Food and metabolism
hexokinase starts with glycolysis
The breakdown of glucose in a red blood cell will render 4 ATP
Obesity is characterized by BMI>30
30% percentage of the dutch adults are overweight/obese
Health consequences of obesity
- high cholesterol -> cardiac arrest
- Cardiovascular disease
- Type 2 diabetes
- Strokes
- Jointwear
- Non-alcoholic fatty liver disease
- Arthritis
- Cancer
- Sleep apnoea
In a healthy person, blood glucose levels are maintained between 4-6mM
In a healthy (70kg) man, the amount of glucose in the blood is around 4 gram
The liver can not produce fatty acids
Causes for cardiovascular disease:
- atherosclerosis = sti ening of arteries
Atherosclerosis is
- inlfuenced by diet
- In uenced by hyperglycemia
- Common in young aduls
- Accelerated by high LDL cholesterol levels
A diet high in bers reduces the risk for cardiovascular disease
Lecture 1: energy metabolism
Catabolic = breakdown into energy, building blocks, and heat
Anabolic = build up into macromolecules
Metabolism = sum of catabolic and anabolic reactions in a cell
ATP = the universal currency of free energy
Sources of ATP during exercise
ATP -> ADP by motion, active transport, biosynthesis and signal
ampli cation
ADP -> ATP (regeneration) by oxidation of fuel molecules or
photosynthesis
Creatine phosphate is in muscles
fl fi fi ff
, Standard free energies of hydrolysis of compounds in biological systems
- e.g. breakdown of creatine phosphate can create …
Stages of catabolism
- breakdown of food:
- proteins into amino acids
- Breakdown of polysaccharide chains into glucose and other sugars
- Fats into fatty acids and glycerol
- Then glucose is broken down into acetyl CoA (glycolysis); renders littel ATP
- Transport to mitochondria to enter citric acid cycle
followed by oxidative phosphorylation -> lots of ATP
produced
Glycolysis
= the process of getting from glucose to Acetyl CoA
- if there’s low oxygen (e.g. last second of a sprint) pyruvate
is made into lactate because it cannot go into the CAC cycle
- If there’s enough oxygen, pyruvate enters CAC and oxidative phosphorylation -> resulting ATP enters
muscle ber
- The ATP gain from glycolysis itself is also entering the muscle ber
Hexokinase ‘traps’ glucose in the cell by adding a phosphate group
(normal glucose can passively transport in and out of the cell)
This costs 2 ATP
Result: two C3 chains (glyceraldehyde 3-phophate) which then enters
the anaerobic reaction (also happens in the cytoplasm)
The depicted steps happen two times, so in total: 2 NADH are gained
and 4 ATP are gained
Net generation of glycolysis
- 2 ATP
- 2 NADH
NAD+ needs to be regenerated, to keep the redox balance, otherwise glycolysis stops
- this can be done through 3 metabolic pathways using pyruvate
NAD+ is regenerated through through metabolism of pyruvate -> if you cannot make
fi fi
,lactate in you muscle, glycolysis stops and you have no energy generation
Easiest way is through the citric acid cycle. If there’s not enough O2, lactate metabolism works too. Also
yeast and microbes regenerate NAD+ by producing ethanol
Regulation of glycolysis during high ATP; thus in rest
-inhibition
If there’s a lot of ATP abundant in the cytoplasm, it acts as an inhibitor for
pyruvate kinase and phosphofructokinase. This then leads to lots of G6P build-
up in the cell, which again inhibits the enzyme hexokinase via negative
feedback. Then, less glucose is going to be trapped in the cell and it can be
released into the blood to be stored as fat for instance
Regulation of glycolysis during low ATP
Low pH -> phosphofructo kinase is sensitive for pH and will stimulate
During exercise for instance there can be low ATP in the cytoplasm because it
has been used up by the muscles. The resulting high abundance of AMP
stimulates phosphofructokinase. This leads to a buildup in F1,6BP which again
stimulates the enzyme pyruvate kinase, producing ATP.
