CELLULAR BASIS OF MEDICINE – COURSE 2

Course 2

Biochemistry

Definitions:

Matter – anything that occupies space and has a mass

In the body O, H, C, N, are making up 96% of the whole-body mass

Trace elements Trace elements are the elements in our body that make up 0,4% of the body
mass; all of them are crucial for the proper body functions.

Compound – a substance that contains atoms of two or more elements

Free radical – an atom or group of atoms with the unpaired electrons which makes it
unstable and highly reactive

Cation – positively charged ion

Anion – negatively charged ion

Electrolyte – ionic compound that breaks down into positive and negative ions in the
solutions

Electronegativity – the power of an atom to attract electrons to it

Exergonic reactions – reactions that release more energy than they absorb

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Endergonic reactions – reactions that release less energy than they absorb

Synthesis – combining something

Anabolism – to build up molecules (synthesis)
Catabolism – to break up molecules (decomposition)

Oxidation – loss of electrons

Reduction – gain of electrons

Inorganic compounds: usually lack carbon, structurally simple, hold together by ionic or
covalent bonds

Organic compounds: always contain carbon, usually hydrogen, always has covalent bonds

A colloid is a solution, but it differs in the size of the particles. In the colloid, the particles are
large enough to scatter light just like water droplets.

An acid is a compound which donates protons

A base is a compound which accepts protons

Salts are very important for carrying of the electric current. To create a salt, acid, and base
have to react between each other.

Normal pH in the body is around 7.35-7.45

- lower than 7.35 is considered acidosis
- higher than 7.45 is considered alkalosis

In the body, we have buffer systems which convert strong acids and bases into the weak
ones – all for the protection of the organism

Molecules which have the same molecular formula, but different structures are called
isomers.

Enzymes
Enzymes are catalysts of the biochemical reactions; catalyst – lowers the amount of energy
needed to start a chemical reaction without being consumed in the reaction itself (they
decrease activation energy, but do not change the equilibrium constant of the reaction)

Isoenzymes are the enzymes which catalyze the same reactions but differs in their
physiochemical properties. For example, glucose in our body can be converted into glucose-
6-P by:
- glucokinase in liver and pancreas
- hexokinase in the rest of the body

Cofactors are the helper molecules that are required for proper function of the enzyme
Apoenzyme + cofactor = holoenzyme

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Examples of cofactors:
- metals – required within 2/3 of all enzymes
o Zn, Mg, Cu, Fe
- Coenzymes – bound loosely to the enzyme
o NAD+, ubiquinone, ATP, CoA
- Prosthetic group – bound tightly to the enzyme
o Heme, FAD, lipoamide

Allosteric enzymes are the enzymes which consist of several subunits.

An effector – small molecule which either increases or decreases the activity of the allosteric
enzyme by binding to its regulatory site.

Classification of the enzymes

- Oxidoreductases – catalyze redox reactions. They need vitamin C as the cofactor,
also NAD, FAD, heme and NADP (dehydrogenases, oxidases, reductases, oxygenases,
peroxidases, catalazes, hydrolases, desaturases)
- Transferases – transfer functional units. (aminotransferases, kinases)
- Hydrolases – protein degradation enzymes. They do not need coenzymes (esterases,
glycosidases, peptidases, amidases, proteases, lipases, pepsin, phosphatase)
- Lyases – synthases, they remove and ass small molecules to and from the substrates
and form double bonds. (decarboxylases, hydrotases, lyases)
- Isomerases – epimerases, mutases
- Ligases – synthetases – catalyze reactions where two molecules are joined together
– bond formation. For the reaction they use ATP. (polymerases, carboxylases, ligases)

Thermodynamics
1. Energy cannot be created or destroyed (law of conservation of energy)
2. Any spontaneous reactions increase the disorder of the universe

Entropy (s) is a measure of molecular randomness, aka disorder

Enthalpy (H) is the sum of internal energy, volume, and the pressure

Gibbs energy (delta G)

Delta G = H (enthalpy) – T (temperature) * S (entropy)

U – internal energy

Enzyme kinetics
It is the measure of the rates of chemical reactions, and it deals with the factors which can
affect the rates.
Michaelis Menten Model tells us how the velocity of reaction of enzymes relates to the
concentration of the substance.
Vmax – describes the velocity of the reaction – reached at the infinite concentration of the
substrate

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Michaelis constant (Km) – describes the affinity of the enzyme to the substrate
- High Km – low affinity
- Low Km – high affinity

Gibbs free energy tells us whether or not the chemical reaction will proceed

Km – the concentration of the substrate at which the rate of the reaction is equal to vmax/2

Inhibition of enzymes
There are two basic types of inhibitors – reversible and irreversible.

