Essay: NORMAL HEMOGLOBIN STRUCTURE

Essay details:

  • Subject area(s): Science essays
  • Reading time: 21 minutes
  • Price: Free download
  • Published on: July 24, 2019
  • File format: Text
  • Number of pages: 2
  • NORMAL HEMOGLOBIN STRUCTURE Overall rating: 0 out of 5 based on 0 reviews.

Text preview of this essay:

This page of the essay has 1698 words. Download the full version above.

NORMAL HEMOGLOBIN STRUCTURE:
Hemoglobin is present in erythrocytes and is important for normal oxygen delivery to tissues. Hemoglobinopathies are disorders affecting the structure, function or production of hemoglobin.
Different hemoglobins are produced during embryonic, fetal and adult life. Each consists of a tetramer of globin polypeptide chains: a pair of ”-like chains 141 amino acids long and a pair of ”-like chains 146 amino acids long. The major adult hemoglobin, HbA has the structure ”2”2. HbF (”2”2) predominates during most of gestation and HbA2 (”2”2) is the minor adult hemoglobin.

Each globin chain surrounds a single heme moiety, consisting of a protoporphyrin IX ring complexed with a single iron atom in the ferrous state (Fe2+). Each heme moiety can bind a single oxygen molecule; a molecule of hemoglobin can transport up to four oxygen molecules as each hemoglobin contains four heme moieties.
The amino acid sequences of various globins are highly homologous to one another and each has a highly helical secondary structure. Their globular tertiary structures cause the exterior surfaces to be rich in polar (hydrophilic) amino acids that enhance solubility and the interior to be lined with nonpolar groups, forming a hydrophobic pocket into which heme is inserted Numerous tight interactions (i.e.,”1”1 contacts) hold the ” and ” chains together. The complete tetramer is held together by interfaces (i.e., ”1”2 contacts) between the ”-like
chain of one dimer and the non-” chain of the other dimer. The hemoglobin tetramer is highly soluble, but individual globin chains are insoluble. (Unpaired globin precipitates, forming inclusions that damage the cell and can trigger apoptosis. Normal globin chain synthesis is balanced so that each newly synthesized ” or non-” globin chain will have an available partner with which to pair.)

FUNCTION OF HEMOGLOBIN:
Solubility and reversible oxygen binding are the two important functions which were deranged in hemoglobinopathies. Both depend mostly on the hydrophilic surface amino acids, the hydrophobic amino acids lining the heme pocket, a key histidine in the F helix and the amino acids forming the ”1”1 and ”1”2 contact points. Mutations in these strategic
regions alter oxygen affinity or solubility.
Principal function of Hb is to transport oxygen and delivery to tissue which is represented most appropriately by oxygen dissociation curve (ODC).

Fig: The well-known sigmoid shape of the oxygen dissociation curve (ODC), which reflects the allosteric properties of haemoglobin.
Hemoglobin binds with O2 efficiently at the partial pressure of oxygen (Po2) of the alveolus, retains it in the circulation and releases it to tissues at the Po2 of tissue capillary beds. The shape of the curve is due to co-operativity between the four haem molecules. When one takes up oxygen, the affinity for oxygen of the remaining haems of the tetramer increases dramatically. This is because haemoglobin can exist in two configurations – deoxy (T) and oxy (R). The T form has a lower affinity than the R form for ligands such as oxygen.
Oxygen affinity is controlled by several factors. The Bohr effect (e.g. oxygen affinity is decreased with increasing CO2 tension) is the ability of hemoglobin to deliver more oxygen to tissues at low Ph. The major small molecule that alters oxygen affinity in humans is 2,3-bisphosphoglycerate (2,3-BPG; formerly 2,3-DPG) which lowers oxygen affinity when bound to hemoglobin. HbA has a reasonably high affinity for 2,3-BPG. HbF does not bind 2,3-BPG, so it tends to have a higher oxygen affinity in vivo. Increased levels of DPG, with an associated decrease in P50 (partial pressure at which haemoglobin is 50 per cent saturated), occur in anaemia, alkalosis, hyperphosphataemia, hypoxic states and in association with a number of red cell enzyme deficiencies.
Thus proper oxygen transport depends on the tetrameric structure of the proteins, the proper arrangement of hydrophilic and hydrophobic amino acids and interaction with protons or 2,3-BPG.
GENETICS OF HEMOGLOBIN:

