1. Biochemistry of
the liver

2. LIVER STRUCTURE
sinusoids
central vein
portal vein
bile canaliculi
bile duct
hepatic artery

5. Liver’s functions.
1. Liver is a main organ which is responsible for dividing of
nutritional substances in our organism (for example,
glucose, triacylglicerides and ketone bodies).
2. Hepatocytes synthesizes as lot of blood plasma proteins
and lipoproteins, low-weight bioactive substances
(creatin, 25-oxicalciferol, hem), cholesterol.
3. Synthesis of urea (final product of nitrogen metabolism)
also takes place in the liver.
4. Liver synthesizes bile acids and excrete a bile into
intestinal tract. This process plays a very important role
in lipids digestion and excretion of cholesterin and some
products of metabolism into intestine.
5. Liver play a big desintoxification role, inactivates
endogenic and exogenic substances (drugs, some
hormones, different toxins).
6. Liver is a depo for iron, some another metals, vitamines
A, D, E, B12, folic acid.

8. Role of the liver in carbohydrate metabolism.
From intestine glucose pass into the liver, where
most part of it undergone the phosphorillation.
Glucose-6-phosphate formed in result of this
reaction, which catalyzed by two enzymes –
hexokinase and glucokinase.
Glucose-6-phosphate is a key product of
carbohydrates metabolism. In the liver this
substance can metabolized into different ways
depend of liver’s and whole organism’s
necessity.

9. The fate of glucose molecule in the cell
Glucose
Pentose phosphate
Glycogenesis pathway supplies
(synthesis of the NADPH for lipid
glycogen) is synthesis and
activated in well Glucose-6-
pentoses for nucleic
fed, resting state phosphate acid synthesis
Gluconeoge
nesis
Ribose,
is activated NADPH
Glycogen if glucose is
Glycogenolysis required
(degradation of
glycogen) Pyruvate Glycolysis
is activated if
energy is required
TCA cycle

10. • Synthesis of glycogen. Content in the liver – 70-100g
• Glucose-6-phosphatase catalize dephosphorillation of
glucose-6-phosphate and formation of free glucose
• Excess of glucose-6-phosphate, which not used for
synthesis of glycogen will follow to form free glucose
• Glucose-6-phosphate decomposed to H2O and CO2,
and free energy for hepatocytes formed.
• Part of glucose-6-phosphate oxidized in
pentosophosphate cycle.
• Hepatocytes content full set of gluconeogenesis
necessary enzymes. So, in liver glucose can be
formed from lactate, pyruvate, amino acids, glycerol.
• Gluconegenesis from lactate takes place during
intensive muscular work. Lactate formed from glucose
in muscles, transported to the liver, new glucose
formed and transported to the muscles

11. Role of the liver in lipid metabolism.
In the liver all processes of lipid metabolism take place. Most
important of them are following:
Lipogenesis (synthesis of fatty acids and lipids). Substrate for
this process – acetyl-CoA, formed from glucose and amino
acids, which are not used for another purposes
Liver more active than another tissues synthesizes saturated
and monounsaturated fatty acids. Fatty acids then used for
synthesis of lipids, phospholipids, cholesterol ethers.
Liver play a central role in synthesis of cholesterin, because
near 80 % of its amount is synthesized there. Biosynthesis
of cholesterin regulated by negative feedback. When the
level of cholesterin in the meal increases, synthesis in liver
decreases, and back to front. Besides synthesis regulated
by insulin and glucagon.
Liver is a place of ketone bodies synthesis. These substances
formed from fatty acids after their oxidation, and from liver
transported to another tissues, first of all to the heart,
muscles, kidneys and brain

15. Role of the liver in protein metabolism.
Liver has full set of enzymes, which are necessary for
amino acids metabolism. Amino acids from food used in
the liver for following pathways:
1. Protein synthesis.
2. Decomposition for the final products.
3. Transformation to the carbohydrates and lipids.
4. Interaction between amino acids.
5. Transformation to the different substances with amino
group.
6. Release to the blood and transport to another organs
and tissues.

16. Liver synthesizes 100 % of albumins, 90 % of
α1-globulines, 75 % of α2-globulines, 50 % of β-
globulins, blood clotting factors, fibrinogen,
protein part of blood lipoproteins, such enzyme
as cholinesterase.
Liver can synthesize non-essential amino acids.
Liver synthesizes purine and pyrimidine
nucleotides, hem, creatine, nicotinic acid,
choline, carnitine, polyamines.

17. Role of the liver in detoxification processes.
A xenobiotics is a compound that is foreign to the body.
The principal classes of xenobiotics of medical relevance
are drugs, chemical cancerogens, and various
compounds that have found their way into our
environment by one route or another (insecticides,
herbicides, pesticides, food additions, cosmetics,
domestic chemical substances).
Some internal substances also have toxic properties (for
example, bilirubin, free ammonia, bioactive amines,
products of amino acids decay in the intestine).
Moreover, all hormones and mediatores must be
inactivated.
Reactions of detoxification take place in the liver.
Big molecules like bilirubin excreted with the bile to
intestine and leaded out with feces. Small molecules go
to the blood and excreted via kidney with urine.

