Chapter 9. Regulation of Metabolism Regulation of metabolisms can be at different levels: Systemic...
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Transcript of Chapter 9. Regulation of Metabolism Regulation of metabolisms can be at different levels: Systemic...
Chapter 9. Regulation of Metabolism
Regulation of metabolisms can be at different levels:
Systemic level: neuro-hormone regulation
Cell level: induction or inhibition of enzymeprotein expression
Metabolic pathway level: effect of metaboliteson 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.
Glucose
Glucose-6-phosphate
Dihydroxyacetone phosphateGlycerol Glyceraldehyde 3-phosphate
Phosphoenolpyruvate
Pyruvate
Acetyl CoA
Fatty acidAla, Trp, Ser, Thr, Cys, Gly
Ketone bodies
OxaloacetateAsp
Purine, Pyrimidine
Fumarate
Succinate
a-ketoglutarate
Citrate
Val, Met, Ile, Thr
Heme
Tyr, Phe
Glu
Gln
Purine
Arg, His, Pro
Purine, hemeCholesterol
Leu, Lys
Fat
Citric acid cycle
Metabolic pathwaysand their links
Control sites of mainstream metabolic pathways(1)Pathway Key enzymes Activators inhibitors Hormone effectsGlycolysis 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 Glucagongenesis 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 effectsGlycogeno- Phosphorylase AMP, Ca++ ATP,G-6-P Glucagonlysis 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,insulinsynthesis 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 effectsCholesterol 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 PPicyclase
H2O H+
cAMP phosphodiesterase
P
P P
P
P
PPhosphorylase bkinase
Phosphorylasephosphatase
2ATP 2ADP
2Pi 2H2O
Inactive high activity low activity
Effects of some hormones on cAMP conc. and ultimate functions
Hormone Targets cAMP Effects and functions
Adrenaline Liver Glycogen synthesis Glycogenolysis
Fatty tissue Lipolysis Heart,muscle Glycogenolysis
Glucagon Liver,heart Glycogenolysis Fatty tissue Lipolysis -cell insulin secretion
ACTH Adrenal cortex Corticosteroid synthesisTSH Fatty tissue,thyroid Glycogenolysis,T3,T4Insulin 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
mRNAproteineffects
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.