Metabolism 6 Flashcards
- Regulation of Metabolic Pathways:
- Occurs at rate-limiting steps
- Small changes greatly affect the flow of metabolites through the pathway.
- Regulation occurs at the first committed step of a pathway
- Not necessarily the first step of the pathway
- Regulatory enzymes catalyze irreversible reactions
- Different enzymes are used for synthetic and degradative pathways (reciprocal regulation)
- “Feedback regulation” is an important mechanism
- Catalytic activity
- Reversible allosteric control (___ control)
- Reversible covalent modification (phosphorylation and dephosphoryation)
- Hormonal regulation – ___ control (occurs in one or more tissues)
- Accessibility of substrates
- Synthetic/degradative pathways distinct
- Compartmentalization
- Regulation may vary in different organs
- *
Regulation of Metabolic Pathways:
Occurs at rate-limiting steps
Small changes greatly affect the flow of metabolites through the pathway.
Regulation occurs at the first committed step of a pathway
Not necessarily the first step of the pathway
Regulatory enzymes catalyze irreversible reactions
Different enzymes are used for synthetic and degradative pathways (reciprocal regulation)
“Feedback regulation” is an important mechanism
Catalytic activity
Reversible allosteric control (local control)
Reversible covalent modification (phosphorylation and dephosphoryation)
Hormonal regulation – global control (occurs in one or more tissues)
Accessibility of substrates
Synthetic/degradative pathways distinct
Compartmentalization
Regulation may vary in different organs
Regulatory molecules involved in glycolysis, citric acid cycle and gluconeogenesis
Glycolysis
CAC
Gluconeogenesis
Regulatory molecules involved in glycolysis, citric acid cycle and gluconeogenesis
Glycolysis
Hexokinase
Glucose 6 Phosphate
PFK1
AMP, F26BP
ATP, Citrate, H+
Pyruvate Kinase
ATP, Alanine
CAC
Pyruvate Dehydrogenase
Acetyl CoA, NADH, ATP
Isocitrate Dehydrogenase
ATP, NADH
AKG Dehydrogenase
Succinyl CoA, ATP, NADH
Gluconeogenesis
Pyruvate Carboxylase
Acetyl CoA
PEP Kinase
Phosphofructobisphosphatase
AMP, F26 BP
Key Junctions or Crossroads of metabolic pathways
___: Glycoylsis, PPP, Glycogen
____: Acetyl CoA for CAC and can act as backbone for aa. When you degrade aa, you form pyruvate
_____ is the center of it all.
Key Junctions or Crossroads of metabolic pathways
G6P: Glycoylsis, PPP, Glycogen
Pyruvate: Acetyl CoA for CAC and can act as backbone for aa. When you degrade aa, you form pyruvate
Acetyl CoA is the center of it all.
Eukaryotic cells compartmentalize pathways to help control regulation
Cytosol
____
____
____
Mitochondrial Matrix
___
____
___
____
Interplay of both compartments
____
____
Eukaryotic cells compartmentalize pathways to help control regulation
Cytosol
Glycolysis
PPP
Fa synthesis
Mitochondrial Matrix
CAC
Oxidatative Phosphorylation
B ox of fa
Ketone Body Formation
Interplay of both compartments
Gluconeogenesis
Urea Synthesis
Metabolic Adaptations
1st priority—_____
2nd priority—___ ____
Stored fuels (glycogen, TAGs and proteins) can meet needs for approximately __ ____
Carbohydrate reserves (glycogen) exhausted in ____
Brain needs continual supple of glucose.
Priority in starvation—glucose for____ (and survival of ____).
In muscle, ___ ____ can be converted to glucose but muscle needs to be ____
Muscle is the last resort
Metabolic Adaptations
1st priority—Glucose
2nd priority—Preserve muscle
Stored fuels (glycogen, TAGs and proteins) can meet needs for approximately 3 months.
Carbohydrate reserves (glycogen) exhausted in 1 day
Brain needs continual supple of glucose.
Priority in starvation—glucose for brain (and survival of RBC).
In muscle, amino acids can be converted to glucose but muscle needs to be preserved.
Muscle is the last resort
Brain
Depends on continual supply of glucose: Starvation: ketone bodies can replace glucose as major fuel source.
Ketone bodies are transportable equivalents of acetyl groups.
Fatty acids cannot be used as fuel because blood/brain barrier prevents entry.
Brain
Depends on continual supply of glucose: Starvation: ketone bodies can replace glucose as major fuel source.
