Chapter 9. Regulation of Metabolism Regulation of metabolisms can be at different levels: Systemic level: neuro-hormone regulation Cell level: induction or inhibition of enzyme protein expression Metabolic pathway level: effect of metabolites on enzyme activity

1.At the metabolic pathway level: effect of metabolites on enzyme activity  A metabolite may play multiple regulatory roles: not only affects the enzyme activity of the pathway in which it is produced, but also have effects on other pathways.  e.g. fatty acyl CoA is an intermediate of lipid metabolism. It inhibits acetyl CoA carboxylase in lipogenesis, and also inhibits pyruvate kinase in glycolysis.

Metabolic pathways and their links

Control sites of mainstream metabolic pathways(1) Pathway Key enzymes Activators inhibitors Hormone effects Glycolysis Phosphofructo- F-2,6-BP Citrate, ATP Glucagon  kinase AMP Hexokinase G-6-P Pyruvate F-1,6-BP Ala, ATP, Glucagon  kinase fatty acylCoA Gluconeo- Pyruvate Acetyl CoA F-2,6-BP Glucagon  genesis carboxylase, ATP AMP PEP carboxykinase, F-1,6-bisphosphatase, G-6-Phosphatase Glycogenesis Glycogen high[G-6-P] Insulin  synthase Glucagon  epinephrine 

Control sites of mainstream metabolic pathways(2) Pathway Key enzymes Activators inhibitors Hormone effects Glycogeno- Phosphorylase AMP, Ca ++ ATP,G-6-P Glucagon  lysis G-1-P Glucose Insulin  Pentose-P G-6-P induced by pathway dehydrogenase insulin Citric acid isocitrate AMP,ADP ATP cycle dehydrogenase Fatty acid Acetyl CoA Citrate Fatty acylCoA Glucagon ,insulin  synthesis carboxylase isocitrate Lipolysis triacylglycerol Glucagon  lipase epinephrine  insulin   -Oxidation Carnitine acetyl Malonyl CoA transferase-I

Control sites of mainstream metabolic pathways(3) Pathway Key enzymes Activators inhibitors Hormone effects Cholesterol HMG-CoA Cholesterol synthesis reductase  enzyme synth. Deoxy- Ribonucleotide ATP dATP nucleotide reductase synthesis Purine PRPP amido- PRPP AMP,GMP nucleotide transferase IMP synthesis Pyrimidine Carbamoylphosphate UTP,CTP synthesis synthase II Urea cycle Carbamoylphosphate N-Acetyl synthase I glutamate

2. On the cell level: induction or inhibition of enzyme protein expression  Enzymes are synthesized in the cytosol. The factors that stimulate biosynthesis of an enzyme are called “inducers”, while those that reduce synthesis of the enzyme are called “repressors”. DNA mRNA Enzyme protein repressorsinducers + -

 Inducers and repressors may affect transcription (mRNA synthesis) or translation (protein synthesis), but they usually regulate the synthesis of the mRNA for the enzyme protein.  Usually the substrate of an enzyme is an inducer of the enzyme, especially in microorganisms. e.g. dietary proteins induce the arginase in the liver urea production 

 The product of an enzyme catalyzed reaction may be a repressor of the enzyme. e.g. HMG-CoA reductase in the liver is repressed by cholesterol. DNA mRNA HMG-CoA reductase Cholesterol -

 Some hormones and drugs may induce biosynthesis of enzymes. e.g. some enzymes in amino acid degradation and gluconeogenesis are induced by corticosteroid hormones. Phenobarbital is an anti-insomnia drug which induces biosynthesis of mixed- function oxygenase, an enzyme catalyzes degradation of the drug in the liver.

3. On the systemic level: the neuro-hormone regulation of metabolisms plays an important role especially when the homeostasis or external environments change.  Stress sympathetic nerves  glucagon and epinephrine  TAG hydrolysis , glycogenolysis , gluconeogenesis  [blood glucose] .

 Starvation glucagon , insulin  glycogenolysis ,gluconeogenesis , adipose mobilization , protein degradation , glycolysis  maintenance of stable [blood glucose]

4. Mechanisms of hormone regulation: Hormone regulation of metabolisms is mediated by receptors on the cell membrane or inside the cell. A signal transduction system is responsible for flow of the information from the hormone to the cell.  Characteristics: A) highly specificity—a hormone only effects on one or a few metabolic pathways of specific tissues or cells;

B) Hormone regulation can reach a state of saturation—the receptor can be saturated by the hormone. C) Because the signal transduction is a cascade of reactions, the effect of a hormone on metabolisms is greatly magnified.

 Receptors on the cell membrane: they are integral proteins with a part exposed on the cell membrane serving as a binding-site for the hormone molecule. epinephrine receptor cAMP ATP PKA Phosphorylase b kinase Phosphorylase a Glycogenolysis

cAMP works as a second messenger for hormone (the first messenger) regulation ATP cAMP 5’-AMP Phosphorylase has three forms: Adenylate PPi cyclase H 2 O H + cAMP phospho diesterase

Effects of some hormones on cAMP conc. and ultimate functions Hormone Targets cAMP Effectsand functions AdrenalineLiver  Glycogen synthesis  Glycogenolysis  Fatty tissue  Lipolysis  Heart,muscle  Glycogenolysis  GlucagonLiver,heart  Glycogenolysis  Fatty tissue  Lipolysis   -cell  insulin secretion  ACTH Adrenal cortex  Corticosteroid synthesis  TSH Fatty tissue,thyroid  Glycogenolysis ,T3,T4  Insulin Fatty tissue  Lipolysis  liver, muscle  Glycogenolysis ,Gluconeogen.  Glycogen synthesis 

 Receptors inside the cells: the receptors of corticosteroid hormones and thyroxine belong to this class. The hormone can enter the cell to bind to the receptor forming a hormone-receptor complex, which in turn causes expression of the specific gene.

hormone DNA mRNA proteineffects receptor

 Receptors and diseases: abnormal change in the number or function of a receptor may result in severe diseases. e.g. non-insulin dependent diabetes mellitus (NIDDM) is a result of reduced number or functional abnormality of the insulin receptor on the cell membrane the sensitivity of cells to insulin  blood glucose  diabetes.