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Summary Medical Biochemistry
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- Vrije Universiteit Amsterdam (VU)
Medical Biochemistry
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MedBio 1 Monday, 6 September 2021Overview Human Metabolism
Glycolysis is the main pathway in the human metabolism. The three main compounds of
human metabolism are G6P, pyruvate, and Acetyl CoA.
In G6P, you decide whether you’re making glycogen, pyruvate, or a ribose phosphate.
Pyruvate can make alanine and lactate, but also oxaloactetate (which can reform G6P)
Many metabolic pathways can form Acetyl CoA. The most important are FA, ketone bodies,
ethanol metabolism, glucose and pyruvate (from Alanine)
In the fat state, major fuels come from carbohydrates, fats and proteins (AA). Every pathway
is regulated, except of fat storage. This also causes weight gain or loss. The fuels contain
free energy carriers during their fed state, occurring as ATP, ADP etc. int he fed state, as
much ATP is made as possible. However, there is only a limited amount of ATP precursor
(ADP + Pi), which results in that ATP is made based on your needs.
When burning your food, there is oxidation by O2, and energy is caught as ATP. All other
compounds are released from the body as heat. This also why underfeeding can eventually
cause hypothermia.
ATP has high energy phosphate bonds. When breaking these, the energy is released and
‘fed’ to the body. This bondage break is an exothermic reaction
Energy requiring -> endothermic reactions (before < after)
Energy releasing -> exothermic reactions (before > after)
When you regulate what enter the mitochondria, the reactions occurring can also be
controlled. This can for example be done via shuttles in the cells. In the inner mitochondrial
membrane, there are electron transport chains, which help with the generation of ATP. Here
is also the b-oxidation of the fatty acids.
There is also organ compartmentalisation. Many organs have their own metabolism
processes. The most important organ for the human metabolism is the liver.
ATP synthase uses energy from the proton gradient to produce ATP. When all ADP has been
converted to ATP, the enzyme stops. This causes a stop of NAD+ generation. When Acetyl
CoA enters the TCA cycle, NADH is released at multiple steps with the insert of NAD+.
Without oxidative phosphorylation (recycling NADH to NAD+) , NAD+ can not be inserted
into the TCA cycle, NADH can not be released, and energy can not be captured from the
TCA cycle, causing energy to be released as heat instead of fuel.
When there is enough ATP generated, the TCA cycle stops, causing accumulation of acetyl
CoA and citrate. This causes formation of fatty acids. Excess dietary fuels, will be stored as
fat, glycogen (and proteins, but no storage for AA). When fasting occurs, energy will be
generated from the fuels via oxidation, causing energy to be released again.
A negative nitrogen balance causes the body to breakdown protein to receive energy. This
also causes the darker colour of the urine after a night rest, as the protein ureum is broken
down and excreted by the kidneys. When there is a distinctive calorie deficiency for a
longer time, the body stops with protein breakdown to not break down essential proteins
(cardiac muscle).
This is where the ketone body pathway comes in, as backup pathway. This is mostly used
by the brain when a longer period of fasting is initiated in the body. This is done via fatty
acids being converted into the ketone bodies.
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Carbohydrate and Glucose Management
INTRODUCTION AND DIGESTION
During the fasting process, glucose stores are finished in one day. Then the use of ketone
bodies is started for the brain. Ketone bodies are used as brain and neuronal cells have no
beta oxidation, as they can not absorb long chain FA like myelin. So, when glucose levels
are low, everything goes to the brain while other structures use FA and protein breakdown.
There are different sugars since there are stereo-isomers. Sugar can change conformation
from cyclic to linear to cyclic again by equilibrium distribution. The conformation of the
sugar has consequences since enzymes are often very specific. For example, B-d-glucose
can be metabolised, whereas B-L-glucose cannot be metabolised. The only difference
between these two sugars is that they are mirrored.
Starch, plants, diary, and sugars are dietary sources of carbohydrates. Polymers like starch
need several enzymes to be degrades, as only monosaccharides can be taken up by the
human body. Also, the human body can only degrade alpha-1,4-bonds, which is done by
alpha-amylase. Beta-1,4-bonds cannot be degraded as there are no enzymes in the human
body to do so. These structures are also known as fibers.
Monosaccharides are taken up in the small intestine via facilitated transport. Facilitate
transport works with gradient, the molecules are transported from high to low
concentration. This is mainly done by GLUTs, which are glucose transporters. In the
intestine, there is also active uptake. Active uptake needs a free energy source that drives
the reaction. Active uptake is used when the concentration of the monosaccharides is low
and therefore competes with bacteria.
Diseases concerning digestion
Lactose intolerance is an intestinal problem where the human body lacks the lactase
enzyme. This causes the inability to degrade lactose. This is beneficial for bacteria in the
gut, as these like lactose.
Galactosemia is a disease where there is lack of multiple enzymes (galactokinase and/or
galactose 1-phosphate uridylyltransferase). It gives problems in the liver, instead of the
intestines. It will lead to a toxic reaction, where there is phosphate buildup in the human
body creating damage to the liver and other organs. It can be noticed to toxic buildup in the
eyes and ovaries.
Fructosemia is a fruit intolerance which is the consequence of the lack of multiple enzymes
like aldolase B. Due to this, these patients have troubles forming ATP, leading to a lower
energy level and chronic fatigue.
GLYCOGEN
Glycogen is the storage compound of glucose. It is a branched polymer made of glucose
residues. Glycogen is branched due to the fact that if there are more sites to chop of
glucose, it will go faster when in need of glucose. Glycogen can be inverted into glucose by
the enzyme glycogen phosphorylase for mobilisation. Glucose can be inverted into
glycogen by energy and the enzyme glycogen synthase for synthesis.