However, if there’s not enough O2 abundant for glycolysis in the cell, the
buildup of lactate will result in a low pH which then downregulates glycolysis
again, preventing over-acidity
Glycolysis in muscle and liver are di erently regulated
Liver:
- Liver needs to sense blood glucose levels
- ATP levels are more stable
- Lactate is normally not produced, like in muscles
- Fructose 2,6-biphosphate activates PFK
- Increased cytosolic [citrate] inhibits PFK
- Glucokinase is not inhibited by glucose 6- phosphate
- High ATP and alanine levels inhibit pyruvate kinase L type; muscle is not sensitive to
such amino acids, but the liver is
- Glucagon-cAMP cascade decreases the activity of pyruvate kinase L type
Rapidly growing cells use glycolysis -> you can visualize tumors via PET scan due to their high glucose
intake
Hypoxia alters gene expression and increases ux through glycolysis (hypoxia = decrease in oxygen)
ff fl
, - Low oxygen in cell -> activation of HIF-1 transcription factor -> more transcription of glycolytic enzymes
and more blood-vessel growth
- There is also more lactate in the tumors
- high lactate production -> inhibition of local immune system
- Runners also use this concept to increase their muscle
strenght by enhancing their glycolytic e ciency as well as the
blood supply of the muscles = anaerobic exercise training ->
enhance muscle strength
Summary
Citric acid cycle
Results in the oxidation of an acetyl unit to two CO2 within the
mitochondria
The reaction from pyruvate to AcetylCoA is catalyzed by pyruvate
dehydrogenase, a very large complex in the cell, and irreversible
During the reaction, 1 carbon is lost and 2 electrons (making
NADH+H+) are gained
Regulation of pyruvate dehydrogenase complex
If there’s high energy charge, lots of NADH, AcetylCoA and ATP are
all inhibiting pyruvate dehydrogenase
If there’s low energy charge, lots of pyruvate and ADP are stimulating
PDH
Coupling the CAC with oxidative phosphorylation generates the most ATP
Oxidative phosphorylation
Electrons ow through the electron transport chain, powering proton pumping, which results in the
reduction of O2 into H2O
FADH2 yields less energy because it skips the rst proton pump and only enters the second complex
The electron transport chain then generates a proton gradient
which is used by ATP synthase to generate ATP
fl ffi fi
hexokinase starts with glycolysis
The breakdown of glucose in a red blood cell will render 4 ATP
Obesity is characterized by BMI>30
30% percentage of the dutch adults are overweight/obese
Health consequences of obesity
- high cholesterol -> cardiac arrest
- Cardiovascular disease
- Type 2 diabetes
- Strokes
- Jointwear
- Non-alcoholic fatty liver disease
- Arthritis
- Cancer
- Sleep apnoea
In a healthy person, blood glucose levels are maintained between 4-6mM
In a healthy (70kg) man, the amount of glucose in the blood is around 4 gram
The liver can not produce fatty acids
Causes for cardiovascular disease:
- atherosclerosis = sti ening of arteries
Atherosclerosis is
- inlfuenced by diet
- In uenced by hyperglycemia
- Common in young aduls
- Accelerated by high LDL cholesterol levels
A diet high in bers reduces the risk for cardiovascular disease
Lecture 1: energy metabolism
Catabolic = breakdown into energy, building blocks, and heat
Anabolic = build up into macromolecules
Metabolism = sum of catabolic and anabolic reactions in a cell
ATP = the universal currency of free energy
Sources of ATP during exercise
ATP -> ADP by motion, active transport, biosynthesis and signal
ampli cation
ADP -> ATP (regeneration) by oxidation of fuel molecules or
photosynthesis
Creatine phosphate is in muscles
fl fi fi ff
, Standard free energies of hydrolysis of compounds in biological systems
- e.g. breakdown of creatine phosphate can create …
Stages of catabolism
- breakdown of food:
- proteins into amino acids
- Breakdown of polysaccharide chains into glucose and other sugars
- Fats into fatty acids and glycerol
- Then glucose is broken down into acetyl CoA (glycolysis); renders littel ATP
- Transport to mitochondria to enter citric acid cycle
followed by oxidative phosphorylation -> lots of ATP
produced
Glycolysis
= the process of getting from glucose to Acetyl CoA
- if there’s low oxygen (e.g. last second of a sprint) pyruvate
