Hemoglobin

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Introduction

Hemoglobin is the oxygen-carrying protein present in animals. It is a globular protein belonging to the group of hemeproteins. Such globular proteins have a heme group tightly bound to the protein structure. The function performed by the heme group depends upon the structure of the protein. In hemoglobin, heme group serves to bind oxygen molecules.

Hemoglobin is responsible for carrying oxygen from the air in the lungs to all the cells in the body via red blood cells present in the blood. It also performs several other roles to maintain homeostasis. In this article, we will discuss the structure of hemoglobin, its synthesis, and degradation, the role of hemoglobin in the human body as well as the major clinical conditions associated with it.

Structure

Hemoglobin is a protein having a globular structure. Based on its structural properties, hemoglobin can be divided into two parts; a protein part and a heme group.

The structure of the protein part can be studied at four levels; primary structure, secondary structure, tertiary structure, and quaternary structure.

Primary Structure

Recall that the primary structure of proteins deals with the number and sequence of amino acids in a polypeptide chain. One molecule of hemoglobin is made up of four polypeptide chains; two alpha chains and two beta chains.

The number of amino acids is different in both types of polypeptide chains.

  • Each alpha chain contains 141 amino acids.
  • Each beta chain contains 146 amino acids.

Thus, a total of 574 amino acids are present in one molecule of amino acid. The sequence of amino acids in alpha chains is different than that of the beta chain. Any disturbance in the normal sequence of amino acids impairs the normal functioning of hemoglobin.

Secondary Structure

Secondary structure deals with the stable structures formed by polypeptide chains. In the structure of hemoglobin, each alpha and beta chain has an alpha-helical structure. These alpha helices are held together via hydrogen bonding. They are terminated by the presence of either proline amino acid or by beta bends and loops connecting the different helices.

Tertiary Structure

The tertiary structure involves the folding of polypeptide chains. Alpha and beta chains undergo folding to attain a globular shape. This folding of polypeptide chains occurs in such a way that the hydrophilic amino acids are exposed on the surface of the molecule while the hydrophobic amino acids are buried inside the globular structure. The hemoglobin molecule thus formed is composed of four subunits and thus, is called a tetramer.

Quaternary Structure

The quaternary structure involves the arrangement of multiple polypeptide chains within the same molecule. One hemoglobin molecule is made up of four subunits and thus, is called a tetramer. Hemoglobin tetramer is considered to be composed of two identical dimers.

Each dimer is formed by one alpha chain and one beta chain. The two chains within each dimer are held together via hydrophobic interactions.

On the other hand, the two dimers are linked to one another via weak polar interactions. These weak attractive forces allow the dimers to move relative to one another. As a result, the two dimers occupy different positions in oxygenated and deoxygenated forms of hemoglobin.

Based on the oxygenation status, hemoglobin can have the following two forms;

  • T form: The ‘T’ or taut (tense) is the deoxy form of hemoglobin. During this state, the two dimers are held together via ionic and hydrogen bonds. These bonds limit the movement of the polypeptide chains, thus called the taut or tense (T) form.
  • R form: The oxygenated form of hemoglobin is called the ‘R’ (relaxed) form. When oxygen binds to a molecule of hemoglobin, it causes the breaking of weaker polar forces among the two dimers. This allows the polypeptide chains to undergo some movement, thus called the relaxed (R) form.

These two forms of hemoglobin are interchangeable.

Structure of Heme

Heme is the most important structural component of hemoglobin. It is complex formed by protoporphyrin IX and a ferrous ion (Fe+2). It is a planar cyclic compound having one ferrous ion at its center. This ferrous ion can form two additional bonds, one with the oxygen molecule and one with the amino acid. These bonds are formed on two sides of the planar protoporphyrin ring. 

One heme group is coupled with each polypeptide chain in hemoglobin. It is attached to the alpha or beta chain via a bond between ferrous ion and the side chain of histidine. Thus, four heme groups are present in one molecule of hemoglobin. Therefore, one hemoglobin molecule carries four molecules of oxygen.

Synthesis

Hemoglobin synthesis takes place within the erythrocyte producing cells of the bone marrow. It involves the synthesis of the polypeptide chains (globin synthesis) as well as the synthesis of heme groups (heme synthesis).

Globin Synthesis

The alpha and beta globin chains are made via the process of protein synthesis. The information about these polypeptide chains is present in the DNA of the red blood cells. 

The synthesis of the protein part of hemoglobin involves two steps;

  • Copying of the information present in the gene in the form of messenger RNA. The mRNA copies of the gene are made by RNA polymerase 2 in a process called transcription. Once the mRNA molecule has undergone post-transcriptional changes, it moves out of the nucleus into the cytoplasm of the cell. Here, it is acted upon by the protein manufacturing machinery of the cell.
  • The second step involves translating the information present in the mRNA to the sequence of amino acids in the polypeptide chains. The codons on the mRNA are read by the tRNA on the surface of the ribosomes and complementary amino acids are added making a polypeptide chain. Once a termination codon is reached, the polypeptide chain is released from the translation complex.