The human hemoglobins are encoded in two tightly linked gene clusters; the ”-like globin genes are clustered on chromosome 16, and the ”-like genes on chromosome 11. The ”-like cluster consists of two ”-globin genes and a single copy of the ” gene. The non-” gene cluster consists of a single ” gene, the G” and A” fetal globin genes, and the adult ” and ” genes. The ”-like cluster consists of two ”-globin genes and a single copy of the ” gene. The non-” gene cluster consists of a single ” gene, the G” and A” fetal globin genes, and the adult ” and ” genes.
DEVELOPMENTAL BIOLOGY OF HUMAN HEMOGLOBINS:
Red cells first appearing at about 6 weeks after conception contain the embryonic hemoglobins Hb Portland (”2”2), Hb Gower I (”2”2) and Hb Gower II (”2”2). At 10’11 weeks, fetal hemoglobin (HbF; ”2”2) becomes predominant and synthesis of adult hemoglobin (HbA; ”2”2) occurs at about 38 weeks. Fetuses and newborns therefore require ”-globin but not ”-globin for normal gestation. Small amounts of HbF are produced during postnatal life. A few red cell clones called F cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF. Profound erythroid stresses, such as severe hemolytic anemias, bone marrow transplantation, or cancer chemotherapy, cause more of the F-potent BFU-e to be recruited. HbF levels thus tend to rise in some patients with sickle cell anemia or thalassemia. This phenomenon probably explains the ability of hydroxyurea to increase levels of HbF in adult and agents such as butyrate and histone deacetylase inhibitors can also activate fetal globin genes partially after birth.
HEMOGLOBINOPATHIES:
Hemoglobinopathies are disorders affecting the structure, function or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. Different forms may present as hemolytic anemia, erythrocytosis, cyanosis or vaso-occlusive stigmata.
Structural hemoglobinopathies occur when mutations alter the amino acid sequence of a globin chain, altering the physiologic properties of the variant hemoglobins and producing the characteristic clinical abnormalities. The most clinically relevant variant hemoglobins polymerize abnormally as in sickle cell anemia or exhibit altered solubility or oxygen-binding affinity.
Thalassemia syndromes arise from mutations that impair production or translation of globin mRNA leading to deficient globin chain biosynthesis. Clinical abnormalities are attributable to the inadequate supply of hemoglobin and imbalances in the production of individual globin chains, leading to premature destruction of erythroblasts and RBC. Thalassemic hemoglobin
variants combine features of thalassemia (e.g., abnormal globin biosynthesis) and of structural hemoglobinopathies (e.g., an abnormal amino acid sequence).
Hereditary persistence of fetal hemoglobin (HPFH) is characterized by synthesis of high levels of fetal hemoglobin in adult life. Acquired hemoglobinopathies include modifications of the hemoglobin molecule by toxins (e.g., acquired methemoglobinemia) and clonal abnormalities of hemoglobin synthesis (e.g., high levels of HbF production in preleukemia and ” thalassemia in myeloproliferative disorders).

There are five major classes of hemoglobinopathies.
Classification of hemoglobinopathies:
CLASS HEMOGLOBINOPATHIES
1 Structural hemoglobinopathies’hemoglobins with altered amino acid sequences that result in deranged function or altered physical or chemical properties

A. Abnormal hemoglobin polymerization’HbS, hemoglobin sickling

B. Altered O2 affinity

1. High affinity’polycythemia

2. Low affinity’cyanosis, pseudoanemia

C. Hemoglobins that oxidize readily

1. Unstable hemoglobins’hemolytic anemia, jaundice

2. M hemoglobins’methemoglobinemia, cyanosis
2 Thalassemias’defective biosynthesis of globin chains

A. ” Thalassemias

B. ” Thalassemias

C. ”, ”, ” Thalassemias
3 Thalassemic hemoglobin variants’structurally abnormal Hb associated
with coinherited thalassemic phenotype

A. HbE

B. Hb Constant Spring

C. Hb Lepore
4 Hereditary persistence of fetal hemoglobin’persistence of high levels of
HbF into adult life
5 Acquired hemoglobinopathies

A. Methemoglobin due to toxic exposures

B. Sulfhemoglobin due to toxic exposures

C. Carboxyhemoglobin

D. HbH in erythroleukemia

E. Elevated HbF in states of erythroid stress and bone marrow dysplasia
TABLE 127

GENETICS OF SICKLE HEMOGLOBINOPATHY:
This genetic disorder is due to the mutation of a single nucleotide, from a GAG to GTG codon on the coding strand, which is transcribed from the template strand into a GUG codon. Based on genetic code, GAG codon translates to glutamic acid while GUG codon translates to valine amino acid at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of hemoglobin in conditions of normal oxygen concentration. But under conditions of low oxygen concentration, the deoxy form of hemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic side chain of the valine residue at position 6 of the beta chain in hemoglobin is able to associate with the hydrophobic patch, causing hemoglobin S molecules to aggregate and form fibrous precipitates. It also exhibits changes in solubility and molecular stability.
These properties are responsible for the profound clinical expressions of the sickling syndromes.
‘ HbSS disease or sickle cell anemia (the most common form) – Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival
‘ HbS/”0 thalassemia – Double heterozygote for HbS and b-0 thalassemia; clinically indistinguishable from sickle cell anemia (SCA)
‘ HbS/”+ thalassemia – Mild-to-moderate severity with variability in different ethnicities
‘ HbSC disease – Double heterozygote for HbS and HbC characterized by moderate clinical severity
‘ HbS/hereditary persistence of fetal Hb (S/HPHP) – Very mild or asymptomatic phenotype
‘ HbS/HbE syndrome – Very rare with a phenotype usually similar to HbS/b+ thalassemia
‘ Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia and HbO Arab
Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of hemoglobin a person makes in the red blood cells depends on what hemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of having sickle-cell trait. When both parents have sickle-cell trait, a child has a 25% chance of sickle-cell disease, 25% do not carry any sickle-cell alleles, and 50% have the heterozygous condition.
The allele responsible for sickle-cell anemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Several sickle syndromes occur as the result of inheritance of HbS from one parent and another hemoglobinopathy, such as ” thalassemia or HbC (”2”2 6 Glu’Lys), from the other parent. The prototype disease, sickle cell anemia, is the homozygous state for HbS.

...(download the rest of the essay above)

About this essay:

This essay was submitted to us by a student in order to help you with your studies.

If you use part of this page in your own work, you need to provide a citation, as follows:

Essay Sauce, NORMAL HEMOGLOBIN STRUCTURE. Available from:<https://www.essaysauce.com/science-essays/normal-hemoglobin-structure/> [Accessed 23-09-19].

Review this essay:

Please note that the above text is only a preview of this essay.

Name
Email
Rating
Comments (optional)

Latest reviews: