Regulation of Metabolism
Pratt and Cornely Chapter 19
Regulation by Compartmentalization
• Form of reciprocal regulation
• Degradation vs biosynthesis
• Requires transporters
Specialization of organs
Fuel Storage
• Total amounts
• Availability at time of
need
Liver: Tissue Specific
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Gluconeogenesis
ketogenesis
Urea production
Lactate recycling
Alanine recycling
Liver: Fed state
• Glucose uptake
• Glycogen synthesis
• Convert excess sugar,
amino acids to fatty
acid
• Make, transport TAG
Liver: Fast state
• Glycogen breakdown
• Maintain blood sugar
level
• Catabolize glucogenic
amino acids to maintain
glucose and citric acid
cycle
• Catabolize fats and
ketogenic amino acids
for ketone body
Muscle
• Glucose trapped as
glycogen (no blood
sugar regulation)
• Source of energy in
starvation
Muscle: Active State
• Immediate ATP/creatine
• Anaerobic muscle
glycogen
• Aerobic muscle
glycogen
• Aerobic liver glycogen
• Adipose fatty acids
Adipose
• Fed state: uptake of fats
AND glucose (why?)
• Fast state: release of
fats by hormone
sensitive lipase (HSL)
Kidney
• Elimination of waste
• Maintenance of pH
• With liver, carries out
gluconeogenesis
Cori Cycle
Alanine-Glucose Cycle
Chemical Regulation
• Local allosteric
regulation
• Hormone mediated
allosteric regulation
• Covalent modification
Major points of Regulation
Urea:
Local Regulation
• Role of citrate in multiple
pathways
• Regulation by energy
charge (ATP, AMP ratio)
– [ATP] does not change
much
• AMP-dependent protein
Kinase (AMPK) acts as
energy sensor
– High [AMP] activates
kinase to switch off
anabolism and switch on
catabolism
Hormone Regulation: Insulin
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Small protein hormome
Released at high [glucose]
Pancreatic b cells
Release probably triggered by
glucose metabolism, not cell
surface glucose receptor
– May be mitochondrial
difference, explaining why
diabetes changes with age
– May be difference between
hexokinase and glucokinase
isozyme in pancreas
Hexokinase
• Most tissues except
pancreas and liver
• First irreversible reaction
• Linked to glucose uptake
– Locks glucose in cell
• Many isozymes
– Most inhibited by glucose6-phosphate
– Product inhibition
Glucokinase
• Isozyme in liver and
pancreas
• Higher Km
– Hexokinase always
saturated, but
glucokinase sensitive
to [glucose]
• Not inhibited by
glucose-6-P
– Why? Liver serves to
modulate blood sugar
Isozyme kinetics
• Looks allosteric, but this
is monomeric enzyme
• May be due to
conformational change
upon product release—
stays in active state at
high concentration of
glucose
Insulin Signal Transduction
Glucose Entry into Cells
• Tissues have unique function
• Isozymes of glucose transporter, GLUT
– Insulin dependent in muscle
– Higher [glucose] required for liver uptake
Covalent modification
• Signal transdution leads
to phosphatase and/or
kinase activity
• Covalent modification
• Glycogen phosphorylase
– Phosphatase inactivates (b
form)
– Kinase activates (a form)
Insulin Regulation of Glycogen
Insulin
Glucagon and Epinephrine
• Glucagon released with
low blood sugar
(pancreas a cells)
• Epinephrine released by
adrenal glands
• Oppose insulin
– Activates glycogen
breakdown
– Activates gluconeogenesis
– Activates hormone
sensitive lipase
Glucagon Regulation of Glycogen
Glucagon
Obesity
• Hereditary, age, and
environmental
• Set-point
• Leptin
– Appetite suppressant
– Made in adipose
• Brown fat
Diabetes
• Type 1 (Juvenile onset)
– Insulin dependent
• Type 2
– Insulin resistance
• Body feels like a fast
– Gluconeogenesis
increase
– Lower fat storage
– Increase in fat utilization
• ketogenesis
Hyperglycemia
• Non-enzymatic glycosylation
• Sorbitol production leads to
tissue damage
• Drugs aimed at undoing
metabolic problems
• Metformin
– Activates AMPK
» Suppress
gluconeogenesis
– Actuvates glucose and fatty
acid uptake in muscle
Review
• Central molecules
– Relate to reactions
• Enzyme classes
• Cofactors
• Basic reactions
– Redox
– Decarboxylation
– energetics
• Reaction motifs
Central Molecules
Enzyme classes
Problem 6.14. Propose a name for the
enzyme, and indicate metabolic
purpose of reaciton.
Cofactors
Problem 12.26-27
• Identify the metabolic pathway. Indicate
which redox cofactor is necessary.
Problem 33:
• Identify the necessary cofactors
Reaction Motifs