College aantekeningen
Class notes Medical Biochemistry
- Instelling
- Vrije Universiteit Amsterdam (VU)
In the document notes of all the lessons can be found, which I used to obtain a 7.0 for the subject.
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Medical BiochemistryLectures week 1:
Overview human metabolism
Every human has a metabolic network of 500 essential cellular reactions, which are
regulated by hormones, metabolite level, and lifestyle.
Glycolysis is the central pathway in human metabolism. Metabolic processes are
linked -> intermediates of glucose catabolism are building blocks for many anabolic
pathways: other carbohydrates, lipids, amino acids, and DNA/RNA.
Metabolic roads lead to Acetyl-CoA.
Major fates of fuel in the fed state:
1. Glucose:
a. Oxidation -> energy
b. Storage -> glycogen or triglycerides
c. Synthesis -> many compounds
2. Amino acids:
a. Protein synthesis
b. Synthesis of nitrogen-containing compounds
c. Oxidation -> energy
3. Fats:
a. Storage -> triglycerides
b. Oxidation -> energy
c. Synthesis -> membrane lipids
Free energy carriers: ATP, GTP, NAD(P)H, FADH. There are 12 building blocks,
‘precursor metabolites’, which are used to synthesize almost every substance.
Burning food: oxidation by O2, energy caught as ATP, rest lost as het. Two carbons of
Acetyl-CoA released as CO2; hydrogens released as H2O.
In living organisms’ energy requiring processes are (∆G > 0, endothermic), driven by
energy processes (∆ < 0, exothermic), often ATP hydrolysis.
Regulation Oxidative Phosphorylation and ATPase:
1. ATP synthase uses energy from proton gradient to produce ATP.
2. When all ADP has been converted to ATP the enzyme stops.
3. No regeneration of NAD+.
TCA cycle catches energy in small steps (NADH), TCA is regulated by the amount of
NAD+, without NAD+ this reaction (and TCA cycle) cannot proceed.
When OXPHOS stops recycling NADH -> TCA will also stop.
When there is sufficient ATP -> excess Acetyl-CoA is converted to fat.
After meal -> store energy vs between meals -> release energy (protein degradation
and mobilization of fatty acids).
Excess glucose converted to fat; liver stores glycogen limited to 200 grams.
Negative nitrogen balance -> body protein breakdown.
The human body is fuelled by carbohydrates, proteins, and fat.
Metabolism is regulated through intermediate metabolites and hormones, the big
three are glucose, pyruvate, and Acetyl-CoA.
During starvation, to spare muscles, fatty acids are converted to ketone bodies, to
fuel the brain.
, Brain/neuronal cells have no beta-oxidation because they cannot absorb long chain
fatty acids (myelin). Brain relies on glucose, only backup is ketone bodies.
Intro & digestion
We cannot degrade every molecule in our food, like fibers. There is no enzyme
available in humans to digest, for example, the ß-1,4-bond of cellulose.
Uptake by facilitated transport, in epithelial cells through transporters with diffusion.
Intestinal epithelium -> active uptake, active transport for glucose.
Intestinal problems:
1. Lactose intolerance -> unable to breakdown the lactase bond.
2. Galactosemia: very serious disease, problems in liver.
3. Fructosemia: lack of enzymes, unable to breakdown fructose.
Polysaccharides need to be digested by glycosidases, amylase most important. The
resulting tri- and disaccharides are hydrolysed to monosaccharides that are taken up
by epithelial cells in the intestine.
Glycogen metabolism
Key organs for glycogen:
1. Muscle: glycogen is main (local) glucose source during exercise, storage for
internal use only.
2. Liver: key function is glucose storage for blood glucose homeostasis in between
meals or during fasting.
Glucose synthesis & degradation:
1. Glycogen synthase for synthesis
2. Glycogen phosphorylase for mobilization
Glucose is branched so it has many more sites on which to act.
Regulation of glycogen metabolism in liver and muscle:
1. Muscle: responsive to insulin (storage) and epinephrine (via PKA) and activity (via
Ca+)(exercise/stress)
2. Liver: responsive to insulin (storage) and glucagon/epinephrine (via PKA)
(fasting/exercise/stress)
Regulation of glycogen metabolism (in liver):
1. Glucagon + epinephrine activates ‘active protein kinase A’ (PKA) -> PKA is a
signalling molecule (and enzyme) that phosphorylates other enzymes or
molecules.
a. PKA phosphorylates glycogen synthase -> this becomes inactive. Insulin does
the opposite activates glycogen synthase
b. PKA phosphorylates glycogen phosphorylase -> becomes active. Insulin does
the opposite, deactivates glycogen phosphorylase.
Stress and muscle activity reinforce each other, regulation muscle phosphorylase at
2 levels:
1. Allosteric -> internal control by metabolites
2. Phosphorylation -> external control by hormones
Blood glucose regulation
Glucagon release: more glycogenolysis, more gluconeogenesis, more lipolysis, less
liver glycolysis.
, Insulin release -> more glycogen synthesis, more fatty acid synthesis, more
triglyceride synthesis, more liver glycolysis.
