Transcript 38_Chromoproteins. Pathological and physiological forms of h

Chromoproteins
•
In our organism are present: complex proteins - include
Fe2+ - cytochrome oxidase(heme), hemoglobin , mioglobin,
catalase, peroxidase, Cu2+ - cytochrome oxidase, Zn2+ carbonic anhidrase, Mg2+ hexokinase, piruvate kinase and
etc.
Respiratory pigments
• Hemoglobin
Erythrocytes derive their colour from a
complex protein called hemoglobin. This
substance is composed of a pigment, heme,
containing iron, and the protein glohin.
Hemoglobin has the power to attract oxygen
molecules and to hold them in a loose
chemical combination known as
oxyhemoglobin. It is said, therefore, to have a
chemical affinity for oxygen.
Quantity and chemical structure of hemoglobin
• In man – 130-160 g/L;
• in woman – 120-140 g/L.
• It consists of four folded polypeptide chains of amino
acid units. The four chains form the globin, or
protein, part of the molecule. In addition there are
four atoms of iron, each associated with a pigment,
or heme, group of atoms. The heme group provides
the red colour of the blood and also its oxygencombining ability. The iron atoms are bivalent or in
the ferrous state. There are 2 pairs of polypeptides in
each hemoglobin molecule, 2 of the subunits
containing one type of polypeptide and 2 containing
another.
Hemoglobin protein containing
four subunits
(polipeptide
chains).
Each polipeptide
chain is bounded
with heme. Each
couple of the
polipeptide chains
in molecule of
hemoglobin is
equal.
• The main type of hemoglobin in blood of adult
people (96 %) is the form containing two
alpha and two beta chains. It is the adult
hemoglobin or HbA1 or α2β2. Except this form
there is about 2 % of hemoglobin A2 (α2δ2)
and 2-3 % of fetal hemoglobin (α2γ2)
Porphin is formed by linking together of four
pyrrole rings through methenyl bridges.
CH2=CH2
CH
CH3
H3C
CH2=CH2
N
N
++
CH
Fe
N
GLOBIN
CH
N
H3C
CH3
CH
CH2-CH2-COOH
CH2-CH2-COOH
Biosynthesis of heme
The major main in the biosynthesis of heme are the liver
and the erythrocyte - producing cells of the bone
marrow, which are active in hemoglobin synthesis.
I. Formation of A - aminolevulinic acid .
All the carbon two simple bluding blocks;
glycine and succinyl CoA. Glycine and succinyl CoA condense
to form A.L.A in a reaction catalyzed by ALA synthase.
This reaction requires pyridoxal phosphate as a coenzyme
vitamin B6, and is the rate-controlling step
in porphyrin biosynthesis.
By deficiency
By deficiency of the iron Fe is develops - iron
deficiency anemia or hypochromic anemia.
Prophyrias - are caused by inherited or acquired
defects in heme synthesis, resulting in the
accumulation and increased excretion or
porphyrins or porphyrin precurcors. The
porphyries are classified as erythropoietic
or hepatic depending on whuther the enzyme
deficiency occurs in red blood cells or the
liver.
Metabolism of iron
• Daily requirements of for our organism in the iron
Fe=10-20 mg.
• From total iron - 65 - 70% in the structure hemoglobin
20% - contain myoglobin contain
1% - in the
structure cytrochromes, cytrochromoxidase heme contain
enzymes
•
10-15% - in the liver , bone marrow.
•
Transport of iron ensure specific protein transferrin
transport form of iron .
• In the structure this protein the iron has valency - Fe 3+
and joins with anion hydrocarbonate.
Ferritin
•
Ferritin - helps to store iron in certain tissues /
liver, spleen, bone marrow
• Ferririn consists of 24 subunits arranged in the form
of a shell around iron atoms Fe2+. One apoferritin
molecule encloses more than 2000-3000 ferric
atoms. With passage of time lysosomal enzymes
degrade ferritin to hemosiderin which is a molecule
of non-specific structure / a mixture of partially
degraded protein, lipid, iron.
Hemosiderin
Hemosiderin another reserve form of iron. By excess
of iron level of hemosiderin in the liver increase
and develops hemosiderosis of liver damage the
liver. Idiopatic hemochromatosis is often inherited
disease. In primary hemochromatosis there is
excessive accumulation of iron in tissues. Thus
results in tissue damage. In the liver iron
accumulation can cause cirrosis. In the pancreas in
can damage beta - cells resulting in diabetes
mellitus. Iron accumulation in skin can cause
pigmentation of skin bronze colour. Thus the
condition is called bronze diabetes.
Respiratory pigments
Myoglobin
• Hem is also part of the structure of myoglobin, an
oxygen-binding pigment found in red (slow)
muscles and in the respiratory enzyme cytochrome
c. Porphyrins other than that found in hem play a
role in the pathogenesis of a number of metabolic
diseases (congenital and acquired porphyria, etc.) It
may be the reserve pigments, which give the tissue
oxygen in a small oxygen condition.
Hemoglobin derivates
1. Physiological hemoglobin derivatives
• Oxy Hb - it is used for of transport of
O2 in the body (HbO2).
• Hb NH COOH- carbhemoglobin
2. Pathological derivatives of hemoglobin
• /carboxyhemoglobin/ -Hb - CO
• Met-Hb Fe 3+
Physiological
HbCO2
HbNHCOOH is used for
transfer of CO2 from peripheral
tissues
to
the
lungs
(carbhemoglobin, HbCO2)
Methemoglobin
• The iron ion may either be in
the Fe2+ or Fe3+ state, but
ferrihemoglobin
(methemoglobin) (Fe3+)
cannot bind oxygen. In
binding, oxygen temporarily
oxidizes (Fe2+) to (Fe3+), so
iron must exist in the +2
oxidation state to bind
oxygen. The enzyme
methemoglobin reductase
reactivates hemoglobin found
in the inactive (Fe3+) state by
reducing the iron center.
Carboxyhemoglobin
• The binding of oxygen is affected by molecules such as carbon
monoxide (CO) (for example from tobacco smoking, car
exhaust and incomplete combustion in furnaces). CO
competes with oxygen at the heme binding site.
• Hemoglobin binding affinity for CO is 200 times greater than
its affinity for oxygen, meaning that small amounts of CO
dramatically reduce hemoglobin's ability to transport oxygen.
When hemoglobin combines with CO, it forms a very bright
red compound called carboxyhemoglobin, which may cause
the skin of CO poisoning victims to appear pink in death,
instead of white or blue.
Abnormal hemoglobin
Abnormal hemoglobins are the result of mutations in the genes
that code for α or β chains of globin.
Hemoglobinopathias
Sickle-cell anemia (HbS) and hemoglobin C disease (HbC) are
the classical examples of abnormal hemoglobin.
The structure of hemoglobin contains two α- and two β-globin
chains.
• Molecular basis of HbS
In case of sickle-cell anemia, the hemoglobin (HbS) has two
normal α-globin and two abnormal β-globin chains. This is due
to a difference in a single amino acid. In HbS, glutamate at
sixth position of β-chain is replaced by valine
Thalassemias, on the other hand, are caused by decreased
synthesis of normal hemoglobin
Sickle-cell
anemia
This one alteration of the
sequence of amino acids in
hemoglobin changes its
molecular geometry and hence
its ability to carry oxygen and its
solubility characteristics.
The red blood cells change into
a sickled shape instead of the
normal round shape, become
trapped in the small blood
capillaries, and cause a great
deal of pain.
Hemoglobin C Crystals