The genes for alpha-globin chains are present on chromosome 16 while those for beta-globin chains are present on chromosome 11. There are two alpha genes on chromosome 16 while only one beta gene is present on chromosome 11.

The alpha and beta chains formed by the above process undergo further structural modifications as discussed earlier.

Heme Synthesis

The synthesis of the heme group majorly occurs in the bone marrow (up to 85%). It is also synthesized in the liver, the site of production of various other heme proteins like myoglobin and cytochromes, etc.

The process of heme synthesis begins with glycine and succinyl CoA to form Aminolaevulinic acid (ALA). It is further modified via various intermediate reactions to finally form heme.

The first reaction and the last three reactions of this series take place within the mitochondria of the cell. The rest of the steps take place in the cytosol.

One heme group is associated with each alpha and beta chain via its ferrous ion and a molecule of hemoglobin is formed.

The mature red blood cells lack the mitochondria and thus cannot make hemoglobin.

Types of Hemoglobin

It is important to remember that hemoglobin is a family of related proteins. Humans have different types of hemoglobin that are present in the body during the different phases of life. All these hemoglobin forms are tetramers having four polypeptide chains. The four important types of hemoglobin in humans are as follows;

  • HbA or hemoglobin A is the major hemoglobin present in our body. It is composed of two alpha chains and two beta chains. It is also called the adult hemoglobin. More than 90% of hemoglobin in an adult human is HbA.
  • HbF or hemoglobin F is called the fetal hemoglobin. It has two alpha chains and two gamma chains. It is the major hemoglobin during fetal life. after birth, the gamma-globin chains can no longer be made, and its concentration drops. In an adult human, the concentration of HbF is only 2% of the total hemoglobin.
  • HbA2 is made up of two alpha chains and two delta chains. In an adult human, it comprises 2% to 5% of the total hemoglobin in the body.
  • HbA1C is one of the many glycosylated hemoglobin present in the body. It is made up of two alpha and two beta chains but is in glycosylated form. Its concentration varies from 3%-9% of the total hemoglobin in our body. HbA­1C also indicates the blood glucose levels in the past three months.

Functions

In this section, we will discuss the major functions performed by hemoglobin in the human body.

Oxygen Transport

It is the most important function of hemoglobin in our bodies. Hemoglobin is the oxygen-carrying pigment in the red blood cells that transports oxygen from the air in the lungs to the tissue fluid around the cells.

Recall that one molecule of hemoglobin can bind four molecules of oxygen. One oxygen molecule is attached to each of the four heme groups present in hemoglobin.

The four heme groups present in hemoglobin demonstrate cooperative oxygen binding. The binding of oxygen to one heme group increases the oxygen affinity of other heme groups present in the same hemoglobin molecule. This effect is known as the heme-heme interaction.

The oxygen molecules are not permanently bound to the heme groups. Rather, hemoglobin reversibly binds the oxygen molecules meaning that oxygen can be released and bind again to the heme groups any time.

The oxygen affinity of hemoglobin depends upon the following factors;

  • Partial pressure of oxygen (direct relationship)
  • Partial pressure of carbon dioxide (indirect relationship)
  • pH of the environment (direct relationship)
  • Availability of 2,3-bisphosphoglycerate (indirect relationship)

When the blood passed through the lungs having a much greater partial pressure of oxygen, the oxygen affinity of hemoglobin increases, and it readily binds the oxygen molecules.

As the partial pressure of carbon dioxide is higher in the tissue fluid, the oxygen affinity of hemoglobin decreases and oxygen molecules are released in the tissues.

Buffer Effect

Hemoglobin is an important extracellular buffer in the human body. It helps to regulate the pH of the blood by a process known as Bohr’s effect.

The carbon dioxide produced as a result of metabolism reacts with water to form carbonic acid. The carbonic acid disassociates to release hydrogen ions. These hydrogen ions bind to the amino acid side chains in hemoglobin. This causes the hemoglobin to release oxygen in the metabolizing tissues.

The hydrogen ions are thus buffered by the hemoglobin that prevents any decrease in the pH of the blood. If the buffering effect of hemoglobin is not present, cellular metabolism will result in decreasing the pH of the blood.

Transport of Carbon dioxide

Another important function of hemoglobin is its role in the transport of carbon dioxide. Recall that carbon dioxide formed as a result of metabolism is immediately converted into carbonic acid by reacting with water. The protons of the carbonic acid are buffered by hemoglobin while the bicarbonate ions dissolve in the blood.

Carbon dioxide is carried to the lungs in the form of bicarbonate ions. When the blood reaches the lungs, the increased partial pressure of oxygen displaces the hydrogen ions from hemoglobin. These hydrogen ions combine with bicarbonate ions to form carbonic acid. The carbonic acid is acted upon by the carbonic anhydrase enzyme which cleaves the acid into water and carbon dioxide.

