Enzyme‐enzyme interactions and their metabolic role

Srere, Paul A.; Ovádi, Judit

doi:10.1016/0014-5793(90)81286-w

Cited by 104 publications

(65 citation statements)

References 42 publications

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“…Developments in cell biology have revealed an inhomogeneous cytoplasmic infrastructure at the microscopic level (54,60), in which enzymes are highly organized (19 -22, 43). In particular, it has been demonstrated that glycolytic enzymes can bind together to form a multienzyme complex (8,19,42) associated with F-actin (8,64) or other sites such as microtubules and the cellular membrane (24,36). The metabolic advantages of these multienzyme complexes include metabolic channeling, which refers to the transfer of products from an enzyme directly to an adjacent active site without entering the bulk solution (4,32,45,49).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia

Zhou

Salem

Saidel

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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The model has three distinct domains (blood, cytosol, and mitochondria) with interdomain transport of chemical species. In addition to distinguishing between cytosol and mitochondria, the model includes a subdomain in the cytosol to account for glycolytic metabolic channeling. Myocardial ischemia was induced by a 60% reduction in coronary blood flow, and model simulations were compared with experimental data from anesthetized pigs. Simulations with a previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared with experimental results. The addition of a subdomain for glycolysis resulted in simulations showing faster rates of glycogen breakdown and lactate production that closely matched in vivo experimental data. The dynamics of redox (NADH/NAD ϩ ) and phosphorylation (ADP/ATP) states were also simulated. These controllers are coupled to energy transfer reactions and play key regulatory roles in the cytosol and mitochondria. Simulations showed a similar dynamic response of the mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, the cytosolic redox state displayed a time response similar to that of lactate production. In conclusion, this novel mechanistic model effectively predicted the rapid activation of glycogen breakdown and lactate production at the onset of ischemia and supports the concept of localization of glycolysis to a subdomain of the cytosol. redox state; computer simulation; cytosol; mitochondria; metabolic channeling THE PRIMARY EFFECT of myocardial ischemia is impaired oxidative phosphorylation due to decreased oxygen delivery to the mitochondria (68). Reduced aerobic ATP production stimulates glycogen breakdown and ATP formation from glycolysis in the cytosol and results in lactate accumulation in the tissue (52, 68). Various metabolites related to energy transfer (e.g., NADH-NAD ϩ and ADP-ATP) act as modulators of key reactions in the cytosol and mitochondria but have different concentrations in these cellular domains. For example, under aerobic conditions, 5-10% of total ATP (10, 62) and 90% of the NAD ϩ and NADH (61) are in the mitochondria. On the basis of this evidence, it is inappropriate to assume the same concentrations of these metabolites in the cytosol and mitochondria when studying mechanisms controlling glycolysis and lactate metabolism from normal to ischemic conditions. Furthermore, it has been observed that key glycolytic enzymes are bound together in specific intracellular structures to form a multienzyme complex near the sarcolemma and sarcoplasmic reticulum (8,19,42). Because the glycolytic enzymes are not freely distributed, glycolysis can be considered localized in a subdomain within the cytosol.Unfortunately, at present, it is not feasible to measure dynamic changes in the fluxes and concentrations of key cytosolic and mitochondrial species in the transition from normal to ischemic conditions with current experimental techniques. As an alternate approach to conducting e...