Competitive inhibitors:
Are inhibitors which compete with the substrate for binding to the enzyme
Competitive inhibitors usually bind to the active site of the enzyme. After the work of those
enzymes
- Km is increased (the affinity of the enzyme to the substrate becomes lower)
- Vmax remains unchanged

Non-competitive inhibitors
Are inhibitors which do not compete with the substrate and bind the enzyme at the site,
other than the active site which changes the enzyme conformation. à even if we have
infinite amount of the substrate, the enzyme will still not be working as it should.
- Vmax decreases
- Km remains unchanged

Uncompetitive inhibitors
Are the enzymes that bind to the [enzyme-substrate] complex. à even if we keep on adding
substrate, the [ES] complex will be inhibited by binding of the inhibitor to it.
- Vmax decreases
- Km decreases

Acetylcholine esterase – enzyme which removes acetylcholine from the synaptic cleft.
Inhibitors of this enzyme keep acetylcholine in the cleft, thus making the signal last longer.
- Inhibitors
o Alzheimer medications – competitive inhibitors (Tacrine)
o Sarin – irreversible inhibitor used for killing people through the muscle
paralysis), now found in organophosphates.
- Myasthenia gravis (disease) – immune system disorder which destroys acetylcholine
receptors in the synapse; therefore, muscles do not work properly. It is treated with
the acetyl esterase inhibitors.
o Edrophonium is used for the diagnosis – inhibits the enzyme for a short
period which shows the improvement.

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Carbohydrate metabolism
After digestion, polysaccharides are hydrolyzed into monosaccharides, such as glucose
(80%), fructose and galactose. Fructose is converted into glucose and galactose is converted
to glucose (by hepatocytes)

Glycolysis
Happens in the cytosol of the cells.
Glucose is converted into two pyruvates. This reaction produces 2 ATP molecules (in case of
anaerobic metabolism, also 2 NADH+)

Regulation of glycolysis: (-) à inhibition, (+)à activation

- Hexokinase
o (-) high amounts of glucose-6-P
- Glucokinase
o (-) high amount of fructose-6-P
o (-) glucagon
o (+) insulin
- Phosphofructokinase
o (-) citrate
o (-) glucagon
o (+) high amount of AMP
o (+) fructose-2,6-bisphosphate
- Pyruvate kinase
o (-) glucagon

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o (+) insulin
o (+) fructose -1,6-bisphopsphate (in liver)

Gluconeogenesis

- Formation of glucose from other compounds present in our body

This process does not usually occur in the large scale in our body unless a person is starving
or has an endocrine disorder
Glycerol (a part of TAGs), lactic acid, pyruvate, certain amino acids can be used for synthesis
of glucose in liver other than pyruvate. About 60% of amino acids can be used for
gluconeogenesis.
Substrates for gluconeogenesis:
- Glycerol (degradation of TAGs)
o Glycerol phosphate à dihydroxyacetone phosphate
- Lactate (glycolysis, Cori cycle)
- Oxaloacetate/alpha-ketoglutarate à phosphoenolpyruvate

If it starts from oxaloacetate, then gluconeogenesis begins in mitochondrion.

This process is located in both cytosol and mitochondrial matrix.

Regulation of gluconeogenesis
- Fructose-1,6-bisphosphatase
o (-) fructose-2,6- bisphosphate
o (-) high amounts of AMP
o (+) glucagon
o (+) high amounts of ATP
- Phosphoenolpyruvate carboxylase

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o (+) glucagon
- Pyruvate carboxylase
o (+) high amounts of acetyl-CoA
- (+) stress hormones
- (+) citrate
- (-) insulin
Glycolysis together with gluconeogenesis form Cori cycle.

