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M C Kohn

Publications and source records attributed to M C Kohn.

15 recordsLinked to original sources
PubMed1992

Propagation of information in MetaNet graph models.

Information flow in metabolic networks has been studied with a graph model which represents the biochemical transformations occurring in the system under investigation. The "signal strength", an algebraic expression which estimates the probability that an intermediate metabolite is bound to a given enzyme, has been used to derive the "signal transmittance", the fraction of the informational signal at one intermediate that reaches another intermediate. The transmittance has been used to derive the "response ratio", the sensitivity of the rate of change of information at one metabolite consequent to a perturbation at another metabolite. Because the graphical representation corresponds to the biochemical events presumed to occur in the network, these quantities can be used to design experiments to confirm or falsify the hypotheses underlying the model and aid in understanding the regulatory properties of the system. The technique is illustrated by an example model, and its predictions are shown to be sensitive to modest structural changes in the network.

Animals↗
PubMed1991

Identification of regulatory properties of metabolic networks by graph theoretical modeling.

An earlier graph theoretical model of metabolic and gene-expression networks has been modified and extended to include the effect of electrical potentials on binding constants, representation of uncatalyzed processes, and treatment of parallel reactions catalyzed by a single enzyme. Formal operations on the graph, which are facilitated by a set of standardized guidelines, identify the feedback signals in the network and rank them according to their influence. The technique was applied to a model of glycolysis in ascites tumor cells in the absence and presence of 12.5 mM exogenous glucose. Feedback regulation was widely distributed and mostly due to binding of adenine nucleotide cofactors to the enzymes of the network. The major changes in feedback regulation on adding glucose is the relief of inhibition of hexokinase and phosphofructokinase and the activation of pyruvate kinase. We conclude that regulation of tumor cell glycolysis is not restricted to hexokinase or to (Na+,K+)-ATPase as was previously suggested by others.

Animals↗
PubMed1979

Computer simulation of the fructose bisphosphatase/phosphofructokinase couple in rat liver.

Recycling of fructose 6-phosphate and fructose 1,6-bisphosphate in the rat liver under gluconeogenic and glycolytic conditions was investigated with a computer model containing representations of the kinetic properties of phosphofructokinase and fructose 1,6-bisphosphatase under realistic physiological conditions. The two enzyme submodels were constructed from data for the isolated enzymes in vitro by formal optimization. Tissue metabolite concentrations were corrected for cytosolic/mitochondrial compartmentation and effects of chelation and protonation equilibria. This model, which mostly considers the behavior of livers from starved rats, predicts negligible recycling under physiologically realistic conditions. Metabolic regulation of fructose 6-phosphate, the magnesium ion concentration and the distribution of adenine nucleotides appear to prevent operation of a 'futile cycle' in vivo. Rate-limiting chemical species were identified by sensitivity analysis.

Animals↗
PubMed1979

Computer simulation of metabolism in pyruvate-perfused rat heart. I. Model construction.

A computer model of energy metabolism was constructed for the pyruvate-perfused rat heart subjected to a sudden increase in work load. The model construction techniques are explained and justified. Hypotheses defining a plausible sequence of physiological events resulting in the observed behavior of the organ were arrived at from the measured metabolite time profiles. There is a lag in increasing pyruvate utilization following the work-jump. A transient increase in fatty acid oxidation is required to account for the observed respiration rate. The observed increase in lactate production of this preparation is due to a transient "burst" of glycogenolysis after which the remaining lactate is imported from the interstitium and oxidized, reversing lactate dehydrogenase and hence the alpha-ketoglutarate-malate portion of the malate-aspartate shuttle.

Animals↗
PubMed1979

Computer simulation of metabolism in pyruvate-perfused rat heart. II. Krebs cycle.

A realistic metabolic model of the tricarboxylic acid cycle in the perfused rat heart was constructed to help explain the sequence of biochemical events regulating the metabolism of exogenous pyruvate following a large increase in work load. The unchelated Mg2+ level was the most important controlling factor. The resulting mixture of chelated and unchelated nucleotides and tribasic acids effected coordinated control of citrate synthase, aconitase, isocitrate dehydrogenase, succinyl CoA synthetase, fumarase, and nucleoside diphosphokinase, because Mg2+-chelates are generally substrates whereas unchelated species are inhibitors. Succinate dehydrogenase is largely controlled by the ubiquinone redox potential. The fluxes through alpha-ketoglutarate and malate dehydrogenases are largely dependent on thepyridine nucleotide redox potential, but the succinyl CoA-to-CoASH ratio strongly affects the former enzyme as well. The model predicts an accumulation of succinate during the transition to higher work output.

Animals↗
PubMed1979

Computer simulation of metabolism in pyruvate-perfused rat heart. III. Pyruvate dehydrogenase.

