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.