Ketone bodies are transportable equivalents of acetyl groups.
Fatty acids cannot be used as fuel because blood/brain barrier prevents entry.
Muscle
Major fuel sources of skeletal: glucose, fatty acids, ketone bodies, amino acids
Large store of glycogen
Lack glucose 6-phosphatase so can’t export glucose
Contracting muscle—Rate of glycolysis exceeds rate of citric acid cycle
Pyruvate converted to lactate. Lactate transported to liver via blood.
Cori cycle—makes glucose for muscle
Preferred fuels used by the cardiac muscle are fatty acids, lactate and glucose. (lactate converted to pyruvate which is converted to acetylCoA which get oxidized to form ATP through oxidative phosphorylation)Prefers fa over glucose!
You get high amt of ATP when you oxidize fa
Muscle
Major fuel sources of skeletal: glucose, fatty acids, ketone bodies, amino acids
Large store of glycogen
Lack glucose 6-phosphatase so can’t export glucose
Contracting muscle—Rate of glycolysis exceeds rate of citric acid cycle
Pyruvate converted to lactate. Lactate transported to liver via blood.
Cori cycle—makes glucose for muscle
Preferred fuels used by the cardiac muscle are fatty acids, lactate and glucose. (lactate converted to pyruvate which is converted to acetylCoA which get oxidized to form ATP through oxidative phosphorylation)Prefers fa over glucose!
You get high amt of ATP when you oxidize fa
Adipose Tissue
Specialized tissue–Stores triacylglycerols (TAGs)
Esterification of fatty acids to form TAGs
Fatty acids released from TAGs by hormone-sensitive lipases
Glucose is needed for synthesis of TAGs
Glycerol 3-phosphate synthesized from glucose
Glucose level in adipose cell determines fate of fatty acid
Acetyl CoA can be synthesized from glucose and used to syn fa
Adipose Tissue
Specialized tissue–Stores triacylglycerols (TAGs)
Esterification of fatty acids to form TAGs
Fatty acids released from TAGs by hormone-sensitive lipases
Glucose is needed for synthesis of TAGs
Glycerol 3-phosphate synthesized from glucose
Glucose level in adipose cell determines fate of fatty acid
Acetyl CoA can be synthesized from glucose and used to syn fa
Liver
Essential for providing fuel for brain, muscle, etc.
Regulates blood levels of metabolites
Take up large amount of glucose
Glucokinase–enzyme responsible
Release glucose into blood when required
Regulation of lipid metabolism
When fuel abundant, synthesizes fatty acids and releases them as VLDL
Convert fatty acids to ketone bodies when Carbohydrates are low.
Liver
Essential for providing fuel for brain, muscle, etc.
Regulates blood levels of metabolites
Take up large amount of glucose
Glucokinase–enzyme responsible
Release glucose into blood when required
Regulation of lipid metabolism
When fuel abundant, synthesizes fatty acids and releases them as VLDL
Convert fatty acids to ketone bodies when Carbohydrates are low.
Regulation of glucose uptake into the liver
Glucokinase
Isozyme of hexokinase
Glucose is removed from the blood even when glucose levels are high in the blood.
Main function is 1st step in process converting excess glucose to glycogen
Hexokinase can be inhibited by G6P but Glucokinase cannot
Regulation of glucose uptake into the liver
Glucokinase
Isozyme of hexokinase
Glucose is removed from the blood even when glucose levels are high in the blood.
Main function is 1st step in process converting excess glucose to glycogen
Hexokinase can be inhibited by G6P but Glucokinase cannot
Regulation of fatty acid uptake in the liver
Formation of acyl carnitine is regulated
Carnitine acyl transferase (CAT) inhibited by malonyl CoA
Fatty acids do not enter mitochondria because CAT inhibited. No b-oxidation occurs.
[malonyl CoA] low then fatty acids are transported into mitochondria for b-oxidation
Regulation of fatty acid uptake in the liver
Formation of acyl carnitine is regulated
Carnitine acyl transferase (CAT) inhibited by malonyl CoA
Fatty acids do not enter mitochondria because CAT inhibited. No b-oxidation occurs.