18. General ways of xenobiotics biotransformation and their localization in cell
REACTION ENZYME LOCALIZATION
PHASE I
Hydrolysis Esterase Microsomes, cytosol, lysosomes, blood
Peptidase lysosomes
Epoxide hydrolase Microsomes, cytosol
Azo- and nitro-reduction Microflora, microsomes, cytosol
Reduction Carbonyl reduction Cytosol, blood, microsomes
Disulfide reduction Cytosol
Sulfoxide reduction Cytosol
Alcohol dehydrogenase
Oxidation Cytosol
Aldehyde dehydrogenase
Mitochondria, cytosol
Aldehyde oxidase
Cytosol
Xanthine oxidase Cytosol
Monoamine oxidase Mitochondria
Diamine oxidase Cytosol
Flavin-monooxygenases
Microsomes
Cytochrome P450
Microsomes
PHASE II
Glucuronide conjugation Microsomes
Sulfate conjugation Cytosol, microsomes
Glutathione conjugation Cytosol
Amino acid conjugation Mitochondria, cytosol
Acetylation Mitochondria, microsomes
Methylation Cytosol, microsomes, blood

19. The metabolism of xenobiotics has 2 phases:
In phase 1, the major reaction involved is
hydroxylation, catalyzed by members of a class
of enzymes referred to as monooxygenases or
cytochrome P-450 species. These enzymes can
also catalyze deamination, dehalogenation,
desulfuration, epoxidation, peroxidation and
reduction reaction. Hydrolysis reactions and
non-P-450-catalyzed reactions also occur in
phase 2.

22. Cytochrom P450
The highest concentration – in endoplasmic reticulum of
hepatocytes (microsomes).
Hem containing protein.
Catalyzes monooxigenation of oxygen atom into substrate;
another oxygen atom is reduced to water
Electrons are transferred from NADPH to cytochrome
P450 through flavoprotein NADPH-cytochrome P450
reductase.

23. [1] In the resting state, the heme iron is
trivalent. Initially, the substrate binds
near the heme group.
[2] Transfer of an electron from FADH2
reduces the iron to the divalent form that
is able to bind an O2 molecule.
[3] Transfer of a second electron and a
change in the valence of the iron reduce
the bound O2 to the peroxide.
[4] A hydroxyl ion is now cleaved from
this intermediate. Uptake of a proton
gives rise to H2O and the reactive form
of oxygen mentioned above. In this ferryl
radical, the iron is formally tetravalent.
[5] The activated oxygen atom inserts
itself into a C–H bond in the substrate,
thereby forming an OH group.
[6] Dissociation of the product returns
the
enzyme to its initial state.

25. In phase 2, the hydroxylated or other compounds
produced in phase 1 are converted by specific
enzymes to various polar metabolites by conjugation
with glucuronic acid, sulfate, acetate, glutathione, or
certain amino acids, or by methylation.
In certain cases, phase 1 metabolic reaction convert
xenobiotics from inactive to biologically active
compounds. In these instances, the original
xenobiotics are referred to as prodrugs or
procarcinogens. In other cases, additional phase 1
reactions convert the active compounds to less
active or inactive forms prior to conjugation. In yet
other cases, it is the conjugation reactions
themselves that convert the active product of phase
1 to less active or inactive species, which are
subsequently excreted in the urine or bile. In a very
few cases, conjugation may actually increase the
biologic activity of a xenobiotics.

26. There are at least 5 types of phase 2 reactions:
• Glucuronidation. UDP-glucuronic acid is the
glucuronyl donor, and a variety of glucuronyl
transferases, present in both the ER and cytosol,
are the catalysts. Molecules such as bilirubin,
thyroxin, 2-acetylaminofluorene (a carcinogen),
aniline, benzoic acid, meprobromate (a
tranquilizer), phenol, crezol, indol and skatol, and
many steroids are excreted as glucuronides. The
glucuronide may be attached to oxygen, nitrogen,
or sulfur groups of substrates.
2. Sulfation. Some alcohols, arylamines, and phenols
are sulfated. The sulfate donor in these and other
biologic sulfation reactions is adenosine 3´-
phosphate-5´-phosphosulfate (PAPS); this
compound is called active sulfate

27. 3. Conjugation with Glutathione. Glutathione (γ-
glutamylcysteinylglycine) is a tripeptide consisting of
glutamic acid, cysteine, and glycine. Glutathione is
commonly abbreviated to GSH; the SH indicates the
sulfhydryl group of its cysteine and is the business
part of the molecule. A number of potentially toxic
electrophilic xenobiotics (such as certain
carcinogens) are conjugated to the nucleophilic
GSH. The enzymes catalyzing these reactions are
called glutathione S-transferases and are present in
high amounts in liver cytosol and in lower amounts
in other tissues.

