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Regulation of Metabolism
Pratt and Cornely Chapter 19
Regulation by Compartmentalization
• Form of reciprocal regulation
• Degradation vs biosynthesis
• Requires transporters
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Specialization of organs
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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
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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 4
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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
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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
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Cori Cycle
Alanine‐Glucose Cycle
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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
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Metabolism of Ethanol
OH
• Liver damage
NAD+
alcohol DH
– Too much NADH and acetyl CoA
– Shuts down citric acid cycle
– Fatty acid synthesis upregulated
• “fatty liver”
NADH
O
NAD+
aldehyde DH
NADH
O-
O
ATP
acyl CoA
synthetase
– Ketone bodies form
• acidosis
AMP
O
SCoA
Obesity
• Hereditary, age, and environmental
• Set‐point
• Leptin – Appetite suppressant
– Made in adipose
• Brown fat
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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
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Review of Chemical Regulation
• Local vs hormone‐level regulation
• Signal transduction pathways
• Allosteric effectors
• Logic of regulation
– Know all purposes of pathway
– Know differences in tissue physiology
– Covalent modification
• Product inhibition, feedback inhibition, feed forward activation
• Energy charge
• Reciprocal Regulation
• Isozymes
Hormone Regulation: Insulin
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Small protein hormome
Released at high [glucose]
Pancreatic  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
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Hexokinase
• Most tissues except pancreas and liver
• First irreversible reaction
• Linked to glucose uptake
– Locks glucose in cell
• Many isozymes
– Most inhibited by glucose‐
6‐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
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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
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Glucagon and Epinephrine
• Glucagon released with low blood sugar (pancreas  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.”
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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
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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 F‐
2,6‐bP
Hormone Regulation of Glycolysis/Gluconeogenesis
and AMPK activates phosphoprotein phosphatase
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Glycogen Metabolism
Glycogen
metabolism
#Pompe (II)
Shaded boxes: name and structure
of substrates
Glucose
(outside
cell)
(lysosomal)
Glycogen Synthesis
Boxes: name of enzyme
(Type
XI)
implicated in glycogen storage
disease
Glucose
UDP-glucose
(inside cell)
(Type 0)
Glycogen Synthase
*Von
Gierke (I)
Glycogen
Glycogen Degradation
*Cori Disease (III)
Glygogen
phosphorylase
#Anderson Disease (IV)
Phosphorylase
Kinase
Glucose-1-phosphate
Glucose-6-phosphate
**McArdle (muscle) (V)
*Hers (liver) (VI)
*Type VIII, IX, X
branched glycogen
*Enlarged liver/muscle, hypoglycemia, abnormal glycogen
**Muscle cramping,limited physical ability
#early death from liver/heart failure
**Type VII
(muscle)
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
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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
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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
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Regulating regulators
• Influx of calcium in active muscle partially activates kinase
• Hormone response fully activates
Reciprocal Regulation
Glucagon
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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
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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
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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
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Review
• Principles of Metabolism
• Central molecules
– Relate to reactions
• Enzyme classes
• Cofactors
• Basic reactions
– Redox
– Decarboxylation
– energetics
• Reaction motifs
Central Molecules
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Enzyme classes
Problem 6.14. Propose a name for the enzyme, and indicate metabolic purpose of reaciton.
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Cofactors
Problem 12.26‐27
• Identify the metabolic pathway. Indicate which redox cofactor is necessary.
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Problem 33: • Identify the necessary cofactors
Reaction Motifs
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