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Section: Discussionmentioning

confidence: 99%

Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia

Zhou

Salem

Saidel

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Instead, it has become evident that there is a high degree of organization where different lipid and protein structures associate among themselves and with other molecules. The high molecule concentration found in the cytoplasm promotes macromolecule associations such as protein-protein, protein-membrane, protein-nucleic acid, protein-polysaccharide and thus is a control factor for all biological processes (Srere & Ovadi, 1990). Indeed, the classical studies by Green (Green et al, 1965), Clegg (Clegg, 1964) 102 and Fulton (Fulton, 1982) have suggested that enzymes are not dispersed in the cytoplasm.…”

Section: Metabolons: Enzyme Complexes That Channel Substratesmentioning

confidence: 99%

“…Channeling requires stable interactions of the multienzymatic metabolons (Al-Habori, 2000;Cascante et al, 1994;Ovadi & Srere, 1996;Ovadi & Saks, 2004;Srere & Ovadi, 1990;Srere, 1987). The metabolon stability is facilitated by the compartmentalization of the cell in different organelles and structures (Jorgensen et al, 2005).…”

Section: Metabolons: Enzyme Complexes That Channel Substratesmentioning

confidence: 99%

Metabolic Optimization by Enzyme-Enzyme and Enzyme-Cytoskeleton Associations

Araiza‐Olivera¹,

Uribe‐Carvajal²,

Chiquete-Félix³

et al. 2012

Cell Metabolism - Cell Homeostasis and Stress Response

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“…The first reason is that the system is in quasi-equilibrium, that is (14) where K,, K:, K,, Ki are real dissociation constants. This situation is trivial and need not be discussed.…”

Section: The Modelmentioning

confidence: 99%

Coordination of catalytic activities within enzyme complexes

Kellershohn

Ricard

1994

European Journal of Biochemistry

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If two enzymes are physically and permanently associated as a bi-enzyme complex and if these enzymes catalyze non-consecutive chemical reactions, either of these reactions may inhibit or activate the other. If these reactions belong to two different metabolic cycles, the functioning of one of these cycles will control the fine tuning of the other.Thus simple kinetic considerations lead to the conclusion that, owing to the spatial organization of enzymes as multimolecular complexes, a fine tuning and a coordination of different metabolic networks, or cycles, may be exerted. It thus appears that channelling of reaction intermediates within a multienzyme complex does not represent the only functional advantage brought about by this type of spatial molecular organization.The view that is emerging from the quantitative study of the overall metabolic processes is that of a sort of 'molecular democracy' [l], that is, the various enzyme reactions of the same metabolic network cooperate as to maintain the fine tuning of that process [1-101. It is however evident that these metabolic networks, or cycles, have to be regulated one with respect to the other. There must therefore exist a coordination between these different metabolic processes. This coordination is usually believed to be exerted thanks to metabolic intermediates, such as ATP, NAD, NADP, etc., which appear in many metabolic networks and cycles. One may wonder, however, whether the presence of these intermediates common to different metabolic processes is sufficient p e r se to maintain a strict coordination between these metabolic processes.The existence of enzyme compartmentalization and spatial organization in the living cell offers a new possibility of understanding how this coordination may be effected. It is often considered that the functional advantage brought about by enzyme association is the existence of channelling of the reaction intermediates between the different catalytic sites within the multienzyme complex [11-281. This view is often substantiated by the experimental finding that the enzymes that are associated as a complex catalyze consecutive reactions [13-211. The reality of channelling is often difficult to prove experimentally [20-251. Moreover, in a number of cases, enzymes that do not catalyze consecutive reactions exist under the form of multimolecular complexes. This is the case, for instance, of a complex made up of glyceraldehyde-3-phosphate dehydrogenase and phosphoribulokinase of chloroplasts [29, 301; of fructose 1,6-bisphosphatase and phosphoribulokinase isolated from a photosynthetic bacterium [31], of up to nine aminoacyl-tRNA synthetases in higher eukaryotes [32-371, of isoleucyl-tRNA synthetase and threonine deaminase [38] and of ornithine carbamoyltransferase and arginase [39]. Therefore if there is a funcCorrespondence to J. Ricard,

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Enzyme‐enzyme interactions and their metabolic role

Cited by 104 publications

References 42 publications

Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia

Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia

Metabolic Optimization by Enzyme-Enzyme and Enzyme-Cytoskeleton Associations

Coordination of catalytic activities within enzyme complexes

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