Gluconeogenesis in the liver and glycolysis in the muscles

1. Muscles and red blood cells take glucose and convert it into lactate (glycolysis)
2. The liver takes up the lactate and converts it back into glucose (gluconeogenesis)

Glycolysis and gluconeogenesis together with some extra steps also forms the glucose-
alanine cycle.
It transports toxic ammonia from the muscles into the liver by pairing it with the pyruvate à
forming alanine. Alanine then is transported into the liver, and there it is transaminated to
pyruvate and ammonia then goes into the urea cycle.
1. Muscles take glucose and convert it to pyruvate (glycolysis)
2. Muscles convert pyruvate into alanine by adding NH2 to it
3. Liver deaminates alanine and turns it into pyruvate
4. Liver converts pyruvate into glucose (gluconeogenesis)

Pyruvate + glutamate à alanine + alpha-ketoglutarate (alanine aminotransferase)

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Formation of Acetyl-CoA
After glycolysis has taken its place, and pyruvate is produced, pyruvate is commonly
converted to Acetyl-CoA, which is then used as a substrate for the Krebs cycle. The reaction
of conversion of pyruvate into Acetyl-CoA is irreversible under physiological conditions.

Pyruvate dehydrogenase is a complex of three enzymes which are catalyzing reactions into
acetyl-CoA

Formation of lactate
After glycolysis ended, and in case of no presence of oxygen, or levels of NADH are very
high, lactate will be produced from pyruvate instead of Acetyl-CoA

This reaction takes place in erythrocytes since they do not have mitochondria.

Pyruvate can also form oxaloacetate, which is another compound to initiate the Krebs cycle.
This reaction requires biotin as a cofactor. The enzyme catalyzing it is called pyruvate
carboxylase, and ATP with bicarbonate is needed.

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Krebs cycle
Also known as the citric acid cycle. It takes place in mitochondria. Acetyl-CoA is oxidized
(aerobically). The cycle produces 2 CO2, 3 NADH+, 1 FADH2, and 1 GTP

The cycle is activated when there are low levels of ATP in cells and NADH+.

Anaplerotic reactions are the reactions that form intermediates from other metabolic
pathways.
Krebs cycle is amphibolic – both anabolic and catabolic.

Regulation of Krebs cycle:

- Citrate synthase
o (+) high amounts of Ca2+
o (+) high amounts is AMP and ADP
o (-) high amounts of ATP
o (-) Succinyl-CoA
- Aconitase
o (-) fluroacetate
- Isocitrate dehydrogenase
o (+) high AMP and ADP
o (+) High Ca2+
o (-) High ATP
o (-) High NADH2
- Alpha-ketoglutarate dehydrogenase

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o (-) GTP, ATP, NADH2, succinyl-CoA

o (+) high Ca2+
- Succinate dehydrogenase
o (-) oxaloacetate

Electron transport chain

Electron transport chain transfers electrons through a series of electron carriers along with
the increasing redox potential, and their goal is to reduce O2 to H2O eventually. In total, the
electron transport chain generates 32-38 ATP molecules from one molecule of glucose
(glycolysis and Krebs)

Complex 1,3 and 4 are also functioning as proton pumps as they pump protons from the
mitochondrial matrix into the intermembrane space. This process creates a concentration
gradient across the membrane, therefore the electric gradient. This gradient then fuels a
complex called ATP synthase and generates ATP as the protons are returning to the matrix.
The synthesis of ATP happens as the ATP synthase spins around, which causes the
turbulence inside of it and it triggers ADP and inorganic phosphate to combine creating the
ATP.
UCPs – aka uncoupling proteins. They decrease the membrane potential across the
membrane and produce heat. They are found in high concentrations in the brown adipose
tissue.
Cyanide – deadly poison – an inhibitor of cytochrome C oxidase (complex 4). They bind to it,
blocking the last reaction.
Coenzyme Q 10 – aka ubiquinone. In its structure, it contains the isoprenoid chain. It can be
synthesized in our body, so it is not an essential component in our diet.
Ubiquinone ubiquinol (reduction) CoQ10 can carry 2 electrons at a time, whereas
Cytochrome C carries only 1 electron and passes them one by one to the complex 4.
UCPs – aka uncoupling proteins. They decrease the membrane potential across the
membrane and produce heat. They are found in high concentrations in the brown adipose
tissue.
Cyanide – deadly poison – inhibitor of cytochrome C oxidase (complex 4). They bind to it
blocking the last reaction.
Coenzyme Q 10 – aka ubiquinone. In its structure it contains isoprenoid chain. It can be
synthesized in our body, so it is not an essential component in our diet.
Ubiquinone à ubiquinol (reduction) CoQ10 is able to carry 2 electrons at a time, whereas
Cytochrome C carries only 1 electron and passes them one by one to the complex 4.

