Lecture 1 Hemoglobin Structure and Function PDF

Faculty of Medicine Academic Year: 2024-2025 Year: 1 Semester:1 Module: BLOOD and body fluids (blf) 103  Hemoglobin Structure & Function By: Manar Yehia Lecturer at Ain Shams University Biochemistry and Molecular Department: Biol...

Faculty of Medicine Academic Year: 2024-2025 Year: 1 Semester:1 Module: BLOOD and body fluids (blf) 103  Hemoglobin Structure & Function By: Manar Yehia Lecturer at Ain Shams University Biochemistry and Molecular Department: Biology 12/28/2024 2 2  Objectives  Identify what are hemeproteins  Explain the general structure of hemoglobin and myoglobin.  Explain the different functions of hemoglobin  Explain the structure of heme group.  Describe the biochemical effect of 2, 3 BPG.  Illustrate the importance of inosine in blood banks. 12/28/2024 BLF - 103 3 3  Introduction Hemoglobin and myoglobin are hemeproteins whose physiological importance is principally related to their ability to bind molecular oxygen. 12/28/2024 BLF - 103 4 4  Hemoproteins - Hemeproteins are a group of specialized proteins that contain heme as a tightly bound prosthetic group. Protein Function Hemoglobin Transport of oxygen in blood Myoglobin Storage of oxygen in muscle Catalase Decomposition of H2O2 Peroxidase Decomposition of peroxides Cytochromes Components of respiratory chain Cytochrome P-450 Hydroxylation reactions Hemoglobin Heme globin hemoglobin  Hemoglobin functions 1. Oxygen Transport  Hemoglobin binds oxygen in the lungs where oxygen concentration is high.  Transports oxygen to tissues and organs where it is released for cellular respiration.  Each hemoglobin molecule can carry up to 4 oxygen molecules.  Hemoglobin functions 2. Carbon Dioxide Transport  Hemoglobin helps transport carbon dioxide, a waste product of metabolism, from tissues to the lungs.  Binds carbon dioxide directly or indirectly by buffering hydrogen ions (H+).  Facilitates its removal through exhalation.  Hemoglobin functions Buffering Blood pH  Hemoglobin acts as a buffer by binding to hydrogen ions (H+).  Helps maintain blood pH within a narrow range (7.35– 7.45).  Prevents acidosis or alkalosis, which can disrupt cellular functions.  Hemoglobin functions 1. Oxygen Transport  Hemoglobin binds oxygen in the lungs where oxygen concentration is high.  Transports oxygen to tissues and organs where it is released for cellular respiration.  Each hemoglobin molecule can carry up to 4 oxygen molecules.  Hemoglobin functions 2. Carbon Dioxide Transport  Hemoglobin helps transport carbon dioxide, a waste product of metabolism, from tissues to the lungs.  Binds carbon dioxide directly or indirectly by buffering hydrogen ions (H+).  Facilitates its removal through exhalation.  Hemoglobin functions Buffering Blood pH  Hemoglobin acts as a buffer by binding to hydrogen ions (H+).  Helps maintain blood pH within a narrow range (7.35– 7.45).  Prevents acidosis or alkalosis, which can disrupt cellular functions. 13 12/28/2024 Structure and Properties of Heme Condense 4 pyrole rings through methenyl bridges Incorporate Fe 2+ to form protoporphyrin IX  Structure and Properties of Heme Heme consists of a complex organic ring structure known as protoporphyrin IX to which is bound a single iron atom in its ferrous (Fe2+) state.  The iron atom has six coordination bonds 5th bond the fifth bond is bound to The sixth imidazole group of proximal bond will be Four of them bound to nitrogen atoms histidine amino acid in the 6th bound to that are part of the flat porphyrin ring. globin chain (His f8) bond oxygen In the same plane of the ring The remaining two bonds are perpendicular to the plane of protoporphyrin  The sixth position lies between FeII and another molecule of histidine termed distal histidine (His E7).  It is unoccupied in absence of O2. Structure and Properties of Heme. The coordinated nitrogen atoms help in preventing the conversion of the which does not bind O2 heme iron to the ferric (Fe3+) state Binding of Heme to the Polypeptide Chain: The heme group of myoglobin (and hemoglobin) is sequestered within a pocket, in the globin chain This burying of the heme within the globin pocket prevents a reaction that would occur with free heme in solution In which one O2 binds to two sandwiched heme groups and oxidizes iron to Fe3+.  