is made into lactate because it cannot go into the CAC cycle
- If there’s enough oxygen, pyruvate enters CAC and oxidative phosphorylation -> resulting ATP enters
muscle ber
- The ATP gain from glycolysis itself is also entering the muscle ber
Hexokinase ‘traps’ glucose in the cell by adding a phosphate group
(normal glucose can passively transport in and out of the cell)
This costs 2 ATP
Result: two C3 chains (glyceraldehyde 3-phophate) which then enters
the anaerobic reaction (also happens in the cytoplasm)
The depicted steps happen two times, so in total: 2 NADH are gained
and 4 ATP are gained
Net generation of glycolysis
- 2 ATP
- 2 NADH
NAD+ needs to be regenerated, to keep the redox balance, otherwise glycolysis stops
- this can be done through 3 metabolic pathways using pyruvate
NAD+ is regenerated through through metabolism of pyruvate -> if you cannot make
fi fi
,lactate in you muscle, glycolysis stops and you have no energy generation
Easiest way is through the citric acid cycle. If there’s not enough O2, lactate metabolism works too. Also
yeast and microbes regenerate NAD+ by producing ethanol
Regulation of glycolysis during high ATP; thus in rest
-inhibition
If there’s a lot of ATP abundant in the cytoplasm, it acts as an inhibitor for
pyruvate kinase and phosphofructokinase. This then leads to lots of G6P build-
up in the cell, which again inhibits the enzyme hexokinase via negative
feedback. Then, less glucose is going to be trapped in the cell and it can be
released into the blood to be stored as fat for instance
Regulation of glycolysis during low ATP
Low pH -> phosphofructo kinase is sensitive for pH and will stimulate
During exercise for instance there can be low ATP in the cytoplasm because it
has been used up by the muscles. The resulting high abundance of AMP
stimulates phosphofructokinase. This leads to a buildup in F1,6BP which again
stimulates the enzyme pyruvate kinase, producing ATP.
However, if there’s not enough O2 abundant for glycolysis in the cell, the
buildup of lactate will result in a low pH which then downregulates glycolysis
again, preventing over-acidity
Glycolysis in muscle and liver are di erently regulated
Liver:
- Liver needs to sense blood glucose levels
- ATP levels are more stable
- Lactate is normally not produced, like in muscles
- Fructose 2,6-biphosphate activates PFK
- Increased cytosolic [citrate] inhibits PFK
- Glucokinase is not inhibited by glucose 6- phosphate
- High ATP and alanine levels inhibit pyruvate kinase L type; muscle is not sensitive to
such amino acids, but the liver is
- Glucagon-cAMP cascade decreases the activity of pyruvate kinase L type
Rapidly growing cells use glycolysis -> you can visualize tumors via PET scan due to their high glucose
intake
Hypoxia alters gene expression and increases ux through glycolysis (hypoxia = decrease in oxygen)
ff fl
, - Low oxygen in cell -> activation of HIF-1 transcription factor -> more transcription of glycolytic enzymes
and more blood-vessel growth
- There is also more lactate in the tumors
- high lactate production -> inhibition of local immune system
- Runners also use this concept to increase their muscle
strenght by enhancing their glycolytic e ciency as well as the
blood supply of the muscles = anaerobic exercise training ->
enhance muscle strength
Summary
Citric acid cycle
Results in the oxidation of an acetyl unit to two CO2 within the
mitochondria
The reaction from pyruvate to AcetylCoA is catalyzed by pyruvate
dehydrogenase, a very large complex in the cell, and irreversible
During the reaction, 1 carbon is lost and 2 electrons (making
NADH+H+) are gained
Regulation of pyruvate dehydrogenase complex
If there’s high energy charge, lots of NADH, AcetylCoA and ATP are
all inhibiting pyruvate dehydrogenase
If there’s low energy charge, lots of pyruvate and ADP are stimulating
PDH
Coupling the CAC with oxidative phosphorylation generates the most ATP
Oxidative phosphorylation
Electrons ow through the electron transport chain, powering proton pumping, which results in the
reduction of O2 into H2O
FADH2 yields less energy because it skips the rst proton pump and only enters the second complex
The electron transport chain then generates a proton gradient
which is used by ATP synthase to generate ATP
fl ffi fi
