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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
• Fuel Usage: About 7000 kJ/day
minimum
• Storage: About 700,000 kJ
– Fats and muscle protein: 1-3 months
– Glucose: 7000 kJ (1 day)
• Glucose is essential for brain
Liver: Tissue Specific Functions
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Gluconeogenesis
Ketogenesis
Urea production
Lactate recycling
Alanine recycling
Liver in the Fed State
• Glucose uptake
• Glycogen synthesis
• Convert excess sugar,
amino acids to fatty
acid
• Make, transport TAG
Liver in the 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
Metabolic Issues
• Starvation
• Alcoholism
• Metabolic Syndrome
– Obesity
– Diabetes
Starvation
• Early starvation: convert
protein to glucose
(cannot convert fat to
glucose)
• Later starvation
– Preserve muscle
– Muscle uses fat as fuel;
buildup of acetyl CoA shuts
down pyruvate acetyl
CoA
– Low [OAA] means acetyl
CoA buildup
– Ketone bodies produced
– Brain uses KB, glucose is
conserved
Metabolism of Ethanol
• Liver damage
– Too much NADH
and acetyl CoA
– Shuts down citric
acid cycle
– Fatty acid synthesis
upregulated
• “fatty liver”
– Ketone bodies form
• acidosis
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
– Activates glucose and fatty
acid uptake in muscle
Review of Chemical Regulation
• Local vs hormone-level
regulation
• Signal transduction
pathways
• Allosteric effectors
– Covalent modification
• Product inhibition,
feedback inhibition, feed
forward activation
• Energy charge
• Reciprocal Regulation
• Isozymes
• Logic of regulation
– Know all purposes of
pathway
– Know differences in tissue
physiology
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
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
Hormone Summary
• “Insulin signals fuel
abundance. It decreases the
metabolism of stored fuel
while promoting fuel storage.”
• “Glucagon stimulates the liver
to generate glucose by
glycogenolysis and
gluconeogenesis, and it
stimulates lipolysis in adipose
tissue.”
Some Major Points of Regulation
• Entry of glucose into cell
• Glycolysis/gluconeogenesis
• Fatty acid
synthesis/breakdown
• Glycogen
synthesis/breakdown
Urea:
Glucose Entry into Cells
• Tissues have
unique function
• Isozymes of
glucose
transporter, GLUT
– Insulin
dependent in
muscle
– Higher [glucose]
required for liver
uptake
Glycolysis/Gluconeogenesis
• 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
– Boosts production of F2,6-bP
Hormone Regulation of
Glycolysis/Gluconeogenesis
and AMPK activates phosphoprotein phosphatase
Glycogen Metabolism
Glycogen Phosphorylase
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Dimeric
Allosteric control
Hormone level control
Tissue isozymes
– Muscle: Purpose it to
release fuel for itself
– Liver: Purpose is to
release fuel for whole
organism
Covalent Modification
• Phosphorylase a
– Phosphorylated
– “usually active”
– Default liver isozyme
• Phosphorylase b
– Dephosphorylated
– “usually inactive”
– Default muscle enzyme
Liver Activity
• Physiological purpose:
release of glucose
– Default setting
• High glucose
concentration favors T
state in Phosphorylase a
• Turns off active glycogen
degradation
Muscle Activity
• Physiological purpose:
conserve glycogen until
a burst is needed
• Detection of energy
charge
– AMP shifts equilibrium
to relaxed state
Glucagon/Epinephrine Regulation
through Phosphorylase Kinase
• Activation of
cascade leads to
active
degradation of
glycogen
• Epinephrine
affects liver
through IP3
pathway
Regulating regulators
• Influx of
calcium in
active muscle
partially
activates
kinase
• Hormone
response fully
activates
Reciprocal Regulation
Glucagon
Protein Phosphatase 1
• Opposite of PKA
– Deactivates
phosphorylase
– Activates glycogen
synthase
• Active in cell unless
epinephrine signals
PKA
– PKA activates its
inhibitors
Insulin stimulates glycogen synthesis
• Insulin blocks the “turn
off” switch for glycogen
synthase
• Allows PP1 to “turn on”
glycogen synthase
Fatty Acid Regulation
• Carnitine Transporter
– Matrix malonyl CoA
• Error in this picture
• Actually produced by
acetyl CoA carboxylase
isozyme in matrix
• Acetyl CoA carboxylase
– Local
• AMP level
• Citrate and Fatty Acids
– Hormones
AMP level
• AMP-activated protein kinase
– Fuel sensor
– Inactivates acetyl CoA carboxylase under low
energy conditions in cell
Citrate and Fatty Acids
• [Citrate] high in well fed
state
– Lots of OAA and acetyl CoA
• Carboxylase forms active
filaments
– If [fatty acids] is high, no
need to synthesize
– Fatty acids break down
filaments
Hormone-level control
• Glucagon and epinephrine
– Suppress acetyl CoA carboxylase by keeping it
phosphorylated
• Insulin—activates storage
– Leads to dephosphorylation of carboxylase
Review
• Principles of Metabolism
• 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