[malonyl CoA] low then fatty acids are transported into mitochondria for b-oxidation
Three factors involved in the regulation of blood glucose levels
- Mobilization of glycogen & release of glucose by liver
- Release of fatty acids from adipose tissue
- Shift in fuel usage from glucose to fatty acids by muscle & liver
Result is maintenance of blood glucose at 80-120 mg/dl
Three factors involved in the regulation of blood glucose levels
- Mobilization of glycogen & release of glucose by liver
- Release of fatty acids from adipose tissue
- Shift in fuel usage from glucose to fatty acids by muscle & liver
Result is maintenance of blood glucose at 80-120 mg/dl
Metabolic adaptations under different physiologically relevant conditions
Exercise
Fed State
Fasting
Starvation
Diabetes
Metabolic adaptations under different physiologically relevant conditions
Exercise
Fed State
Fasting
Starvation
Diabetes
What are the metabolic demands during exercise?
Goal: Maintain energetic status (i.e. ATP/ADP ratio) of the cell
Result: Increase fuel utilization
Question: What are the mechanisms responsible for increasing fuel utilization?
What are the metabolic demands during exercise?
Goal: Maintain energetic status (i.e. ATP/ADP ratio) of the cell
Result: Increase fuel utilization
Question: What are the mechanisms responsible for increasing fuel utilization?
Fuel Utilization during exercise
Glygogen reserves broken down into G6P and converted to Glucose which will move thru blood to skeletal muscle where it will be reconverted in G6P, Pyruvate
Pyruvate will first go thru CAC, but as muscle contracts, rate of glycolysis will beat out CAC so you start to generate Pyruvate
Creatine Phosphate: when it is dephosphorylated, there is a large amount of E released
When you exhaust glycogen, liver will use non carb precursors to generate glucose
Muscle itself also has reserve of glycogen (it will use this first)
Then next best thing is fa which will undergo Box
Fuel Utilization during exercise
Glygogen reserves broken down into G6P and converted to Glucose which will move thru blood to skeletal muscle where it will be reconverted in G6P, Pyruvate
Pyruvate will first go thru CAC, but as muscle contracts, rate of glycolysis will beat out CAC so you start to generate Pyruvate
Creatine Phosphate: when it is dephosphorylated, there is a large amount of E released
When you exhaust glycogen, liver will use non carb precursors to generate glucose
Muscle itself also has reserve of glycogen (it will use this first)
Then next best thing is fa which will undergo Box
Electrical stimulation of skeletal muscle
Increased Calcium leads to stimulation of:Myosin ATPase
Require Ca to fcn
Will take ATPà ADP
Glycogen breakdown via activation of phosphorylase kinase
Flux of molecules through Citric Acid Cycle
Adenylate system within contracting skeletal muscle
Myosin ATPase, ion channels, etc.
ATP → ADP + Pi
Adenylate Kinase (myokinase)
ADP + ADP <–> ATP + AMP
AMPà Muscular Contraction and Signaling
Molecule
Net Result: ADP/ATP ratio and AMP
Electrical stimulation of skeletal muscle
Increased Calcium leads to stimulation of:Myosin ATPase
Require Ca to fcn
Will take ATPà ADP
Glycogen breakdown via activation of phosphorylase kinase
Flux of molecules through Citric Acid Cycle
Adenylate system within contracting skeletal muscle
Myosin ATPase, ion channels, etc.
ATP → ADP + Pi
Adenylate Kinase (myokinase)
ADP + ADP <–> ATP + AMP
AMPà Muscular Contraction and Signaling
Molecule
Net Result: ADP/ATP ratio and AMP
Effects of ADP/ATP - contracting skeletal muscle
Increase activity of:
Creatine kinase (coverts creatine-phosphate to creatine – energy released)
Glycogen phosphorylase
Glycolysis enzymes PFK1
Pyruvate kinase
Pyruvate dehydrogenase
Citrate synthase,
Isocitrate dehydrogenase
Increase in oxidative phosphorylaton
Increase in b-oxidation
Effects of ADP/ATP - contracting skeletal muscle
Increase activity of:
Creatine kinase (coverts creatine-phosphate to creatine – energy released)
Glycogen phosphorylase
Glycolysis enzymes PFK1
Pyruvate kinase
Pyruvate dehydrogenase
Citrate synthase,
Isocitrate dehydrogenase
Increase in oxidative phosphorylaton
Increase in b-oxidation
Effects of AMP - contracting skeletal muscle
- Glucose Uptake (AMP )
- Glycogen Phosphorylase (AMP )
- PFK1 (AMP )
- Decreases malonyl CoA (AMP ) – Inhibition of Acetyl CoA carboxylase by AMP dependent kinase.