High glucose induces release of insulin, glucagon production is suppressed by insulin.
Glucagon production stimulated by amino acids and nerves (not by low glucose in
pancreas).
Insulin production by ß-cells depends on glucose, to find out whether someone has
diabetes, the glucose tolerance test is performed.
Muscle and adipose tissue (fat) can only take up glucose after a meal via insulin
sensitive GLUT4.
Liver and pancreas -> glucokinase (high Km, high Vmax), other cells -> hexokinase
(low Km, low Vmax).
Km: glucokinase > hexokinase, spares glucose for brain, muscle, and other tissues.
Vmax: glucokinase > hexokinase, at fasting glucose concentration hexokinase is at
Vmax (insensitive to change), glucokinase activity varies according to glucose
concentration.
Only hexokinase is inhibited by Glc-6P. Glucose-6P inhibits the binding of glucose to
hexokinase, this does not happen for glucokinase. Glucose-6P signals that peripheral
cell have enough glucose -> stop taking up more. Liver needs to mob up excess
glucose.
Gluconeogenesis
When there is a shortage of glucose, the body starts gluconeogenesis.
Alanine is stimulated when glucose levels are low and glucagon levels are high. In
liver minor acid degradation occurs, amino group is detoxified via urea cycle and
urea is released into the bloodstream and removed from the body by the kidneys.
This happens after a couple hours of fasting.
Only the liver can release glucose back into the bloodstream, uses special enzyme
G6Pase, this enzyme can remove the phosphate group from glucose-6-phosphate.
High carbohydrate meal -> glucose levels rise -> insulin released by pancreas ->
suppression glucagon production.
No glucose but a lot of proteins -> glucagon production stimulated.
Alanine is the favourite precursor to produce pyruvate, lactate (produced by red
blood cells) is also possible to produce pyruvate. From pyruvate you can make
glucose.
Triglyceride -> fatty acids + glycerol; glycerol -> gluconeogenesis pathway, free fatty
acids -> Acetyl-CoA, cannot be reconverted into pyruvate.
Pyruvate is a decision point for gluconeogenesis vs lipogenesis.
Pyruvate -> Acetyl-CoA -> TCA cycle -> Fatty acids
1. Helping enzyme is pyruvate dehydrogenase
2. This cascade happens when glucose levels are high and so insulin levels are high.
3. This is an irreversible reaction, there is no going back.
Pyruvate -> oxaloacetate -> PEP -> glucose
1. Helping enzyme is pyruvate carboxylase
2. This cascade happens when glucagon levels are high (glucose levels low)
External control by hormones:
1. Insulin activates PDC: glucose to acetyl-CoA
2. Glucagon inactivates PDC: glucose to gluconeogenesis.
, Insulin levels are high -> enzymes are dephosphorylated.
Glucagon levels are high -> enzymes get phosphorylated, don’t want fatty acids but
gluconeogenesis, shut down route pyruvate to fatty acid.
Glycolysis: fructose-6-phosphate -> phosphofructokinase -> fructose 1,6-
biphosphate.
Gluconeogenesis: fructose 1,6-biphosphate -> fructose 1,6-biphosphatase ->
fructose-6-phosphate.
Low blood glucose -> release of glucagon -> increased enzyme phosphorylation
(PKA) -> activation of PBPase-2 and inactivation of PFK-2 -> F-2,6-BP concentration
drop -> inactivation of PFK and activation of FBPase -> gluconeogenesis starts (&
glycolysis stops).
Proteins and AA balance; intro & digestion
There is no storage for AA in the body, surplus in dietary AA not needed for protein
synthesis, is immediately used for energy or fat production.
Essential AA in humans -> we cannot produce ourselves and are required to be
present in food: histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
threonine, tryptophane, and valine.
Non-essential AA can be made from glucose, pyruvate and from compounds from
TCA cycle.
When you eat protein, digestion starts in the stomach. This occurs by proteases
which cleave proteins:
1. Proteases are secreted by the pancreas.
2. Protein is cut into smaller AA that can be actively taken up by intestinal epithelial
cells. Then, the AA are transported into the blood.
3. The enzymes that cleave of the proteins are released as an inactive form; these
are called zymogens.
4. The enzymes are released as pro-enzymes. The enzymes need to be cleaved first
themselves before they are active. This enzyme regulation is crucial because
otherwise they will clean up the intestinal epithelial when no food is present.
During digestion, the enzymes get cleaved up themselves, this is because once all the
food is digested, the enzymes won’t start attacking the intestinal wall.
The active sites of the proteases are all very different and therefore can cleave
different AA bonds.
Once the AA are released, they are taken up by intestinal epithelial cells -> this is an
active process:
1. Requires the influx of sodium
2. The sodium is then actively transported out again
3. ATP is required
The AA are then transported to the liver via the portal vein
The gut epithelial cells use AA for their energy:
1. These cells are in close contact with food and have a large amount of protein
present at the border
2. Because the AA are taken up actively there is always high concentrations of AA
present in epithelial cells -> ideal source for the generation of ATP.
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