Complex 4 needs four electrons to reduce O2 to make H2O. This means that Cytochrome C
needs to bring electrons four times. So, complex 4 accumulates electrons until there are 4 of
them so they can then be passed to O2. Though there are many Cytochrome C molecules
surrounding complex 4, and complex 4 can accept electrons from different cytochrome Cs
at the same time to make the process of H2O formation the most productive.

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Metabolism of other saccharides

Fructose metabolism
Sucrose = fructose + glucose

Fructose can be converted to Fructose-6-P by hexokinase in all tissues in our body.

Whereas, enzyme fructokinase in kidneys, liver and small intestine converts fructose into
Fructose-1-P.
Then, Fructose-1-P can be split by aldolase B into dihydroxyacetone phosphate and
glyceraldehyde.
Glyceraldehyde then is converted to glyceraldehyde-3-P by glyceraldehyde kinase.

Excess fructose is not good for our body, since it skips the regulatory step of glycolysis
which can lead to excess lipid synthesis.

Fructose intolerance:
- Caused by the deficiency of aldolase B
- Leads to the accumulation of Fructose-1-P
o Decrease amount of ATP and inorganic phosphate
§ Decreased synthesis of clotting factors and proteins. Causes
hypoglycemia and vomiting due to increased gluconeogenesis. As well
as hyperuricemia due to high amounts of adenine. Causes
hemorrhage, jaundice, hepatic failure and death L
o The only treatment is removal of fructose from diet

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Fructosuria:
- Caused by deficiency of fructokinase
- It is benign, asymptomatic accumulation of fructose in the urine

Mannose metabolism
By enzyme hexokinase in every cell in our body mannose can be converted to mannose-6-P
Mannose-6-P is then converted to fructose-6-P by enzyme phosphomannose isomerase.

Galactose metabolism
Lactose (from milk) is broken down into Galactose and Glucose

By enzyme galactokinase, Galactose is converted to galactose-1-P

Then, Galactose-1-P is combined with UDP-Glucose and by enzyme called galactose-1-
uridyltransferase is converted into UDP-Galactose + Glucose-1-P
Then UDP-Galactose by enzyme UDP-Galactose-4-epimerase is converted into UDP-
Glucose.

Galactosemia:
- Caused by absence of enzyme Galactose-1-p-uridyltransferase
- Leads to mental retardation, liver damage, cramps, galactosurea, diarrhea, jaundice
and cataracts due to accumulation of galactose
- The only treatment is removal of galactose from diet.

Pentose phosphate pathway

This pathway does not form ATP, but produces NADPH for synthesis of fatty acids, nucleic
acids and elimination of reactive oxygen species.

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Its intermediate – ribose-5-P is used for synthesis of nucleotides.

This pathway is located in the cytoplasm
Glucose-6-dehydrogenase deficiency leads to hemolytic anemia due to the damage of
erythrocytes by the oxidative stress.

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Synthesis of glycogen, aka glycogenesis.

If glucose is not immediately needed in the body, it can be turned to glycogen and stored,
also easily broken down when needed. The body stores up to 500g of glycogen. 75% of that
in muscles and 25% in the liver.

Glycogen has two ends: reducing and non-reducing. The non-reducing end takes place in
all of the reactions (lengthening or shortening)
Synthesis of glycogen takes place in the cytosol. And catalyzed by glycogen synthase which
is activated by high amounts of Glucose-6-P

Glycogenolysis, aka degradation of glycogen.

When glucose is needed in the body, glycogen is broken down to form molecules of glucose.

- Enzyme glycogen phosphorylase cleaves off Glucose-1-P from glycogen

- Glucose-1-P then is converted to Glucose-6-P in hepatocytes
- Enzyme glucose-6-P-phosphatase converts glucose-6-P into glucose

Since in the liver glucose-6-P can be converted to glucose, it can cross the membrane and go
into the blood stream with the help of GLUT transporters.