28. Acetylation. These reactions is represented by X + Acetyl-
CoA → Acetyl-X + CoA, where X represents a xenobiotic.
These reactions are catalyzed by acetyltransferases present
in the cytosol of various tissues, particularly liver. The
different aromatic amines, aromatic amino acids, such drug
as isoniazid, used in the treatment of tuberculosis, and
sulfanylamides are subjects to acetylation. Polymorphic
types of acetyltransferases exist, resulting in individuals who
are classified as slow or fast acetylators, and influence the
rate of clearance of drugs such as isoniazid from blood.
5. Methylation. A few xenobiotics (amines, phenol, tio-
substances, inorganic compounds of sulphur, selen,
mercury, arsenic) are subject to methylation by
methyltransferases, employing S-adenosylmethionine as
methyl donor. Also catecholamines and nicotinic acid amid
(active form of vitamin PP) are inactivated due to
methylation.
Very important way of detoxification is ureogenes (urea
synthesis). Free ammonia, which formed due to metabolism
of amino acids, amides and amines, removed from organism
in shape of urea.

29. Muscle
structure

30. Proteins of muscles
3 types:
•proteins of
sarcoplasma
•proteins of
miofibrils
•proteins of
stroma

31. Proteins of Sarcoplasma
•Miogen fraction
(enzymes of glycolysis
etc.)
•Albumins
•Globulins
•Myoglobin
(chromoprotein,
provides the red color
to muscles, responsible
for oxygen storage)

32. Proteins of Stroma
•collage
•keratin
•elastin
are constituents of
connective tissue of
vessel walls, nerves,
sarcolema.

33. Proteins of Miofibrils
•Myosin (56-60 %)
•Actin (20-25 %)
•Tropomyosin (10-15 %)
•Troponin complex (4-6 %)

34. Structure of filaments and myofibrils
Sarcoplasma of
striated muscle
fibers contains
myofibrils
oriented along
which are built
of 2 types
protein
filaments: thick
and thin

35. •Muscle contraction is carried out due to the
sliding of thick and thin filaments
•Chemical energy – ATP hydrolysis
•Contraction is regulated by Ca2+ concentration

36. Structure of Thick Filament
•Thick filaments consist of myosin molecules
•Myosin molecule built of 2 heavy (200000 Da)
and 4 light (16000-25000 Da) chains
•Heavy chains are coiled around each other and
form the “tail” of the molecule
•2 light chains form the globular head of the
molecule
•The head has ATP-ase properties

37. About 400 molecules of myosin are
combined in the thick filament

38. About half of molecules is directed
to one end of filament, another half
– to another end

39. The structure of thin filaments are proteins actin, tropomyosin and
troponin
Two forms of actin: globular G-actin and fibrillar
F-actin.
Globular actin molecules noncovalently connected to form F-actin.
Two F-actin chains screwed into a spiral.
In the groove spiral F-actin is located tropomyosin.
With one molecule of tropomyosin contact 7 pairs of actin.
At 1 tropomyosin molecule is 1 molecule of globular protein troponin.

40. •Two forms of actin: globular G-actin and F-actin fibrillar.
Globular actin molecules nonсovalently connected to
form F-actin.
Two F-actin chains screwed into a spiral.
Troponin is composed of 3 subunits (C, I, T).

41. Myofibrils contain approximately 2500 filaments.
In a thick thread miozynovu contributes 6 thin

42. •structural unit of myofibrils - sarcomere
both ends of thick filaments myosin free
thin filament with one end attached to the Z-disc

43. The sliding filament model describes the
mechanism involved in muscle contraction.
[1 ] In the initial state, the myosin
heads are
attached to actin. When ATP is bound,
the
heads detach themselves from the actin
(the
“plasticizing” effect of ATP).
[2 ] The myosin head hydrolyzes the
bound ATP to ADP and Pi, but initially
withholds the two reaction products.
ATP cleavage leads to allosteric tension
in the myosin head.
[3 ] The myosin head now forms a new
bond with a neighboring actin molecule.
[4 ] The actin causes the release of the
Pi,
and shortly afterwards release of the
ADP as well. This converts the allosteric
tension in the myosin head into a
conformational
change that acts like a rowing stroke.

44. Red fibers provide for their ATP
requirements
mainly (but not exclusively) from
fatty acids, which are broken
down via β-oxidation,
the tricarboxylic acid cycle, and
the respiratory chain (right part of
the illustration). The red color in
these fibers is due to the
monomeric heme protein
myoglobin, which they
use as an O2 reserve. Myoglobin
has a much higher afinity for O2
than hemoglobin and therefore
only releases its O2 when there is
a severe drop in O2 partial
pressure