Binding of Heme to the Polypeptide Chain: - Heme is attached to its polypeptide chain through:  The imidazole group of one histidine (His F8)  Hydrophobic interactions with the nonpolar amino acids.  What will occur when does O2 bind to heme The sixth coordination position of the ferrous atom becomes occupied with 6 66 oxygen. This leads to rupture of some of hydrogen and ionic bonds between α2β2 dimers forming the so called“ relaxed form”. Thus, 2 forms of Hb can be recognized (T form & R form).  O2 binding to heme O2 O2 O2 O2 O2 O2 O2 O2 Rupture of some of hydrogen and ionic bonds between α2β2 dimers forming the so called “relaxed form”. Two forms of hemoglobin: T form R form Deoxygnated Oxygenated Taut =tense Relaxed form More ionic and Less ionic bonds hydrogen bonds Dimer less mobile More mobile Lower affinity for Higher affinity for oxygen oxygen  Cooperative binding of oxygen The first O2 interacting with deoxyhemoglobin binds weakly because it binds to a subunit in the T state. Its binding facilitates binding of O2 to other subunits. Dissociation of the first O2 from fully oxygenated Hb will facilitate dissociation of other O2 molecules from other subunits. 25 12/28/2024 Types of normal hemoglobin: Fetal Hb -It is composed of 2 α and 2 γ chains (α2γ2 ) -It is the major hemoglobin found in the fetus and newborn -It gradually disappears after birth and replaced by HbA at age of 6 months. - It has higher affinity to O2 Adult hemoglobins 1-HbA1 - It is composed of 2 α and 2 β chains (α2 β2) - It represents 98% of adult hemoglobin - It is the major hemoglobin on adult 2-HbA2 - It is composed of 2 α and 2 δ chains (α2 δ2) - It represents 2% of adult hemoglobin - It is a minor hemoglobin - It appears 3 months after birth 3-HA1C - Under physiologic conditions, HbA is slowly and non- enzymically glycosylated (glycated). - The rate of formation of HbA1c is proportional to the average blood glucose concentration over the previous 3 months. - Normally it forms 4-6.5% of HBA1 - Used for follow up of diabetic patients over the past 3 months. https://www.shutterstock.com/search/a1c?image_type=vector Carbon Monoxide(CO) -CO increases the affinity of Hb to O2 : -Co reduces the amount of O2 through --When CO binds to one or competitive binding: more of the four heme sites, hemoglobin shifts to the R -- Carbon monoxide conformation, causing the (CO) binds tightly remaining heme sites to bind (but reversibly) to oxygen with high affinity. the hemoglobin iron, -- Thus, It reduces O2 delivery forming to the tissues (tissue anoxia). carboxyhemoglobin.  2,3 Bisphosphoglycerate (BPG) 2,3 Bisphosphoglycerate (BPG) Glycolytic intermediate in RBCs Binding of BPG decreases BPG binds in the cavity Stabilizes T-conformation so the affinity of Hb to oxygen between the two β-globin it promotes O2 delivery thus making Hb lose oxygen chains of Hb to the tissues easier  2,3 Bisphosphoglycerate (BPG) Fetal Hb (α2γ2) Has low affinity for BPG (NO β chains) &higher Fetal High Stored affinity for O2. Hb Altitude blood This allows fetus to compete for O2 with mother's Hb (α2 β 2) in placenta. RBCS must be supplemented with inosine to regenerate 2,3 BPG in stored blood Inosine It can cross the cell (hypoxyxanthine- membrane to enter the ribose): is an RBC uncharged molecule So, it restores the Its ribose is released, RBCs depleted stores phosphorylated and of 2,3 BPG converted to 2,3 BPG Thus, facilitates delivery of O2 to This is usually done at tissues when this blood banks). stored blood is transfused to patients Hemoglobin Myoglobin  Summary  Hb is a wise molecule  Hb is a heterotetrameric molecule  Mb is a monomeric molecule  Heme is an iron binding prothetic group  Hb structure suites its function  There are many types of Hb According to the types of polypeptide chains 12/28/2024 BLF - 103 33 33  Interactive Question What is the heme group in hemoglobin responsible for? a) Structural support b) Oxygen binding c) Carbon monoxide binding d) Protein binding 12/28/2024 BLF- 103 34 34  Interactive Question How many polypeptide chains does are present in a hemoglobin molecule? a) 1 b) 3 c) 4 d) 6 12/28/2024 BLF- 103 35 35  Interactive Question What is the primary function of hemoglobin in the body? a) Enzyme activity b) Oxygen transport c) Hormone signaling d) Immune response 12/28/2024 BLF- 103 36 36  References Lippincott’s Illustrated Biochemistry Reviews (2017), 7th edition 12/28/2024 BLF - 103 37 37