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Samenvatting Medical Biochemistry
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Carbohydrate and glucose managementThe metabolic network consists of
500 essential cellular reactions. Each
dot is a metabolite and each line is
an enzyme-catalysed reaction. These
are regulated by hormones,
metabolite level and lifestyle.
Humans have a high glucose
consumption. This is because the
brain (under normal conditions) fully
relies on glucose (120-150 g/day),
because fatty acids can’t penetrate
the myelin sheet. Some of the
leftover glucose is stored in the liver
as glycogen. However, during fasting,
all glucose stores are finished within
1 day. Brain and neuronal cells can’t
use fatty acids, because they can’t
absorb these long chain fatty acids.
So, they don’t have beta-oxidation.
There is one back-up mechanism,
which are the ketone bodies.
Glucose comes in many different
types, which are called stereo-
isomers. On top of this, sugars can
change conformation from cyclic to linear and vice versa. A different 3D-structure means a different
enzyme is needed to cleave these carbohydrates. The dietary sources of carbohydrates are starch,
plants, dairy and every processed food in Western society. Polymers like starch need several
enzymes to be degraded: alpha 1,4 bonds by α-amylase.
Digestion
Because carbohydrates are so important for the human metabolism, degradation already starts in
the mouth. It starts with the cleavage of starch by salivary α-amylase. As the carbohydrates transfer
through the intestinal tract, in the stomach and pancreas different enzymes are released, which will
all cleave the sugars to smaller fragments. Finally, in the small intestines, there are carbohydrate
cleavage molecules in the epithelial cells. These cleave the different sugars into the final
monosaccharides. For some of the polymers, there are no enzymes. These polymers are called
fibres. However, some of these fibres can be used by intestinal bacteria or be degraded by them.
The individual monosaccharides are taken up by
the epithelial cells. On these epithelial cells, there
are different transporters. These are called
facilitated transports, which are caused by
diffusion from a high concentration to a low
concentration. Sometimes, in the lumen, the
glucose-levels can be very low or in the epithelial
cells, the glucose-levels can be very high. Now,
transport against the gradient is needed. This
means that there is also active uptake
transporters for glucose, which costs ATP.
,When someone is lactose intolerant, it means that this person is lacking the enzyme lactase. This
means that the lactose can’t be degraded and will stay in the intestine. However, now the bacteria in
the intestine will degrade the lactose. This will lead to the formation of lactic acid and gas. The lactic
acid will have an osmotic effect and attract water from the tissue, which will lead to a lot of water in
the intestine. Hence, this person will get watery diarrhoea.
There can also be a problem with the further metabolism of galactose or fructose. These are very
serious diseases and (usually) diseases of the liver, because this is where these monosaccharides are
being degraded. When there is a problem with the degradation of galactose (galactosemia), the
intermediate products (galactose and galactose monophosphate) will start to build up, which will
give lots of toxic effects. When there is a mutation in galactokinase/fructokinase, the body can get
rid of the galactose/fructose via the urinal tract.
Galactosemia Fructosemia
Glycogen metabolism
Glycogen is a form of glucose storage. It is a very large molecule that is
composed of a lot of glucose-molecules with different types of linkages.
The two main organs that store glycogen in the body are the liver and
the muscle. The liver is the central factory and its key role is glucose
storage for blood glucose homeostasis in between meals or during
fasting. The muscle stores glycogen, but only for its internal use during
exercise.
For the synthesis and degradation of glycogen, two key enzymes are
necessary. Glycogen synthase for the synthesis and glycogen
phosphorylase for the mobilization. The glycogen synthesis starts from
glucose, which is taken up by the blood. This is first converted into
glucose-6-phosphate. This, in turn, is converted into glucose-1-
phosphate. This is used to make glycogen but needs to be activated first.
Putting in UTP (energy source), generates UDP-glucose. The enzyme
glycogen synthase links these different UDP-glucose molecules together
to generate glycogen. Transferase (branching enzyme) is also used in
this step to make the branches of the glycogen molecule.
For the degradation of glycogen, a debrancher enzyme is used to get rid of the branches. It is
actually the glycogen phosphorylase, which cleaves of the individual molecules and connects them
to phosphate. Generating, again, glucose-1-phosphate.
For the making of the branches, glycogen synthase generates a chain of 10 glucose molecules. It is
cleaved in half by transferase and put on a different spot, to generate multiple branches. For the
degradation, it is reversed. Glycogen phosphorylase can cleave of glycogen molecules, until there are
,about 4 left. Now, transferase is needed. It takes the top 3 and attaches them to the glycogen core.
The single glucose molecule that is left, is release by glucosidase.
Making branches Breaking branches
Glycogen is branched for speed. Now, the glycogen phosphorylase can act on multiple residues. This
results in much faster cleavage of the glycogen molecules.
Both muscle and liver are responsive to insulin for storage, however the release of glycogen is very
differently regulated. In the liver, glucose must be released when the body needs it. So, the liver
responds to glucagon, which is one of the hormones that regulates blood glucose levels, but it also
responds to adrenaline/epinephrine. The muscle isn’t involved in the regulation of blood glucose
levels, so the muscle doesn’t respond to glucagon. It actually responds to activity of the muscle (via
Ca2+) and adrenaline/epinephrine.
