hemoglobin handout report

7/28/2019 Hemoglobin Handout Report

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HEMOGLOBIN IS a tetrameric protein that is FOUND EXCLUSIVELY IN RED BLOOD

CELLS (RBCS) WHERE ITS MAIN FUNCTION IS TO TRANSPORT OXYGEN (O2)

FROM THE LUNGS TO THE CAPILLARIES OF THE TISSUES and returns carbon

dioxide to the lungs.

HEME is a cyclic tetrapyrrole consisting of four molecules of pyrrole linked by

methane bridges.

Heterocyclic macromolecules composed of four modified pyrrole subunits

interconnected at their carbon atoms via methyne bridges (=CH-)

HEME PERMITS THE REVERSIBLE BINDING OF ONE OXYGEN MOLECULE

(OXYGENATION)

The iron is held in the center of the heme molecule by bonds to the four

nitrogens of the porphyrin ring.

THE DIAGRAM, YOU CAN SEE IRON THAT IS HELD IN THE CENTER OF HEME

MOLECULES, CAN FORM SIX BONDS; FOUR WITH PORPHYRIN NITROGENS,

PLUS TWO ADDITIONAL BONDS, ONE ABOVE AND ONE BELOW THE PLANARPORPHYRIN RING.

NOTE: orphyrins have complex cyclic structures. All porphyrin compounds absorb

light intensely at or close to 410 nanometres. Structurally, porphyrin consists of four

pyrrole rings

THE GLOBIN PROTEIN PARTS ARE SYNTHESIZED BY RIBOSOMES IN THE CYTOSOL.

TWO DISTINCT GLOBIN CHAINS (EACH WITH ITS INDIVIDUAL HEME MOLECULE

TO FORM HEMOGLOBIN.

THE PAIRING OF ONE ALPHA CHAIN AND ONE BETA CHAIN PRODUCES A HGB

DIMER (TWO CHAINS). TWO DIMERS COMBINE TO FORM HEMOGLOBINTETRAMER W/C IS THE FUNCTIONALFORM OF HGB.

THE GENES THAT ENCODE THE ALPHA GLOBIN ARE ON CHROMOSOMES 16 WHILE

THOSE THAT ENCODE THE BETA GLOBIN ARE ON CHROMOSOME 11

Hemoglobin variants are mutant forms ofhemoglobin in a population (usually of

humans), caused by variations in genetics. Some well-known hemoglobin variants such

as sickle-cell anemia are responsible for diseases, and are considered

hemoglobinopathies. Other variants cause no detectable pathology, and are thus

considered non-pathological variants. Some normal hemoglobin types are;

Hemoglobin A (Hb A), which is 90% of hemoglobin found in adults, Hemoglobin A2 (Hb

A2), which is 2-5% of hemoglobin found in adults, and Hemoglobin F (Hb F), which isnot found in adults and is the primary hemoglobin that is produced by the fetus during

pregnancy.

HEMOGLOBIN A, THE MAJOR HEMOGLOBIN IN ADULTS, IS COMPOSED OF FOUR

POLYPEPTIDE CHAINS- TWO ALPHA CHAINS AND TWO BETA CHAINS HELD

TOGETHER BY A COVALENT INTERACTIONS.
http://global.britannica.com/EBchecked/topic/485130/pyrrolehttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Populationhttp://en.wikipedia.org/wiki/Populationhttp://en.wikipedia.org/wiki/Sickle-cell_anemiahttp://en.wikipedia.org/wiki/Sickle-cell_anemiahttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Sickle-cell_anemiahttp://en.wikipedia.org/wiki/Sickle-cell_anemiahttp://en.wikipedia.org/wiki/Populationhttp://en.wikipedia.org/wiki/Populationhttp://en.wikipedia.org/wiki/Hemoglobinhttp://en.wikipedia.org/wiki/Hemoglobinhttp://global.britannica.com/EBchecked/topic/485130/pyrrole


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HBF composed of 2 alpha and 2 gamma chains

HBS composed of 2 alpha and 2 s chains

HBa2 composed of 2 aplha and 2 delta chains

SICKLE CELL

sickle-cell anemia or Hemoglobin S disease is the most common of the red cell

sickling disease, it is an autosomal recessive genetic blood disorder caused by a

single nucleotide alteration (a point mutation) in the gene for beta globin chain of

HbA, which produces HbS. . Erythrocyte homozygous and heterozygous for HbS .

It is the most commmon inherited disorder in USA affecting 80,000 Americans.

The sickling occurs because of a mutation in the hemoglobin geneThe lifetime of an

erythrocyte in sickle cell anemia is less than 20 days, compared with 120 days or

normal RBCs .

HbS contains 2 normal-globin chains and 2 mutant-globin chains in which

glutamate at position 6 has been replaced by valine

HbS is formed by the substitution of valine for glutamic acid in the second nucleotide of

the sixth codon of the -globin chain of HbA. This single-point mutation changes the

codon determining the amino acid from GAG coding for glutamic acid to GTG coding

for valine.

