Hemoglobin Structure & Function Lecture Notes PDF

Structure, Functions & Types of Hemoglobin Dr. Mehtab Alam Associate Professor Department of Bioscience Muhammad Ali Jinnah University, Karachi, Pakistan  Hemoglobin  Globular protein  Transpo...

Structure, Functions & Types of Hemoglobin Dr. Mehtab Alam Associate Professor Department of Bioscience Muhammad Ali Jinnah University, Karachi, Pakistan  Hemoglobin  Globular protein  Transport protein  Chromoprotein  Metalloprotein Structural levels of hemoglobin  Structural aspects of hemoglobin Molecular weight of hemoglobin (human)—67000 Dalton Normal concentration of hemoglobin(male)—14-16 gm % Normal concentration of hemoglobin(female)—13-15gm % Hemoglobin =heme + globin (TOTAL 574 amino acids ) Normal hemoglobin ⁓ 97% HbA +2% Hb A2 + 1% HbF Globin Structure of HbA (97% ) - 2 alpha chains + 2 beta chains Alpha chain (each )–141 amino acids Beta chain (each ) -146 amino acids Hb F ( < 2% ) = 2 ALPHA chains +2 GAMMA chains Hb A2 ( < 5% ) = 2 ALPHA chains +2 delta chains Subunits held by non covalent interactions, hydrophobic interactions, ionic interactions  Hemoglobin Structure Non protein part = Heme Protein part = Globin  Quaternary Structure of Hemoglobin  Hemoglobin tetramer is composed of two identical dimers, α1β1 and α2β2  The two globin chains within each dimer are held tightly together by inter chain hydrophobic interactions between α and β subunits.  The two dimers are held together primarily by polar bonds and able to move with respect to each other.  The weaker interactions between these mobile dimers result in two different relative positions in Deoxyhemoglobin compared to Oxyhemoglobin  Structure of Hemoglobin Tetrameric structure Helical structure Tetramer: Haemoglobin is a tetramer composed of four polypeptide chain and four heme groups. α chain consist of 141 amino acids β chains has 146 amino acids Alignment of alpha (141 aa) and beta globin (146 aa)  Helical Structure 8-helical segments A-H  Helical Structure Iron of heme is covalently binds to histidine at helical position F on H  Globin Chains  There are four globin chains in each molecule of adult hemoglobin (Hb-A)  These are designated as α and β  There are two α (α1 α2) and two β (β1 β2) chains  These four chains form two dimers i.e. α1 β1 and α2 β2  PROXIMAL (F8) & DISTAL (E7) HISTIDINE  Hemoglobin has a relatively hydrophilic surface and hydrophobic interior.  Polar amino acids are located almost exclusively on the exterior surface of globin polypeptide chain while the hydrophobic amino acids are buried within the interior.  The only exception to this are two histidine residues termed as proximal histidine (F8) and distal histidine (E7)  They play indispensible role in heme pocket and function in oxygen binding  PROXIMAL (F8) & DISTAL (E7) HISTIDINE F8 Histidine E7 Histidine VARIOUS HELICES OF GLOBIN POLYPEPTIDE CHAIN  Structure of Heme  Heme is a cyclic tetrapyrrole i.e. consists of four molecules of pyrrole.  This imparts a red color T OR TAUT FORM R OR RELAXED FORM  This is the De-oxy form of  This is the Oxy form of hemoglobin hemoglobin  The two αβ dimers are tightly  Binding of oxygen to Hb causes interact trough ionic and rupture of ionic & hydrogen bonds hydrogen bonds and constrains b/w dimers and have more the movement of dimers freedom of movement  This is a low oxygen affinity  This is a high oxygen affinity form of hemoglobin form of hemoglobin Bondings in R and T conformations of Hb Structural changes in oxy and deoxy hemoglobin Structural changes assist in cooperative binding of O2  OXYGENATION OF HEMOGLOBIN  The oxygen binding characteristics of hemoglobin change in response to binding of various allosteric modulator. The partial pressure of O2 pH of the surrounding medium Presence of 2,3-diphosphoglycerate OXYGENATION OF HEMOGLOBIN Loading and unloading of Oxygen  Deoxyhemoglobin binds one proton for every two molecules of oxygen released  The slight lower pH in the tissues stabilizes the T state and enhances the O2 delivery.  In lungs the process reverses, as O2 binds to deoxyhemoglobin protons are released and combine with bicarbonate to form carbonic acid.  Iron in heme  Ferrous state (Fe ⁺² -reduced form of iron)  Attached to Six coordinated bonds = 4 coordinated bonds planer + 1 coordinated bond linked to O₂ + 1 coordinated bond linked to His (64 ) of α or β globin chain  Undergoes Fe ⁺² reduced form ↔ Fe ⁺³ oxidized form  Heme is a constituent of Hemoglobin, catalase, cytochromes, chlorophylls, Tryptophan pyrrolase. Orientation of iron  FUNCTIONS OF HEMOGLOBIN  Transport of O2 from lungs to tissues  Transport of CO2 and H+ from tissues to the lungs for excretion  Act as a buffer  Hemoglobin is also found outside red blood cells and their progenitor lines. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism.  NON-PATHOLOGICAL VARIANTS OF HEMOGLOBIN In the embryo;  Gower 1 (δ2ε2)  Gower 2 (α2ε2)  Hemoglobin Portland (δ2γ2) In the fetus:  Hemoglobin F (α2γ2) In adults:  Hemoglobin A(α2β2) The most common with a normal amount over 95%  Hemoglobin A2(α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal range of 1.5-3.5%  Hemoglobin F(α2γ2) - In adults, Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia ANY QUESTION ???