Chapter 9. Regulation of Metabolism

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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
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• 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.

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Metabolic pathways and their links
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• 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 highG-6-P
  Insulin?
• synthase
  
  Glucagon?
• 
  
  epinephrine?

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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? b-Oxidation Carnitine
acyl Malonyl
CoA transferase-I
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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


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• 2. At 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

repressors
inducers
-

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• 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?

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• 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
-
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• 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.

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• 3. At 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?.

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• Starvation glucagon?, insulin?
  glycogenolysis?,gluconeogenesis?,
  adipose mobilization?, protein degradation?,
  glycolysis? maintenance of stable
  blood glucose

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• 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 of receptor mediation
• A) highly specificitya hormone only effects
  on one or a few metabolic pathways of specific
  tissues or cells

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• B) Hormone regulation can reach a state of
  saturationthe 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.

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• 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.

receptor
epinephrine
ATP
cAMP
PKA
Phosphorylase b kinase
Phosphorylase a
Glycogenolysis
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• cAMP works as a second messenger for hormone (the
  first messenger) regulation
• ATP cAMP
  5-AMP
• Phosphorylase has three forms

Adenylate PPi cyclase
H2O H cAMP phospho diesterase
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• 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 ?
• b-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?

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• 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.

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hormone
receptor
DNA
mRNA
mRNA
protein
effects
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• 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.