Integration and Regulation of Metabolism

Compounds of different origin and nature can produce common metabolites and products. Hexoses, glycerol, fatty acids, and amino acids render acetyl-CoA, which is oxidized in the citric acid cycle. The respiratory chain is the final common destination of electrons from different substrates. Carbohydrates generate fatty acids and triacylglycerols. Amino acids form α-ketoacids by transamination. Glucose also produces α-ketoacids. After deamination, amino acids can form carbohydrates (glucogenic amino acids) or ketone bodies (ketogenic amino acids). Some metabolites (glucose-6-P, pyruvate, acetyl-CoA) are “crossroads” compounds of several metabolic pathways. Metabolic regulation is achieved by targeting key enzymes on a pathway, either by modifying the activity of preexistent enzymes (changes in substrate level, allosteric effectors, covalent modification) or changing the amount of enzyme (synthesis or degradation). Glycogenolysis is regulated through the control of glycogen phosphorylase and phosphorylase kinase . Glycogenesis is regulated by modulating the activity of glycogen synthase . Glycolysis is controlled by targeting hexokinase and phosphofructokinase . Gluconeogenesis is modulated at the level of g lucose-6-P phosphatase , fructose-l,6-bisP phosphatase , and pyruvate carboxylase. Oxidative decarboxylation of pyruvate is modulated via the pyruvate dehydrogenase (PDH) multienzyme complex. The citric acid cycle is regulated at various levels, including citrate synthase , isocitrate dehydrogenase , α-ketoglutarate dehydrogenase , and glutamate dehydrogenase . The Pasteur effect describes a phenomenon consisting of the decrease in glucose consumption in the presence of oxygen. Allosteric regulation of phosphofructokinase is responsible for this effect. Triacylglycerols in adipose tissue are hydrolyzed by lipase , a hormone-regulated enzyme. Fatty acid biosynthesis is mainly regulated at the level of acetyl CoA carboxylase . Cholesterol biosynthesis is regulated by controlling 3-OH-3-methylglutaryl-CoA reductase . Metabolism of nitrogenous compounds, such as the synthesis of some amino acids, of purines, and pyrimidines is regulated by the final product. Cellular oxidations are adjusted by the content of nucleotides in the cell. The energy charge of the cell depends on the relative concentration of ATP, ADP, and AMP of cells. When the energy charge is high, energy-consuming metabolic pathways are stimulated, whereas those producing ATP are inhibited.