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Regulation of metabolic pathways at the cellular level EC Overview of the lecture • General principles of regulation of metabolic pathways at the cellular level – regulation by the compartmentalization of the metabolic processes – changing the absolute concentration of enzyme – modulation of the activity of existing enzyme Overview of the lecture • Overview of regulation of metabolic pathways – regulation of respiratory chain and aerobic phosphorylation – regulation of the Krebs cycle – regulation of the oxidative decarboxylation of pyruvate – regulation of glycolysis and gluconeogenesis – regulation of glycogen metabolism – regulation of pentose phosphate pathway – regulation of lipolysis and beta-oxidation – regulation of ketogenesis – regulation of synthesis of fatty acids – regulation of urea cycle General principles of regulation of metabolic pathways at the cellular level General principles of regulation • The activity of metabolic pathways is constantly monitored and adjusted • Synthesis and degradation of metabolites satisfy the physiological requirements of cells and whole organism Regulation of metabolic pathways at the cellular level • 1) Compartmentalization of metabolic pathways • 2) Change in the concentration of active regulatory enzyme: • a) changing the absolute concentration of enzyme • b) modulation of the activity of existing enzyme General principles of regulation of metabolic pathways at the cellular level Regulation by the compartmentalization of the metabolic processes Compartmentalization of metabolic pathways • Eukaryotic cell is separated by membranes into individual compartments • In each cell compartment take place only certain metabolic pathways • Different enzymatic equipment of each compartment • Specific carriers in the membranes (various distribution of substrates and products) Compartmentalization of metabolic pathways • Regulation of opposing processes: synthesis of FA takes place in the cytoplasm and their degradation in the mitochondria • Subsequent processes are close to each other (KC and RC) - the local accumulation of substrate • Transport of excess citrate from MIT to the cytoplasm - AcCoA transfer and regulation of glycolysis and FA synthesis General principles of regulation of metabolic pathways at the cellular level Changing the absolute concentration of enzyme Changing the absolute concentration of enzyme • Induction (activation) or repression (inhibition) of gene encoding the enzyme • Transcription factor - inducer or repressor • Effect of TF is usually reversible and often dependent on ligand binding - ligand-dependent TF • Ligands - signal molecules, metabolites • Takes longer time (hours to days) than the regulation of activity of the existing enzyme (seconds, minutes) Changing the absolute concentration of enzyme • Enzymes of gluconeogenesis are induced by glucocorticoids • Induction of monooxygenase system by xenobiotics • Heme inhibits the synthesis of deltaaminolevulinic acid synthase General principles of regulation of metabolic pathways at the cellular level Modulation of the activity of existing enzyme Modulation of the activity of existing enzyme • 1) Covalent modifications of enzyme molecule • 2) Interventions that affect the enzyme kinetics Covalent modifications of enzyme molecule • A) Formation of active enzymes from inactive precursors • B) Interconversion of enzymes Formation of active enzymes from inactive precursors • Conversion of inactive proenzymes into active enzymes – partial proteolysis • Rapid increase in the concentration of active enzyme • Digestive enzymes, enzymes of coagulation cascade • Following removal of the active enzyme can be done by its proteolytic degradation Interconversion of enzymes • Enzyme is activated / inhibited by other enzyme • Reversible ATP-dependent phosphorylation and dephosphorylation (Ser, Thr, Tyr) • Proteinkinases and phosphatases • Phosphorylation can activate or inhibit • Fast switching between active and inactive form of the enzyme Interventions that affect the enzyme kinetics • 1) Effect of substrates and products concentrations, pH and temperature • 2) Influence of modulators (activators or inhibitors): feedback regulation, cross regulation, feedforward regulation Effect of substrate concentration Effect of product concentration • 1) Removing of the product of one reaction by subsequent reactions (metabolic pathways) • 2) Utilization of a product of one metabolic pathways in other metabolic pathway • 3) Transport of the product to another cell compartment • → acceleration of the first reaction Obrázek převzat z http://web.indstate.edu/thcme/mwking/glycolysis.html Activity modulators • Activators and inhibitors • 1) Accumulation of intermediate or final product of a metabolic pathways leads to inhibition - feedback regulation • 2) Intermediate (or product) of one metabolic pathway influences the rate of the other pathway - cross regulation • 3) Intermediate affects one of the following enzyme - feedforward regulation Overview of regulation of metabolic pathways Regulation of respiratory chain and aerobic phosphorylation • Availability of O2 • Ratio of NADH / NAD+ • Availability of ADP for ATP synthesis • Uncoupling proteins (proton gradien on an inner mitochondrial membrane) Regulation of citric acid cycle • Availability of substrates • Consumption of products (NAD, FAD) • Ratio ATP/ADP • Citrate synthase • Isocitrate dehydrogenase (key enzyme) • 2-oxoglutarate dehydrogenase Regulation of pyruvate dehydrogenase reaction (PDH) • Interconversion of PDH: phosphorylated form is inactive, dephosphorylated form is active – insulin activates - principal regulatory mechanism • Competitive inhibition by products acetyl-CoA and ↑ NADH / NAD+ Regulation of glycolysis • 1) Hexokinase / glucokinase • 2) 6-phosphofructo-1-kinase (6-PFK-1) (key enzyme) • 3) Pyruvate kinase • Regulation of PPK: • A: ↑ ratio AMP / ATP, Fru-2,6-bisP (related to ↑ insulin / glucagon), insulin (induction) • I: ↑ ATP / AMP, citrate, acidic pH Regulation of gluconeogenesis • 1) Pyruvate carboxylase • 2) Phosphoenolpyruvate carboxykinase • 3) Fructose-1,6-bisphosphatase • 4) Glucose-6-phosphatase • General regulation (Ad 1) - 4)): • A: cortisol a glucagon (induction) • I: insulin (repression) • • Ad 3): opposite to regulation of phosphofructokinase • Ad 1): AcCoA activates Regulation of glycogen metabolism • 1) Glycogen degradation - glycogen phosphorylase • 2) Synthesis of glycogen - glycogen synthase • • Ad 1): • A: glucagon, adrenaline (phosphorylation), ↑ AMP / ATP, Ca2+ (in muscle) • I: insulin • • Ad 2): • A: insulin • I: glucagon, adrenaline (phosphorylation) Regulation of pentose cycle • ↑ NADPH / NADP+ inhibits regulatory enzyme: glucose-6-phosphate dehydrogenase • Insulin activates Regulation of lipolysis • Hormone sensitive lipase (adipocytes) • A: catecholamines, glucagon (phosphorylation) • I: insulin Regulation of beta-oxidation • Supply of fatty acids (see regulation of lipolysis) • Velocity of transport of fatty acids into a mitochondrion: carnitine acyltransferase I is inhibited by malonyl-CoA • Consumption of AcCoA, FADH2 and NADH by subsequent reactions Regulation of ketogenesis • Production of acetyl-CoA (= substrate) • Regulation is related to the regulation of lipolysis and beta-oxidation Regulation of fatty acid synthesis • Acetyl-CoA carboxylase - key regulatory enzyme • I: palmitoyl-CoA and other acyl-CoA, glucagon (phosphorylation, repression) and AMP • A: citrate, insulin, low-fat, energy rich, high-saccharide diet (induction) Regulation of urea cycle • Induction of the enzymes by protein-rich diet or by metabolic changes during starvation • Protonproductive reaction - inhibited during acidosis • Carbamoylphosphate synthetase I • A: N-acetylglutamate • N-acetylglutamate synthetase • A: arginine