A physiologically and biochemically realistic model of the regulation of pyruvate dehydrogenase complex (PDH) was constructed for the perfused rat heart. It includes conversion between inactive (phospho) and active (dephospho) forms by a specific protein kinase (PDHK) and phosphoprotein phosphatase (PDHP). The activity of the tightly bound PDHK is influenced by synergistic activation/inhibition by acetyl CoA/CoASH and NADH/NAD. PDHK in this simulation was more sensitive to the fraction of ADP that was Mg2+-chelated than to the ATP-to-ADP ratio. Ca2+ stimulates binding of Mg2+-dependent PDHP to the complex; the bound enzyme was considered to be the active species. The fraction of PDH in the active form, rather than substrate and inhibitor levels, determines PDH activity under these conditions. This fraction depends on the present value and recent history of the difference between PDHK and PDHP activities. Both of these are active continuously and continuously control PDH.

Animals↗
PubMed1979

Computer simulation of metabolism in pyruvate-perfused rat heart. IV. Model behavior.

The behavior of a computer model of energy metabolism was determined for perfused rat hearts utilizing pyruvate as sole exogenous fuel and subjected to a rapid increase in work load. Computer-generated metabolite profiles, which are solutions of the differential equations for 1 min elapsed time, closely match 12 experimental curves (involving 120 concentration measurements) and exhibit the following properties. The computed cytosolic pyruvate level oscillates due to large changes in the rates of the processes that produce and consume this metabolite. Cytosolic Mg2+ seems to act as a coordinated controller of glycolytic enzymes; its transient increase permits a transient increase of glycolysis without an accumulation of glucose 6-phosphate. Lactate is exported to the interstitium by a lactate permease and then reimported and oxidized. As a result, the malate-aspartate shuttle reverses direction, and the Krebs cycle is "unspanned."

Animals↗
PubMed1979

Computer simulation of metabolism in pyruvate-perfused rat heart. V. Physiological implications.

The results of a simulation of metabolism in the pyruvate-perfused rat heart subjected to a sudden increase in work load are interpreted to provide a coherent explanation for the observed physiology. Respiration is most closely correlated with the mitochondrial phosphate potential, calculated from the MgATP and MgADP levels. No correlation between respiration and the pH gradient across the mitochondrial membrane was found. The transient falls in pH in the cytosol and perhaps the mitochondria are due largely to carbonic and lactic acidosis and appear to be only weakly coupled. The heart maintains a high ATP level during the transition to increased work by utilizing its energy reserves in order of decreasing availability in response to physiological signals mediated by Mg2+, Ca2+, and cAMP.

Animals↗
PubMed1977

Computer simulation of ischemic rat heart purine metabolism. I. Model construction.

A model is proposed for the partial depletion of the adenine nucleotide pool in the ischemic perfused rat heart which involves seven enzymes: adenylate cyclase, 3',5'-cyclic AMP phosphodiesterase, 5'-nucleotidase, adenosine kinase, adenosine deaminase, purine nucleoside phosphorylase, and inorganic pyrophosphatase. The computer implementation of this model is in terms of rate laws, several of which were obtained by a systematic least-squares fitting procedure. Depletion of the adenine nucleotide pool is initiated by the release of endogenous noradrenaline into the interstitial fluid, which results from a fall in tissue PO2, and the subsequent activation of adenylate cyclase. In this model the substrate for 5'-nucleotidase is a membrane-bound AMP pool formed by hydrolysis of extracellular fluid and functions as a vasodilator; excess adenosine is incorporated into the tissue by a "permease" with Michaelis-Menten kinetics and converted to AMP, inosine, and hypoxanthine. Alternative mechanisms, such as the deamination of AMP by adenylate deaminase and conversion of AMP to adenine by AMP pyrophosphorylase, were rejected primarily on qualitative biochemical grounds.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Computer simulation of ischemic rat heart purine metabolism. II. Model behavior.

The behavior of a model for the partial depletion of adenine nucleotides in the perfused rat heart has been compared for ischemic and high coronary flow anoxic conditions. The accumulation of noradrenaline in the interstitial fluid greatly activates adenylate cyclase ultimately resulting in the degradation of 11.02 micronmol/g dry wt of ATP to adenosine, inosine, and hypoxanthine in 30 min. The high coronary flow rate during anoxic perfusion promotes washout of the noradrenaline from the interstitial fluid so that the hormone accumulates to only one fifth of its highest level in ischemia. This results in only slight activation of adenylate cyclase and in insignificant degradation of ATP in 2 min. The behavior of the model has been examined for two aerobic conditions--a transition from light to heavy work (2 min) and a transition from substrate-free to glucose perfusion (12 min), In both cases adenylate cyclase was not activated above its basal activity, and insignificant depletion of adenine nucleotides is predicted by the model.

Adenine Nucleotides↗
PubMed1977

Distribution of adenine nucleotides in the perfused rat heart.

A computer technique for determination of the distribution of adenine nucleotides among compartmented, protonated, and metal-chelated species has been developed for the perfused rat heart. This procedure requires knowledge of tissue levels of creatine, creatine phosphate, ATP, ADP, and AMP and the glycolytic and respiration rates. The method is applicable to any physiological state of the organ and has been applied to transient behavior in aerobic, anoxic, and ischemic hearts. The results suggest that ADP uptake and ATP export by mitochondria are normally linked and equal in rate during aerobic metabolism or short-term anoxia but become separate and unequal during ischemia, so that mitochondrial adenine nucleotides, primarily AMP, accumulate.

Actins↗