On the other hand, muscles do not have enzyme glucose-6-P-phosphatase, therefore all the
glucose from the glycogen in the muscles stays phosphorylated, and phosphorylated
glucose cannot use GLUT transporters. Therefore, it cannot be released into the
bloodstream. Instead, it is catabolized and used in glycolysis and then in the Krebs cycle for
energy.

Glycolysis takes place in cytosol. Intracellular Ca2+ in muscle tissue activates glycogen
degradation.

Regulation:
- Glycogen phosphorylase
o (-) high amount of Glucose-6-P
o (-) high amount of glucose in the liver
o (-) high amounts of ATP
o (+) high amounts of AMP

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Protein metabolism
Cells throughout the body can use glucose to form several types of amino acids, which can be
incorporated into proteins.

Amino acids are never stored in the body. They are either oxidized to directly produce ATP,
or used to synthesize new, needed proteins for growth and repair.

Excess proteins are converted into glucose and TAGs

Protein catabolism
Proteins can be broken down into different things in the body:
- Converted into different amino acids
- Converted to fatty acids
- Converted to ketone bodies
- Converted to glucose
- Oxidized to Acetyl-CoA to create ATP via the Krebs cycle and electron transport chain

It is impossible to store amino acids due to the fact that in order for them to be used in any
way possible, they have to be detoxified (ammonia needs to be removed) and it takes a lot
of energy.

When the intake of proteins is higher than required, the excess needs to be degraded, the
process of marking them for degradation is carried out by protein ubiquitin, which binds to
them and then they are degraded by a big complex called proteasome.

Protein anabolism
Is the formation of the peptide bonds between adjacent amino acids to make up a protein
molecule.
This process is activated by insulin growth factors, thyroid hormones (T3, T4), insulin,
estrogen and testosterone.

Amino acids are divided into essential and non-essential. Essential amino acids cannot be
synthesized in the body, therefore, we have to get them from our diet. Whereas, non-
essential amino acids can by synthesized by transamination.

Urea cycle
When there is too much of ammonia in our body, we need to get rid of it. In the urea cycle
ammonia is transformed into the urea which can then be excreted with the urine from our
body. Urea cycle is activated when the protein breakdown in the body increases.

Urea cycle, aka ornithine cycle takes place primarily in liver, but also in kidneys at some
extend. It takes place both in cytoplasm and mitochondria of the cells. Compounds needed
for the cycle: bicarbonate, ammonia, 3 ATP, and aspartate.

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The removal of ammonia is super essential because it is toxic for the brain. Plasma
concentration of ammonia should be below 35 umol/L

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Ammonia is transported in the body as glutamine.

Amino acid metabolism
1. Proteins are broken down into amino acids in the body
2. Then amino acids travel to the liver in the bloodstream
3. In the liver then they can undergo:
a. Protein synthesis
b. Synthesis of glucose
i. From glucogenic amino acids – Ser, Thr, Cys, Met, Asp, Glu, Asn, Gln,
Gly, Ala, Val, Pro, His and Arg
c. Synthesis of fatty acids
i. From ketogenic amino acids – Lys, Leu
d. Amino acids that are both ketogenic and glucogenic are – Ile, Phe, Tyr, Trp
e. Or amino acids can be sent to muscles to be transaminated into different
ones which are needed.

Transamination of amino acids

When amino acid is transaminated, the ammonia is lost. Then it becomes an alpha-
ketoacid. The ammonia(NH3) is then ammonium cation(NH4+) [since it is in the aqueous
solution] and gets excreted undergoing the urea cycle

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Alanine and glutamine are amino acids with the highest concentration in the blood

Glutamine/glutamate
Glutamine is a primary source of energy for enterocytes. It is broken down in liver and
kidneys

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Alpha-ketoglutarate is the most frequent acceptor of amino groups from amino acids. Then
it is converted into glutamate.

Decarboxylation of amino acids produces biogenic amines such as serotonin and histamine.

