Biochemistry of Blood

Haemoglobin is a protein found in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues back to the lungs. It comprises two parts: haem and globin.

Porphyrins are cyclic compounds derived from the Porphin nucleus, which is composed of four pyrrole rings linked by four methenyl bridges. They play a crucial role in heme synthesis.

Type I Porphyrins have symmetrical arrangement of substituted groups in all four pyrrole rings, while Type III Porphyrins have the substituted group on the fourth pyrrole ring arranged in reverse order.

Iron is essential for Haemoglobin, present in its ferrous state. It binds to four Nitrogen atoms of the four pyrrole rings in the porphyrin molecule. The 5th and 6th coordination bonds allow Oxygen to attach and detach reversibly.

Globin is a simple protein composed of four polypeptide chains: two alpha chains and two beta chains. Each chain is folded into a helical structure, with alpha chains having seven helices and beta chains having eight helices.

The ratio of Haem to Globin in Haemoglobin is 4:1, meaning there are four Haem molecules for every one Globin protein molecule.

Major Adult Hb (Hb A1) is the most common type of Haemoglobin in adults, constituting about 95% of total Haemoglobin. It consists of two alpha chains and two beta chains.

The 5th coordination bond in Haemoglobin is with the N of the Imidazole ring of the proximal Histidine, while the 6th bond is with oxygen in HbO2, and remains empty in deoxy-Hb. These bonds are crucial for oxygen binding and release.

A minor adult hemoglobin consisting of 2 alpha chains and 2 delta chains, making up 2-4% of total Hb. It differs from Hb A in the beta chain at position 16, with glycine replaced by arginine.

A modified form of Hb A with glucose attached to the lysine at the N-terminal end of the beta chain. Its level reflects average blood glucose over the past 3 months and is useful in managing diabetes.

Hemoglobin found in newborns and fetuses, composed of 2 alpha chains and 2 gamma chains. It has higher affinity for oxygen due to gamma chains' lower binding to 2, 3 BPG.

An inherited blood disorder caused by a mutation in the beta chain, replacing glutamic acid with valine at position 6. This results in abnormal hemoglobin causing red blood cells to become sickle-shaped.

The valine substitution in HbS creates sticky patches that lead to polymerization of deoxy HbS molecules when blood is deoxygenated. This forms long, fibrous precipitates causing red blood cells to sickle.

Sickled red blood cells are fragile, leading to anemia, and easily trapped in small blood vessels causing thrombosis and damage to organs.

Diagnosis involves high reticulocyte counts, microscopic identification of sickle cells, and electrophoresis showing HbS instead of HbA.

HbS migrates slower on electrophoresis than normal Hb, appearing closer to the cathode due to its reduced negative charge.

A group of genetic disorders where the body doesn't produce enough alpha-globin chains for hemoglobin. This leads to a deficiency in functional hemoglobin.

A group of genetic disorders where the body doesn't produce enough beta-globin chains for hemoglobin. This leads to reduced hemoglobin production.

A type of α-Thalassemia where there are only β-globin chains in hemoglobin. The resulting HbH is unstable and causes hemolytic anemia.

A type of α-Thalassemia where only gamma-globin chains are present. This is severe and results in fetal hydrops and, often, death.

A condition where iron in hemoglobin is in its oxidized state (Fe³⁺), making the protein unable to carry oxygen effectively.

A condition where an individual is born with a mutation in their globin genes that prevents proper hemoglobin function.

Exposure to certain medications or chemicals that oxidize hemoglobin.

A system of enzymes and cofactors responsible for reducing Met Hb back to its normal, oxygen-carrying state.

Haem, also known as heme, is a porphyrin ring complex containing ferrous iron (Fe+2) that is essential for oxygen transport in red blood cells (RBCs). It is synthesized in both bone marrow and liver.

Haem synthesis takes place primarily in bone marrow (85%) for the production of hemoglobin and in the liver for the synthesis of cytochromes. The initial and final three enzymatic steps occur in mitochondria, while intermediate steps happen in the cytoplasm.

5-Aminolevulinic Acid (ALA) is a key precursor molecule in haem synthesis. It is synthesized from the amino acid glycine and succinyl CoA, with the involvement of the enzyme ALA synthase and pyridoxal phosphate (PLP).

Porphobilinogen (PBG) is an important intermediate in haem synthesis. Two molecules of ALA are joined together by the enzyme ALA dehydratase, releasing water in the process.

Tetrahydrofolic Acid (THF) is a coenzyme crucial for one-carbon metabolism. It acts as a carrier for one-carbon units in various metabolic pathways.

These one-carbon units play vital roles in: (1) biosynthesis of certain amino acids (glycine, serine, methionine, histidine); (2) purine biosynthesis; (3) synthesis of deoxythymidylic acid (dTMP).

Folate deficiency can be either primary (true) or secondary (due to vitamin B12 deficiency). It leads to macrocytic anemia (large, fragile red blood cells due to impaired DNA synthesis) and gastrointestinal disturbances.

Folic Acid, also known as Folacin or Pteroyl Glutamic Acid, is a vital nutrient that is converted into the coenzyme Tetrahydrofolic Acid (THF). THF plays a crucial role in one-carbon metabolism.

Pre Prothrombin is the inactive precursor form of Prothrombin, synthesized in the liver.

Vitamin K is essential for the carboxylation of glutamic acid to γ-carboxy glutamic acid in Pre Prothrombin, converting it to active Prothrombin.

γ-carboxy glutamic acid allows Prothrombin to bind to calcium, forming a complex that then binds to phospholipid membranes.

Calcium ions are necessary for Prothrombin to bind to phospholipid membranes, bringing it closer to where it needs to be activated.

Iron deficiency actually enhances iron absorption. The body tries to compensate for the lack of iron by absorbing more from the diet.

Phytates and Oxalates are compounds found in food that can inhibit iron absorption. They bind to iron and make it harder for the body to absorb.

DMT1 is a protein on the surface of intestinal cells that transports iron (Fe+2) into the cell.

Heme iron is absorbed directly into enterocytes by a specific transporter called the Heme Transporter (HT).

These are substances, like Methotrexate and Aminopterin, used to treat cancer. They stop the conversion of Folic Acid into Tetrahydrofolic Acid (THF), which is crucial for DNA synthesis in cells, thus hindering the growth of cancerous cells.

Vitamin B12 is essential for various bodily functions, including red blood cell formation and maintaining nerve health. It acts as a coenzyme in reactions involving the conversion of homocysteine to methionine and for the synthesis of myelin sheath.

Vitamin B12, bound to protein in food, is first released in the stomach through acid hydrolysis. Then, it binds to intrinsic factor (a protein secreted by the stomach) which carries it to the ileum for absorption.

A lack of B12 leads to pernicious anemia, characterized by large, immature red blood cells. It also causes neurological problems due to impaired myelin sheath formation, leading to sensory and motor deficits.

Plant foods lack B12. Animals and plants cannot produce it. B12 is synthesized by microorganisms in the intestines of animals, so animal products like liver, kidney, meat, milk, and eggs are excellent sources.

Trimethoprim is a folic acid antagonist used as an antibiotic. It inhibits bacterial growth by blocking the synthesis of tetrahydrofolic acid, a crucial molecule for DNA synthesis.

Vitamin K plays a vital role in blood clotting by activating several clotting factors (II, VII, IX, and X). These factors are necessary for the formation of a blood clot, preventing excessive bleeding.

Vitamin K1 is present in green leafy vegetables like spinach and cabbage, and vegetable oils. Vitamin K2 is synthesized by intestinal flora and found in animal tissues. Good sources also include tomatoes, cheese, egg yolk, and liver.