, K. F., Bryla, J. and Williamson, J. R., 1972. J. Biol. Chem., 247, 667–679.
Williamson, J. R., Sofer, B., La None, K. F., Smith, C. M. and Walajtys, B. 1973. Symp. Soc. Exp. Biol. XXVII. Cambridge University Press p. 241.
Singer, T. P., Gutman, M. and Kearney, E. B., 1971. FEBS Lett., 17, 11–13.
Whereat, A. F., Hull, F. E., Orishimo, M. W. and Rabinowitz, J. L., 1976. J. Biol. Chem. 242, 4013–4022.
Gutman, M., 1977. International Symposium on “Membrane Bioenergetics” Packer, L., Papageorgiou, G. C. and Trebst, A., eds. Spetsai, Greece. Elsevier Amsterdam, 1977, p. 165.
Kroger, A. and Klingenberg, M., 1970. Vitamins and Hormones, 28, 533–573.
Zeylemaker, W. P., Dervartanian, D. V., Veeger, C. and Slater, E. C., 1969. Biochim. Biophys. Acta., 178, 213–244.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gutman, M. Modulation of mitochondrial succinate dehydrogenase activity, mechanism and function. Mol Cell Biochem 20, 41–60 (1978). https://doi.org/10.1007/BF00229453
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00229453