Erythrocytes containing mutant HbS have abnormal properties. Although the

mutant -hemoglobin subunits are normal in their ability to bind oxygen, they are

considerably less soluble in deoxygenated blood than normal hemoglobin. As such,and under conditions of low oxygen tension, interaction between the abnormal

valine residue and complementary regions on adjacent molecules results in the

formation of intracellular, rod-shaped polymers. These abnormal hemoglobin

polymers aggregate to disrupt the cytoskeleton and distort the shape of the

erythrocytes, making them brittle and poorly deformable. Thus, unlike normal

erythrocytes, the sickle-shaped cells cannot squeeze through the microcirculatory

vessels, blocking blood flow and resulting in local hypoxia

In addition to causing the obvious shape change, HbS is also injurious to the

erythrocyte membrane. The hemoglobin polymers disrupt the attachment of the

membrane to the protein cytoskeleton, resulting in exposure of transmembrane

protein epitopes and negatively charged glycolipids that are normally found insidethe cell. Subsequent effects of this exposure include cellular dehydration, oxidative

damage, increased adherence to endothelial cells, and a state of chronic

inflammation and hemolysis


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HOW SICKLING OCCUR:

In Hb S, the nonpolar amino acid valine has replaced the polar surface residue Glu6

of the subunit, genErating a hydrophobic sticky patch on the surface of the

subunit of both oxy Hb S and deoxy Hb SBoth Hb A and Hb S contain a complementary sticky patch on their surface that is

exposed only in the deoxygenated state. Thus a low pO2, deoxy Hb S can polymerize

to form long, insoluble fibers. Binding deoxy H A terminates fiber polymerization,

since Hb A lacks the second sticky patch necessary to bind another HB molecule

FIGURE: representation of sticky patch on hemoglobin S and its receptor on deoxyA

and deoxyS.

IN SICKLE CELL HEMOGLOBIN, VALINE REPLACES B6 GLU OF HbA CREATING A

STICKY PATCH THAT HAS A COMPLEMENT ON DEOXYHb. Deoxypolymerizes at low

concentrations forming a fibers that distort erythrocytes into the sickle shape.

When Hb S is fully oxygenated, it remains soluble in erythrocyte similar to Hb A,

maintaning a normal biconcave shape of RBCs.

On deoxygenation, however, Hb S in the RBCs become less soluble, forming liquid

crystals of Hb S polymers that grow in length beyond the diameter of the RBC and

causing sickling

Figure A shows normal red blood cells flowing freely in a blood vessel. The inset

image shows a cross-section of a normal red blood cell with normal hemoglobin.

Figure B shows abnormal, sickled red blood cells blocking blood flow in a bloodvessel. The inset image shows a cross-section of a sickle cell with abnormal (sickle)

hemoglobin forming abnormal strands.

Normal red blood cells are disc-shaped and look like doughnuts without holes in the

center. They move easily through your blood vessels. Red blood cells contain an

iron-rich protein called hemoglobin .This protein carries oxygen from the lungs to

the rest of the body.

Sickle cells contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S.

Sickle hemoglobin causes the cells to develop a sickle, or crescent, shape. These cells

stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and

organs. Blocked blood flow can cause pain and organ damage. It can also raise the

risk for infection

SICKLE CELL BY LIPPINCOTT

The replacement of the chraged glutamate with the nonpolar valine forms a

protrusion on the b globin that fits into a complementary site on the beta chain of

another hemoglobin molecule in the cell. At low OXYGEN TENSION,

DEOXYHEMOGLOBIN S POLYMERIZES INSIDE THE RBC, FORMING A NETWORK OR


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FIBROUS POLYMERS THAT STIFEEN AND DISTORT THE CELL PRODUCING RIGID,

MISSHAPEN ERYTHROCYTES. SUCH SICKLE CELLS FREQUENTLY BLOCKED THE

FLOW OF THE BLOOD IN CAPILLARIES. THE INTERRUPTION INSIDE THE OXYGEN

LEADS TO LOCALIZED ANOXIA (O2 DEPRIVATION) IN THE TISSUE AND CAUSING

PAIN AND EVENTUALLY DEATH OF CELLS IN THE VICINITY OF BLOCKAGE.

Heterozygotes have one normal and one sickle cell gene. The blood cells of such

heterozygotes contain HB S and HB A. These individuals have sickle cell trait but

usually do not show clinical symptoms and can have a normal life span.

How Sickle Cell Trait is Inherited

If both parents have SCT, there is a 50% (or 1 in 2) chance that any child of theirs

also will have SCT, if the child inherits the sickle cell gene from one of the parents.

Such children will not have symptoms of SCD, but they can pass SCT on to their

children. If both parents have SCT, there is a 25% (or 1 in 4) chance that any child of t heirswill have SCD. There is the same 25% (or 1 in 4) chance that the child will not have

SCD or SCT. If one parent has SCT, there is a 50% (or 1 in 2) chance that any child of this parent

will have SCT and an equal 50% chance that the child will not have SCT.

The signs and symptoms of sickle cell disease are caused by the sickling of red blood

cells

Supportive care has been the mainstay of therapy for SCD. The main foci of

supportive therapy include:

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