Important notes to remember:

- Tyrosine is synthesized from phenylalanine in cells by phenylalanine hydroxylase
- Methionine is turned into homocysteine and cysteine then is synthesized
- Serine is converted to glycine
- Serotonin is formed from tryptophan
- Dopamine is formed from tyrosine

Carboxylation of amino acids gives rise to biogenic amines, aka monoamines

- Tyrosine à catecholamines
- Tryptophan à serotonin
- Histidine à histamine
- Serine à acetylcholine
- Cysteine/ aspartate à Aetyl-CoA
- Glutamate à GABA

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Lipid metabolism
Lipids may be oxidized to produce ATP, but if they are not in need at the moment, they can
be stored in the adipose tissue. TAGs are stored in adipocytes and have the reserve as much
as 98% of the body energy.

Lipolysis
Lipolysis is the process of splitting TAGs into glycerol and fatty acids. The reactions are
catalyzes by lipases.

In order for the body to use fatty acids as an energy source following steps have to occur:
1. TAGs need to be mobilized and split into glycerol and fatty acids which are
transported in blood bound to albumin.
2. Fatty acids are activated in the cytosol and transported bound to carnitine inside the
mitochondria.
3. Betta oxidation occurs

Glycerol formed from lipolysis is converted to glyceraldehyde-3-P and in case of:

- High ATP – converted to glucose and glycogen
- Low ATP – enters catabolic pathway of pyruvate and then Krebs cycle.
Fatty acids formed from lipolysis are undergoing:
- Betta oxidation (acyl-CoA à acetyl-CoA)
o Acetyl-CoA enters then Krebs cycle
o Acetyl-CoA can form Ketone bodies (ketogenesis) (acetoacetate, beta-
hydroxybutyrate, and acetone)
Activation – by glucagon and epinephrine
Inhibition – by insulin

Carnitine shuttle
Fatty acids are activated in the cytosol, but they need to get inside of mitochondria to get
oxidized. Long chain fatty acids can not freely diffuse into the mitochondrial matrix, they
need a transport system.

Carnitine acyltransferase 1 is located on the outer mitochondrial membrane, it takes acyl-

CoA and a free carnitine and catalyzes it to form acylcarnitine. This complex can translocate
inside of the matrix.
There, another enzyme called carnitine acyltransferase 2 splits acylcarnitine into free
carnitine and fatty acid and fatty acid can then enter betta-oxidation.
Carnitine, though, moves freely back into the cytosol.
Malonyl-CoA (the first step in fatty acid synthesis is the inhibitor for both acyltransferases).

Hormone-sensitive lipase is an enzyme which releases fatty acids from adipocytes. It is

activated by glucagon.

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Lipogenesis
Hepatocytes and adipocytes can convert amino acids and glucose into lipids. This process
occurs when a person eats more calories than the body requires.
- Glucose à glyceraldehyde-3-P à glycerol
- Glucose à glyceraldehyde-3-P à acetyl-CoA à fatty acids
Both of those compounds (glycerol
and fatty acids) can either be
converted into storage TAGs or can
undergo series of reactions to
become lipoproteins, phospholipids
and cholesterol

Enzymes required for the synthesis

of fatty acids are localized in the
cytoplasm, but Acetyl-CoA (the
substrate) is in mitochondria.
Mitochondrial membrane in
impermeable for Acetyl-CoA, but in
combination with oxaloacetate it
makes up citrate, which is
permeable. Therefore, citrate goes
out of mitochondria and enters
cytosol, there it splits back to
oxaloacetate and Acetyl-CoA.
Acetyl-CoA then can enter Fatty Acid
synthesis, whereas oxaloacetate is
converted to malate which can
freely go back into the mitochondrial
matrix.

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Betta- oxidation
Betta-oxidation is the breakdown of fatty
acids into Acetyl-CoAs. It produces FADH2
and NADH
Betta -oxidation got its name due to the
fact that the oxidation proceeds on the
third carbon.

Ketogenesis
Ketogenesis, aka synthesis of
ketone bodies (acetone,
acetoacetate and beta-
hydroxybutyrate) takes place in
mitochondria of hepatocytes. It is
used as the energy source
mostly during starvation in most
tissues in the body (except liver).
For the brain, Ketone bodies are
not the most favorable source of
energy, but in starvation they
still use it as an energy source.
Under the normal conditions,
production of ketone bodies is
very low, and Acetyl-CoA is used
to produce energy via Krebs and
electron transport chain.
Lack of insulin contributes to very
high rate of catabolic processes
in the body, therefore
production of ketone bodies is
very high and it leads to
ketoacidosis.
Ketogenesis is increased during
increased during breakdown of
fatty acids in liver.

