HC 1: Intro & Overview of human metabolism
Carbohydrates à most important fuel for the body à glucose
Proteins à amino acids (long chains are called peptides or proteins)
Fat/triglycerides à composed of glycerol molecule and 3 fatty acids coupled to it
- Palmitate
- Oleate
- Stearate
Glycolysis is the central pathway in human metabolism à carbohydrates, lipids, amino acids,
DNA/RNA
Big three
- Glucose 6 phosphate: Ribose 5 phosphate (DNA), Pyruvate, Glycogen
- Pyruvate: Lactate, Alanine (amino acid), Acetyl coA, oxaloacetate (à glucose 6
phosphate à pyruvate)
- Acetyl CoA: Fatty Acids, 3 hydroxy 3 methyl glutaryl coa (cholesterol or ketone bodies)
Major fates of fuels in the fed state
- Glucose à Energy (Oxidation), glycogen/TG (storage), many compounds (synthesis)
- Amino acids à protein synthesis, energy (oxidation), synthesis of nitrogen-containing
compounds
- Fats à TG (storage), membrane lipids (synthesis), energy (oxidation)
Free energy carriers: ATP, GTP, NADPH, FADH
- ATP: major energy carrier à (hydrolysis) ADP + Pi (continuous cycle)
- TCA cycle and ATP generation à in mitochondria
o 2 carbons of Acetyl Coa released as CO2
o Hydrogens releases as H2O
- Other pathways in cytoplasm (glycolysis)
- Liver: central factory
- Many tissues have their own tissue metabolism
Regulation OXPHOS and ATPase
- ATP synthase uses energy from proton gradient to produce ATP
- When all ADP has been converted to ATP the enzyme stops
- No regeneration of NAD+
- Regulation TCA: without NAD+ this reaction and the TCA cycle cannot proceed
When OXPHOS stops recycling NADH: TCA will also stop
à NADH is a negative factor for OXPHOS
à ADP is a stimulator
When there is sufficient ATP: excess Acetyl CoA is converted to fat
Excess dietary fuel à (fed) Fuel stores: fat, glycogen, protein à (fasting) oxidation à energy
Excess glucose converted to fat: glucose à pyruvate à acetylcoa à citrate à acetylcoa à
malonyl coa à FA à palmitate
Fatty acids cannot pass the myelin sheets in the brain à brain cannot use FAs
, - Fatty acids à Acetyl CoA à Ketone bodies (brain can use this as fuel), but this will only
happen after a couple of days of starvation
Nitrogen excretion during fasting
- Urea excretion will increase when fasting à proteins are used as fuel
- After more days à ketone bodies are made and then the urea excretion will drop
again
o B-hydroxybutyrate
o Acetoacetate
,HC 2: Carbohydrate and glucose metabolism
Brain requires glucose! à first priority, most of the glucose goes to the brain (75%)
Storage as glycogen à 190 gram (liver)
During fasting all glucose stores are finished within 1 day
Brain neuronal cells have no beta cells
Stereo-isomers à different enzymes also needed for these different isomers (3D difference)
- D-glucose
o Beta-D-glucose
o Beta-L-glucose à cannot be metabolized
- D-mannose
- D-galactose
Dietary sources of carbohydrates
- Starch, plants à amylose and amylopectin
- Dairy (milk products) à lactose (galactose + glucose)
- Every processed food in Western society à sucrose (glucose + fructose)
Amylase is beginning in the mouth à as soon as possible to get as much glucose directly to
the brain
Fibers à a kind of carbohydrate that we cannot digest
- Intestines can use it to promote normal digestion
Uptake by facilitated transport
- Passive diffusion (through concentration gradient) à simple diffusion or facilitative
diffusion
- Active transport (against the concentration gradient) à energy is needed
Lactose intolerance: intestinal problems
- Lack enzyme (lactase) to break the bond between galactose and glucose
- Cannot digest the lactose sugar
- Bacteria can digest à so sugar that is not digested, will be used by bacteria à diarrhea
- Western world less people are lactose intolerant
Galactosemia: very serious disease (no relation to lactose intolerance)
- No intestinal problems, but liver
- Galactose à galactose 1-phospase (non classical) or galactose-1-phosphate à glucose
1-phosphate cannot occur
- Traps all the phosphate in the body (galactose 1-phosphate, galactose an galactitol
increase)
- Management: elimination of galactose (milk and dairy products)
Fructosemia
- Lack enzyme fructokinase (not severe) or dihydroxyacetone-P (severe)
- Remedy à do not eat any fruits
, Glycogen: storage unit of glucose
- You can degrade it very fast, that’s why it is all bonded to each other (also takes up
less space)
- Liver: key function in glucose storage for blood glucose homeostasis in between
meals or during fasting
- Muscle: glycogen is main glucose source during exercise
- Glucose-6-phosphatase à leads to the making of glucose back to the blood
- Synthesis: glucose à glucose-6-P à glucose-1-P à glycogen
(à glycogen synthase, ß glycogen phosphorylase)
o Glucose-6-P can go to glycolysis, PPP and other pathways
- Glycogensynthese: will add branches on glycogen
- Glycogen phosphorylase: chops off at any free ends the different glucose molecules
until reached 4 …
- It is branched because it can increase the speed of synthesis, many more sites to
react
- Regulation
o Muscle: insulin (storage), epinephrine (via PKA) and activity (via CA2+)
(exercise), not responsive to glucagon!