The partial pressure of carbon dioxide in the blood is greater than that in the air. It diffuses from the blood in the lungs to the air present in the air sacs.

Besides this indirect role, hemoglobin also transports a small amount of carbon dioxide directly bound to its globin chains. This form of hemoglobin is known as carbaminohemoglobin.

Source of Heme Intermediates

Hemoglobin provides important heme intermediates such as bilirubin and biliverdin etc.  upon degradation. Red blood cells in the human body have an average life span of 120 days. Once the RBCs are destroyed, hemoglobin is broken down by enzymes to form heme and globin. The globin part is recycled while the heme portion undergoes further processing to give physiologically important intermediates.

These intermediates are discussed under the heading of degradation.

Degradation

Once the red blood cells have completed their life span, they are taken up by the cells of the reticuloendothelial system majorly in the liver and spleen. These cells destroy red blood cells and hemoglobin undergoes degradation.

The heme and the globin parts are separated. The globin chains are either recycled or broken down into individual amino acids by the action of proteases enzymes.

The heme groups are degraded to0 form bilirubin by the microsomal enzymes in the macrophages. Heme degradation involves the following steps;

  • Heme oxygenase enzyme converts heme into biliverdin
  • Biliverdin reductase enzyme reduces biliverdin to form bilirubin

The bilirubin thus formed is released into the blood. As bilirubin is water-insoluble, it is immediately bound by albumin to form a bilirubin-albumin complex. This complex transports bilirubin to the hepatocytes where it is converted into water-soluble bilirubin diglucuronide. The bilirubin diglucuronide is then released into the bile.

Bilirubin is converted into some other metabolites as it passes through the digestive system.

Clinical Conditions

Hemoglobin is an essential compound for the life of an individual as it performs a primary role in the exchange and transport of gases. The following are some important clinical conditions associated with it.

Sickle Cell Anemia

Anemia is a condition in which the hemoglobin concentration in the body is less than the normal. There are multiples types of anemia resulting from various reasons. One very common type of anemia is sickle cell anemia.

It is a genetic disorder in which one of the amino acids in the beta-globin chain of hemoglobin is misplaced. This misplaced amino acid introduces a grove in the hemoglobin molecule. As a result, hemoglobin molecules tend to precipitate in the deoxygenated state to form piles or stacks. These precipitates cause the sickling of the red blood cells that are unable to squeeze through the small capillaries and are ruptured. The oxygen-carrying capacity of such individuals is much decreased.

Thalassemia

It is another genetic disorder of the blood in which an imbalance occurs between the globin chains. Normally, the synthesis of alpha and beta chains are coordinated so that each alpha-chain has a partner beta-chain.

In thalassemia, the synthesis of one of the chains is decreased causing an imbalance between the globin chains. Different types of thalassemia are as follows;

  • Alpha Thalassemia: The synthesis of alpha chains is decreased or absent.
  • Beta Thalassemia: The synthesis of beta chains is decreased or absent.

Thalassemia patients need regular blood transfusions to continue their life.

Summary

Hemoglobin is the oxygen-carrying pigment present in the red blood cells.

It is a tetramer having two alpha chains and two beta chains. It is considered to be made up of two dimers, each dimer including one alpha and one beta chain.

One heme group is associated with each polypeptide chain. Oxygen molecules bind the ferrous ion of these heme groups.

The synthesis of hemoglobin takes place in the erythrocyte producing cells of the bone marrow. Mitochondria are required for the synthesis of the heme group.

Four important types of hemoglobin present in humans are;

  • Hemoglobin A
  • Hemoglobin F
  • Hemoglobin A2
  • Hemoglobin A1C

Hemoglobin is involved in;

  • Transport of oxygen
  • Transport of carbon dioxide
  • Regulation of blood pH via Bohr’s Effect
  • Providing physiologically important heme intermediates

Hemoglobin is broken down by the macrophages after the red blood cells have completed their life span.

The important clinical conditions associated with hemoglobin include various types of anemia and thalassemia.

References

  1. Maton, Anthea; Jean Hopkins; Charles William McLaughlin; Susan Johnson; Maryanna Quon Warner; David LaHart; Jill D. Wright (1993). Human Biology and Health. Englewood Cliffs, New Jersey, US: Prentice Hall. ISBN 978-0139811760
  2. Costanzo, Linda S. (2007). Physiology. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 978-0781773119.
  3. Patton, Kevin T. (2015-02-10). Anatomy and Physiology. Elsevier Health Sciences. ISBN 9780323316873Archived from the original on 2016-04-26. Retrieved 2016-01-09.
  4. Epstein, F. H.; Hsia, C. C. W. (1998). “Respiratory Function of Hemoglobin”. New England Journal of Medicine. 338 (4): 239–47. doi:10.1056/NEJM199801223380407PMID 9435331.