Glycogen branching
Glycogen phosphorylase can break the outer branches, transferase will break the middle
part of the branches, and glycosidase the last part of the branch. The synthesis of the
branches will use two enzymes: glycogen synthesis to build to branches, and the branching
enzyme to chops of the branches and puts them somewhere else on the chain.
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Liver and Muscle storage
Glycogen storage is located in the liver and muscle. The liver is responsible for blood
glucose homeostasis in between meals and or during fasting. The muscle uses the
glycogen as glucose source during exercise. The liver can give back glucose, whereas the
muscle cannot.
The liver regulates the blood glucose level, so its responds to
homeostasis hormones. It is responsive to insulin for storage and
glucagon/epinephrine via PKA for fasting/exercise/stress state.
The muscle is also responsive to insulin for storage and only
epinephrine via PKA. It also responses to activity via calcium
during exercise and stress state.
Glycogen metabolism regulation
Glucagon activates cAMP, activating active protein kinase A
(PKA), which is phosphorylated with the use of ATP molecules.
this will make sure the glucose enters the bloodstream.
Insulin works the other way around. It activates glycogen
synthase which converts glucose into glycogen.
The muscle has the important function to invert glycogen to glucose during exercise.
Epinephrine activates cAMP, which will activate the PKA. This all occurs when a nerve
impuls is noticed by the muscle.
Muscle phosphorylase can be regulated at two levels. Allosteric regulation occurs via intern
control of the metabolites. Phosphorylation is the external control, which is regulated by
hormones
GLUCOSE REGULATION
The human body has different systemic metabolisms for each organ and state. When we
are fed, we take the glucose from our dietary carbohydrate and the extra’s will be taken up
as fat. Between the mails, the body is in fasting state, and glycogen is used as main source
of energy. When there is not enough glycogen, there are other sources to get glucose via
gluconeogenesis via glycerol, amino acids, and lactate.
Blood glucose homeostasis is mainly regulated via
the hormone’s insulin and glucagon. Insulin is the
signal of a fed/high blood glucose state. Insulin
release increases glycogen synthesis, fatty acid
synthesis, triglyceride synthesis, and liver
glycolysis. Glucagon is the signal of a fasting/low
blood glucose state. Glucagon release increase
glycogenolysis, gluconeogenesis, and lipolysis,
and decreases liver glycolysis. High glucose
induces release of insulin, which suppresses glucagon production. Glucagon production is
stimulated by amino acids and nerves, not by low glucose in the pancreas. The production
of insulin depends on beta-cells which is dependent on glucose. Vessels inside the beta
cells are released into the bloodstream via exocytosis.
In diabetes, normal glucose levels are higher. This causes loss of glucose via the urine,
resulting in sweet-‘tasting’ urine. Also an ethanol-like breath and high thirst levels are
symptoms of diabetes
Glucose uptake is regulated by facilitated diffusion, which
follows the enzyme kinetics. A high Km means a high Vi = Vm a x[s] : k m + [s]
Vmax and a low affinity. Km is concentration at which the
enzyme is half saturated and thus works at 0.5 Vmax.
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Hexokinase activity (always active) is always maximal
around 5 mM which means that it is insensitive to
change. Glucokinase is maximally sensitive around blood
glucose levelswhich can be found in the liver and the
pancreas. Only hexokinase is inhibited by its product
glucose-6-phosphate. Glucose-6-phosphate signals that
peripheral cells have enough glucose so they stop taking
up more. This does not happen for glucokinase since the
liver needs to mob up excess glucose.
GLUT transporter
There are different types of GLUT transporters
GLUT1: high-affinity glucose transport system (BBB,
Erythrocytes)
GLUT2: low-affinity transporter (liver, kidney, beta-cells)
GLUT3: high-affinity (brain, neurones)
GLUT4: insulin sensitive transporter (adipose, muscle
skeletal & cardiac)
Diabetics do not have the GLUT4 transporters on their
muscles and adipose tissue, which causes the inability to
take up glucose. This causes the glucose levels to
become sky-high, as it cannot be degraded to energy.
Liver and pancreas: glucokinase (high Km, high Vmax)
Other cells: Hexokinase (low Km, low Vmax)
Hexokinase lies at Vmax and is insensitive to change.
Glucokinase activity varies according to the glucose
concentration.
Glucose 6p inhibits the binding of glucose to hexokinase, not for glucokinase. Glucose6p
signals that peripheral cells have enough glucose, causing a stop on take-up. However, the
liver will ‘cleanup’ the excess glucose
GLUCONEOGENESIS
When there is a shortage of glucose, gluconeogenesis is used to make glucose from
different sources, like lactate, alanine, and amino acids. This process is already starting up
after a nights sleep. This process only occurs in the
liver where the glucose-6-phosphate will be
converted into glucose by the enzyme G6Pase.
Glucagon is the main activator of gluconeogenesis.
Gluconeogenesis is the reverse of glycolysis which is
why they look similar except of three steps which are
thermodynamically irreversible. Those
thermodynamically irreversible steps require ATP and
enzymes which are only present in the liver.
Pyruvate is an important source for glucose after
converting the original sources. The first step to convert pyruvate into oxaloacetate (+ COO
- ). Then the COO - will get of to make PEP. Pyruvate can also be converted into Acetyl CoA
by removing the CO2 for the TCA cycle.
This process is controlled by hormones: insulin activated PDH (glucose to Acetyl CoA) and
glucagon inactivated PDH (glucose to gluconeogenesis). Acetyl CoA can be converted into
multiple CO 2 , but then there is no way back to glucose. From fructose-6-phosphate to
fructose-1,6-biphosphate is also managed by hormones since you can’t go back to glucose
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