o Liver: insulin (storage), glucagon (fasting), epinephrine (via PKA,
exercise/stress)
Carbohydrates à most important fuel for the body à glucose
Proteins à amino acids (long chains are called peptides or proteins)
Fat/triglycerides à composed of glycerol molecule and 3 fatty acids coupled to it
- Palmitate
- Oleate
- Stearate
Glycolysis is the central pathway in human metabolism à carbohydrates, lipids, amino acids,
DNA/RNA
Big three
- Glucose 6 phosphate: Ribose 5 phosphate (DNA), Pyruvate, Glycogen
- Pyruvate: Lactate, Alanine (amino acid), Acetyl coA, oxaloacetate (à glucose 6
phosphate à pyruvate)
- Acetyl CoA: Fatty Acids, 3 hydroxy 3 methyl glutaryl coa (cholesterol or ketone bodies)
Major fates of fuels in the fed state
- Glucose à Energy (Oxidation), glycogen/TG (storage), many compounds (synthesis)
- Amino acids à protein synthesis, energy (oxidation), synthesis of nitrogen-containing
compounds
- Fats à TG (storage), membrane lipids (synthesis), energy (oxidation)
Free energy carriers: ATP, GTP, NADPH, FADH
- ATP: major energy carrier à (hydrolysis) ADP + Pi (continuous cycle)
- TCA cycle and ATP generation à in mitochondria
o 2 carbons of Acetyl Coa released as CO2
o Hydrogens releases as H2O
- Other pathways in cytoplasm (glycolysis)
- Liver: central factory
- Many tissues have their own tissue metabolism
Regulation OXPHOS and ATPase
- ATP synthase uses energy from proton gradient to produce ATP
- When all ADP has been converted to ATP the enzyme stops
- No regeneration of NAD+
- Regulation TCA: without NAD+ this reaction and the TCA cycle cannot proceed
When OXPHOS stops recycling NADH: TCA will also stop
à NADH is a negative factor for OXPHOS
à ADP is a stimulator
When there is sufficient ATP: excess Acetyl CoA is converted to fat
Excess dietary fuel à (fed) Fuel stores: fat, glycogen, protein à (fasting) oxidation à energy
Excess glucose converted to fat: glucose à pyruvate à acetylcoa à citrate à acetylcoa à
malonyl coa à FA à palmitate
Fatty acids cannot pass the myelin sheets in the brain à brain cannot use FAs
, - Fatty acids à Acetyl CoA à Ketone bodies (brain can use this as fuel), but this will only
happen after a couple of days of starvation
Nitrogen excretion during fasting
- Urea excretion will increase when fasting à proteins are used as fuel
- After more days à ketone bodies are made and then the urea excretion will drop
again
o B-hydroxybutyrate
o Acetoacetate
,HC 2: Carbohydrate and glucose metabolism
Brain requires glucose! à first priority, most of the glucose goes to the brain (75%)
Storage as glycogen à 190 gram (liver)
During fasting all glucose stores are finished within 1 day
Brain neuronal cells have no beta cells
Stereo-isomers à different enzymes also needed for these different isomers (3D difference)
- D-glucose
o Beta-D-glucose
o Beta-L-glucose à cannot be metabolized
- D-mannose
- D-galactose
Dietary sources of carbohydrates
- Starch, plants à amylose and amylopectin
- Dairy (milk products) à lactose (galactose + glucose)
- Every processed food in Western society à sucrose (glucose + fructose)
Amylase is beginning in the mouth à as soon as possible to get as much glucose directly to
the brain
Fibers à a kind of carbohydrate that we cannot digest
- Intestines can use it to promote normal digestion
Uptake by facilitated transport
- Passive diffusion (through concentration gradient) à simple diffusion or facilitative
diffusion
- Active transport (against the concentration gradient) à energy is needed
Lactose intolerance: intestinal problems
- Lack enzyme (lactase) to break the bond between galactose and glucose
- Cannot digest the lactose sugar
- Bacteria can digest à so sugar that is not digested, will be used by bacteria à diarrhea
- Western world less people are lactose intolerant
Galactosemia: very serious disease (no relation to lactose intolerance)
- No intestinal problems, but liver
- Galactose à galactose 1-phospase (non classical) or galactose-1-phosphate à glucose
1-phosphate cannot occur
- Traps all the phosphate in the body (galactose 1-phosphate, galactose an galactitol
increase)
- Management: elimination of galactose (milk and dairy products)
Fructosemia
- Lack enzyme fructokinase (not severe) or dihydroxyacetone-P (severe)
- Remedy à do not eat any fruits
, Glycogen: storage unit of glucose
- You can degrade it very fast, that’s why it is all bonded to each other (also takes up
less space)
- Liver: key function in glucose storage for blood glucose homeostasis in between
meals or during fasting
- Muscle: glycogen is main glucose source during exercise
- Glucose-6-phosphatase à leads to the making of glucose back to the blood
- Synthesis: glucose à glucose-6-P à glucose-1-P à glycogen
(à glycogen synthase, ß glycogen phosphorylase)
o Glucose-6-P can go to glycolysis, PPP and other pathways
- Glycogensynthese: will add branches on glycogen
- Glycogen phosphorylase: chops off at any free ends the different glucose molecules
until reached 4 …
- It is branched because it can increase the speed of synthesis, many more sites to
react
- Regulation
o Muscle: insulin (storage), epinephrine (via PKA) and activity (via CA2+)
(exercise), not responsive to glucagon!
o Liver: insulin (storage), glucagon (fasting), epinephrine (via PKA,
exercise/stress)