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Alcohol metabolism
Ethanol is converted to acetaldehyde and then to acetate (both of the reactions produce
NADH)
Or it is converted to formaldehyde

Since consumption of alcohol produce elevated levels of NADH, it activates alternative

pathways of our metabolism which includes:
- Increased lactate production
- Stimulation of TAG synthesis à fatty liver
- Decreased glucose synthesis à hypoglycemia

Fast-feed cycle
When we eat, our body is in the absorptive state – ingested nutrients go to the bloodstream.
Pancreatic betta cells release insulin which increases the activity of anabolic enzymes.

When the body is done digesting, it is in post-absorptive state [digestion of normal meal
usually takes around 4 hours]. Therefore, glucose blood levels start to drop, which signals to
pancreatic alpha cells to produce glucagon.

It is important to keep glucose levels stable because:

- Glucose is the primary source for nerve cells
- Red blood cells get all of the ATP from glycolysis since they don’t have mitochondria
The body can get glucose from:
- Breakdown of liver glycogen
- Glycerol from lipolysis
- Gluconeogenesis using lactate or amino acids

The body though can get ATP from different sources:

- Fatty acid oxidation
- Oxidation of lactate in the heart
- Oxidation of amino acids
- Oxidation of ketone bodies
- Breakdown of muscle glycogen for use in muscles

Regulation of metabolism
Hormonal:
- Insulin (decreases blood glucose levels)
o Has anabolic effect and contributes to the glucose storage
o Activates glycolysis, gluconeogenesis and lipogenesis
o Increases levels of GLUT channels for the glucose take up
o Increases tissue growth
- Glucagon (increases blood glucose levels) [epinephrine, GH, cortisol]
o Has catabolic effect and wants to produce glucose from other intermediates
o Activated gluconeogenesis, lipolysis, proteolysis and ketogenesis
o Works via cAMP

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Hemostasis
Hemostasis is the process of the bleeding stoppage in the body. Imbalance of it occurs in
sepsis and tumors.
Steps of hemostasis:
1. Reflex vasoconstriction
2. Platelet activation and aggregation à formation of primary clot
3. Hemocoagulation à formation of fibrin clot
4. Thrombolysis after the healing à removal of the “bandage”

Coagulation is the process of conversion of soluble fibrinogen into the insoluble fibrin.
Trombin catalyzes a cascade of coagulation factors.
Platelets
Platelets are the fragments of megakaryocytes. They have a central zone with the granules,
aka granulomere; the granules contain:
- Delta – dense bodies – ATP, ADP, Ca2+ and serotonin
- Alpha – fibrinogen, platelet-derived growth factor (PDGF), fibroblast growth factor
(FGF) , von Willebrand factor (vWF) [aka factor VIII] and platelet factor 4
- Lambda – lysosomes
And the lighter peripheral area – hyalomere – which has canalicular system, important for
the secretion.

Since thrombocytes do not have a nucleus, there is no proteolysis in them. They gain energy
from aerobic glycolysis. They contain mitochondria and Golgi apparatus. The cytoplasm
contains microtubules and actin with myosin which help to extract the granules from the
platelet. Platelets produce phospholipids which are crucial for the primary homeostasis.
1. Adhesion: binding to subendothelial collagen – vWF binds to collagen
2. Activation: platelets are activated by exposed collagen, thrombin, ADP and TXA2 is
expressed, which activates the expression of GP IIb/IIIa receptor. It triggers platelets
to change its shape.
3. Aggregation

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Heme and iron metabolism

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Genetics

Enzymopathy – heritable disorders of metabolism

Hereditary metabolic disorders have recessive character, which means that heterozygotes
are phenotypically healthy.
The diseases in recessive homozygotes though can manifest in different ways:
- Accumulation of molecules, proteins and enzymes which are not excluded right away
as they should
- The absence of proteins which are enzymes for the pathways
- Formation of toxic by-products and derivatives of them.
The combination of one or another factor together can cause slow or acute poisoning and
sepsis.

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