Effects of AMP - contracting skeletal muscle
- Glucose Uptake (AMP )
- Glycogen Phosphorylase (AMP )
- PFK1 (AMP )
- Decreases malonyl CoA (AMP ) – Inhibition of Acetyl CoA carboxylase by AMP dependent kinase.
The effect of epinephrine during muscle contraction
Skeletal Muscle
Stimulate phosphorylase activity
Inhibit glycogen synthase
Adipose Tissue
Stimulate hormone sensitive lipase leading to breakdown of TAG into glycerol and fatty acids and transport of fatty acids to liver and muscle
Glycerol to liver for gluconeogenesis
The effect of epinephrine during muscle contraction
Skeletal Muscle
Stimulate phosphorylase activity
Inhibit glycogen synthase
Adipose Tissue
Stimulate hormone sensitive lipase leading to breakdown of TAG into glycerol and fatty acids and transport of fatty acids to liver and muscle
Glycerol to liver for gluconeogenesis
Epinephrine effects in Liver
glycogen breakdown & ¯ glycogen synthesis
b-oxidation of Fatty acids leads to production of ketone bodies
gluconeogenesis
Epinephrine effects in Liver
glycogen breakdown & ¯ glycogen synthesis
b-oxidation of Fatty acids leads to production of ketone bodies
gluconeogenesis
Endurance exercise
Increasing reliance on Fatty acid b-oxidation
Cannot continue at high pace indefinitely
Fatigue= Inability to maintain a constant power output
If only exercise a little, you use glycogen first.
Then you will start to use fa
But they will not last forever.
Overcome this by building muscle mass and having higher glycogen reserves
Endurance exercise
Increasing reliance on Fatty acid b-oxidation
Cannot continue at high pace indefinitely
Fatigue= Inability to maintain a constant power output
If only exercise a little, you use glycogen first.
Then you will start to use fa
But they will not last forever.
Overcome this by building muscle mass and having higher glycogen reserves
Fed state:s torage of excess calories
Carbohydrate
1st Converted to glycogen (liver and muscle)
Next best thing: Converted to fatty acids (liver and adipose)
Stored in the adipose tissue as TAGs
Fatty Acids
Converted to Lipids (TAGs) (adipose)
Amino Acids
Carbon skeleton converted to glycogen (liver)
Carbon skeleton converted to fatty acids (liver)
Fatty acids converted to TAGs (stored in adipose tissue)
Fed state:s torage of excess calories
Carbohydrate
1st Converted to glycogen (liver and muscle)
Next best thing: Converted to fatty acids (liver and adipose)
Stored in the adipose tissue as TAGs
Fatty Acids
Converted to Lipids (TAGs) (adipose)
Amino Acids
Carbon skeleton converted to glycogen (liver)
Carbon skeleton converted to fatty acids (liver)
Fatty acids converted to TAGs (stored in adipose tissue)
Hormonal Regulators of Fuel Metabolism in the liver, muscle and adipose tissue
Insulin
Signals “fed state”
Stimulates fuel storage & synthesis of proteins
Glucagon
Signals “Absence of glucose ”
Causes breakdown of glycogen, fa, aa
Epinephrine & Norepinephrine
Secreted by adrenal medulla & sympathetic nerve endings in response to low blood glucose
Acute stress
Cortisol
Stimulate amino acid mobilization in muscle, gluconeogenesis, Fatty acid release from adipose tissue.
Hormonal Regulators of Fuel Metabolism in the liver, muscle and adipose tissue
Insulin
Signals “fed state”
Stimulates fuel storage & synthesis of proteins
Glucagon
Signals “Absence of glucose ”
Causes breakdown of glycogen, fa, aa
Epinephrine & Norepinephrine
Secreted by adrenal medulla & sympathetic nerve endings in response to low blood glucose
Acute stress
Cortisol
Stimulate amino acid mobilization in muscle, gluconeogenesis, Fatty acid release from adipose tissue.