What happens, is that glucagon and epinephrine bind to the receptor. This activates protein kinase
A (PKA). It is a signalling molecule (and an enzyme), which phosphorylates other enzymes or
molecules. PKA phosphorylates glycogen synthase, which then becomes inactive. This makes sense,
because when there is glucagon, glycogen needs to be broken down and not synthesised. So, the
glycogen phosphorylase should be active to break down the glycogen. This is done by the PKA
phosphorylating phosphorylase kinase, which will in turn phosphorylase glycogen phosphorylase to
get it activated. Insulin basically does the opposite. It dephosphorylates these proteins, resulting in
an inactive glycogen phosphorylase and an active glycogen synthase.
In the muscle, there is an additional regulation. The first one is via nerve impulses (indicates
activity), via which calcium phosphorylates phosphorylase kinase, which will activate glycogen
phosphorylase. There is a second pathway, which goes via AMP. This AMP is an internal regulation
via metabolites. So, during muscle contraction, ATP is being used and this generates AMP. This AMP
is an indicator that there is muscle activity and that there is extra energy needed to keep the muscle
contraction going. The AMP can bind to the glycogen phosphorylase in the muscle and there will be
a conformational change. This results in an active muscle glycogen phosphorylase.
Regulation of blood glucose levels
Important to realise is that different organs have a different metabolism. Blood glucose homeostasis
is typical for the liver and aided by the pancreas for the release of the hormones. Two major
hormones in this regulation are glucagon and insulin. Insulin is present when there is a lot of glucose
in the bloodstream. This stimulates the synthesis of glycogen and it promotes glycolysis. Glucagon
, releases nutrients to generate ATP, so it will release glucose from glycogen (gluconeogenesis) and it
slows down glycolysis.
After eating, there is a high blood glucose level, which is sensed by the pancreas. The pancreas
releases insulin and this stimulates the liver to store glycogen. It also stimulates glucose uptake by
other cells, especially the muscle and adipose tissue. However, in between meals, the blood glucose
levels will drop. Then, the pancreas will release glucagon, which releases glucose from the glycogen
stores in the liver.
High glucose levels induce the release of insulin. The glucagon production is suppressed by insulin.
So, the glucagon production isn’t stimulated by a low glucose level. It is actually stimulated when
eating a lot of amino acids (carbohydrates) and by some nerve impulses (fight or flight). Insulin
production is done by the β-cells in the pancreas and depends on the
blood glucose level. Glucose is taken up by the β-cell and is processed in
these cells, which releases ATP. So, the ATP levels rise in these β-cells
and through a series of cascades, intracellular stores of insulin are
released to the bloodstream. The uptake of glucose by the β-cells goes
via facilitated diffusion. This diffusion follows the Michaelis-Menten
curve and is thus dependent on the concentration of glucose. When
there is more glucose outside, the transportation of glucose inside will
rise. However, there is a maximum rate at which the transporters can diffuse glucose into the cell. In
this way, it closely resembles enzyme kinetics. The concentration at which halve of the transporters
are active is the Km. For the Km counts that the higher the value, the lower the affinity for the
glucose. There are multiple types of glucose transporters (GLUTs):
1. GLUT 1 → is very broadly expressed and it is a high-affinity glucose, which is
especially important in the brain. So, even at low glucose levels, these transporters
can still transport glucose into the cell.
2. GLUT 2 → mostly expressed in the liver and pancreas. Is a low-affinity glucose
transporter, so it needs a much higher glucose level to become active.
3. GLUT 3 → almost solely expressed in the brain, because it is a high-affinity glucose.
4. GLUT 4 → an insulin-sensitive transporter in skeletal, muscle and adipose tissue.
This is only present on the surface when there is insulin in the system (high
glucose). They only can take up glucose after a meal, when there is high glucose in
the blood.
Next to the transporters, the first step of the glycolysis pathway is
regulated. There are two different iso-enzymes in the human body.
The liver and the pancreas have the glucokinase and the other cells
have the hexokinase. The hexokinase is already at its maximum speed
for very low glucose levels, so it is very independent from the glucose
concentration. Glucokinase becomes more active, when glucose
concentration increase. This is important because the glucokinase
should not start to metabolise all this glucose that might be needed
for the brain, muscle and other tissues. However, the maximum speed for the glucokinase is much
higher and becomes more active when there is more glucose. Hexokinase and glucokinase both
facilitate the reaction from glucose to glucose-6-phosphate. This glucose-6P inhibits hexokinase. So,
when regular cells have taken up enough glucose (and generated enough ATP), accumulation of
glucose-6P signals to the system to stop processing glucose. So, the intracellular glucose levels will
rise and be as high as the glucose levels outside the cell and there will be no more diffusion from a
high to low concentration, so the cell will stop the glucose uptake. The liver needs to mob up the
excess glucose.
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