Insulin Effects
Glucose stimulates secretion of insulin
Increases glucose uptake
Stimulates dephosphorylation of key regulatory enzymes
Glycogen phosphorylase inhibited. Stimulates glycogen synthesis in muscle & liver
Suppress gluconeogenesis in liver
Stimulates glucose uptake into muscle & adipose tissue
Insulin Effects
Glucose stimulates secretion of insulin
Increases glucose uptake
Stimulates dephosphorylation of key regulatory enzymes
Glycogen phosphorylase inhibited. Stimulates glycogen synthesis in muscle & liver
Suppress gluconeogenesis in liver
Stimulates glucose uptake into muscle & adipose tissue
Glucagon Effects
Stimulates glycogen breakdown. Inhibits glycogen synthesis (cAMP cascade)
Activate glycogen phosphorylase
Stimulates gluconeogenesis in the liver
Increases release of glucose by liver & Fatty acids from adipose tissue
Glucagon Effects
Stimulates glycogen breakdown. Inhibits glycogen synthesis (cAMP cascade)
Activate glycogen phosphorylase
Stimulates gluconeogenesis in the liver
Increases release of glucose by liver & Fatty acids from adipose tissue
Epinephrine Effects
Stimulate mobilization of glycogen and TAGs
Inhibit glucose uptake by muscle
Fatty acids used as fuel
Stimulate secretion of glucagon
Inhibit secretion of insulin
Increases release of glucose into blood by the liver.
Epinephrine Effects
Stimulate mobilization of glycogen and TAGs
Inhibit glucose uptake by muscle
Fatty acids used as fuel
Stimulate secretion of glucagon
Inhibit secretion of insulin
Increases release of glucose into blood by the liver.
Fasting
Low blood sugar
Decreased insulin secretion
Increased glucagon secretion
Mobilization of TAGs in adipose tissue
[Acetyl CoA] rises
Gluconeogenesis in liver increases
[Citrate] rises
Glycolysis is inhibited due to increase in acetyl CoA, citrate, & ATP
Uptake of glucose by muscle decreased
Muscle shifts from using glucose to fatty acids as fuel
Lactate exported by muscle to liver to make glucose (Cori cycle)
Fasting
Low blood sugar
Decreased insulin secretion
Increased glucagon secretion
Mobilization of TAGs in adipose tissue
[Acetyl CoA] rises
Gluconeogenesis in liver increases
[Citrate] rises
Glycolysis is inhibited due to increase in acetyl CoA, citrate, & ATP
Uptake of glucose by muscle decreased
Muscle shifts from using glucose to fatty acids as fuel
Lactate exported by muscle to liver to make glucose (Cori cycle)
Fasting
After 3 days:
___ ____(liver) _____ because of lack of Citric acid intermediates (Oxaloacetate)
Ketone bodies used by brain as fuel
Fasting
After 3 days:
Ketone bodies (liver) increases because of lack of Citric acid intermediates (Oxaloacetate)
Ketone bodies used by brain as fuel
Starvation
After several weeksKetone bodies are main fuel source for brain
Decreases need for glucose
Use of ketone bodies spares muscle protein breakdown by preventing need for amino acids for glucose synthesis
Starvation
After several weeksKetone bodies are main fuel source for brain
Decreases need for glucose
Use of ketone bodies spares muscle protein breakdown by preventing need for amino acids for glucose synthesis
Diabetes mellitus
Absence or inability to respond to circulating insulin–Glucose very abundant but cannot be used
Disease characterized by an abnormal pattern of fuel usage
Overproduction of glucose by the liver and an underutilization of glucose by the other organs
Normally, insulin increases
Glucokinase in liver, GLUT-4 in membrane in muscle & adipose leading to increase glucose uptake
Convert glucoseàGlucose 6 Phosphate. From there it can be converted to glycogen or utilized for fa syn
Diabetes
Liver increases gluconeogenesis
No GLUT-4 increase
No activity of glucokinase
Glucose abundant but liver doesn’t take it up so makes more glucose via gluconeogenesis
Diabetes mellitus
Absence or inability to respond to circulating insulin–Glucose very abundant but cannot be used
Disease characterized by an abnormal pattern of fuel usage
Overproduction of glucose by the liver and an underutilization of glucose by the other organs
Normally, insulin increases
Glucokinase in liver, GLUT-4 in membrane in muscle & adipose leading to increase glucose uptake
Convert glucoseàGlucose 6 Phosphate. From there it can be converted to glycogen or utilized for fa syn
Diabetes
Liver increases gluconeogenesis
No GLUT-4 increase
No activity of glucokinase
Glucose abundant but liver doesn’t take it up so makes more glucose via gluconeogenesis
Summary
Metabolic pathways produce ATP, reduced coenzymes, biosynthetic precursors.
Glucose 6-phosphate, pyruvate, acetyl CoA provide key junctions.
Metabolic profiles of organs differ from one another.
Summary
Metabolic pathways produce ATP, reduced coenzymes, biosynthetic precursors.
Glucose 6-phosphate, pyruvate, acetyl CoA provide key junctions.
Metabolic profiles of organs differ from one another.
