L1-Structure and Function of Haemoglobin PDF

L1: Structure and function of haemoglobin GNT Block Color Index: • • • • • • Main text Female slides Male slides Important Doctor’s notes Extra notes Editing file: Objectives: The structure and function of hemoglobin The factors affecting oxygen binding to hemoglobin Examples of normal and ab...

L1: Structure and function of haemoglobin GNT Block Color Index: • • • • • • Main text Female slides Male slides Important Doctor’s notes Extra notes Editing file: Objectives: The structure and function of hemoglobin The factors affecting oxygen binding to hemoglobin Examples of normal and abnormal hemoglobin structures Lecture presented by : Dr. Sumbul Fatma Dr. Zeyad Kurdee Hemoglobin A hemeprotein found only in red blood cells protein part (Globin chain)and non protein part (heme group - attach) Female Dr: Actually hemeproteins are aslo found in Cytochromes & Catalase Oxygen transport function Contains heme as prosthetic group Heme reversibly binds to oxygen (It’s important for binding to oxygen -Load- then release it -unload- in the tissue) The heme group ● ● ● ● ● A-complex of protoporphyrin IX and ferrous iron(Fe2+) Fe2+ is present in the center of the heme Fe2+ binds to four nitrogen atoms of the porphyrin ring Forms two additional bonds with: 1-Histidine residue of globin chain 2-Oxygen Thus making 6 bond in total Fe2+ binds to six molecules because it’s in binds to 6 different molecules. ferrous state: Four nitrogen atoms of the porphyrin ring. Histidine residue of globin chain Oxygen Hemoglobin types Normal Hemoglobin We call them normal because they can bind to oxygen Form Chain composition Fraction of total hemoglobin HbA α2β2 90% HbA1c α2β2-Glucose 3% - 9% HbF α2γ2 <2% HbA2 α2δ2 2%-5% Abnormal Hemoglobin unable to transport oxygen due to abnormal structure They can’t bind to oxygen (For example Met-Hb and Sulf-Hb), or they can’t release oxygen (For example Carboxy-Hb) Carboxy-Hb CO replaces O2 and binds 220X tighter than O2 (in smokers) (reversible) (that’s why they have difficulty in breathing sometimes) Met-Hb Contains oxidized Fe+3 (∼2%) that cannot carry O2 (reversible) Can only form 5 bonds Sulf-HB Forms due to high sulfur level in blood(irreversible reaction) (Maybe caused by drugs that increasing the in sulfur) HbA It is the major Hb in adults Composed of 4 polypeptide chains: ○ 2 α chains and 2 β chains Contains 2 dimers of αβ subunits, held together by noncovalent interactions A hemoglobin molecule contains 4 heme groups and carries 4 molecules of O2 or 8 atoms of O Each chain is a subunit with a heme group in the center that carries oxygen There are two types of bonding in the HbA structure: ● Intra-dimer bonding: strong bonds between 2 subunits (between α and β) (hydrophobic bond) ● Inter-dimer bonding: weak bonds between 2 dimers (between αβ and αβ) T-Form (Found in tissues ) R-Form (Found in lung) Deoxy form of Hb Oxygenated form of Hb “Taut” or “Tense” form Relaxed form The movement of dimers is constrained Dimers have more freedom of movement Low oxygen affinity form High oxygen affinity form Hemoglobin function ● ● ● Hemoglobin carries oxygen from the lungs to tissues Hemoglobin carries some carbon dioxide (In form of carbaminohemoglobin) and protons from tissues back to the lung Normal level of hemoglobin (g/dL) Male: 14-16 (g/dL) Female: 13-15 (g/dL) (Menstrual cycle is the reason that female has less Hb) factors affect O2 binding four allosteric effectors: ( bind to Hb and modify O2 binding capacity) 1. PO2 (partial O2 pressure) 2. PH of the environment 3. PCO2 ( partial CO2 pressure) 4. Availability of 2,3-bisphosphoglycerate (2,3BPG) O2 dissociation curve ● ● ● ● The curve is sigmoidal in shape (S shaped curve), It indicates cooperation of subunits in O2 binding. Binding of O2 to one heme group increases O2 affinity of others (hence the term cooperation) Heme-heme interaction Oxygen dissociation curve Oxygen-dissociation curve for hemoglobin is sigmoidal in shape indicating that the subunits cooperate in binding oxygen. Cooperative binding of oxygen by the four subunits of hemoglobin means that the binding of an oxygen molecule at one heme group increases the oxygen affinity of the remaining heme groups in the same hemoglobin tetramer . This effect is referred to as heme–heme interaction . Although it is more difficult for the first oxygen molecule to bind to hemoglobin, the subsequent binding of oxygen occurs with high affinity, as shown by the steep upward curve in the region near 20–30 mmHg P50 Video Indicates affinity of Hb to O P50(mm Hg): the pressure which Hb is 50% saturated with O High affinity (left shift) → slow unloading of O Low affinity (right shift)→ fast unloading of O When lung partial pressure of O is 100 mmHg ,Hb saturation is 100% When tissue partial pressure of O is 40 mmHg ,Hb saturation reduces, hence O is delivered to tissue The bohr effect It is the shift of the ODC Oxygen dissociation curve to the right in response to an increase in pCO2 or a decrease in pH (acidity) ● ● ● ● It describe the effect of of pH and pCO2 on: Oxygenation of Hb in the lungs Deoxygenation in tissues Affinity is showing by saturations, if the curve shifts to the right that means the affinity is reduced and lead to unload (release) the oxygen In simple the Bohr effect shows how the production of CO2 leads to increase the production of protons (Hydrogens) that lowers the affinity between the Hb and O2 (so increase the release of O2 to the tissues) ● Tissues have lower pH (more acidic) than lungs due to proton (H+) generation (two reactions) ● CO2 + H20 ⇋ H2CO3 (carbonic acid) ● H2CO3 ⇋ HCO3- + H+ HCO3- is bicarbonate (Base) ● ● Protons (H+) reduce O2 affinity of Hb causing easier O2 release into the tissue. The free Hb bind to two protons (H+) ● Protons are released at the lungs and react with HCO3- to form CO2 gas (it will be exhaled) ( HCO3-+ H+→ CO2+H2O) The proton-poor Hb now has greater affinity for O2 (in lungs) ● ● The Bohr effect remove insoluble CO2 from blood stream and produce soluble Bicarbonate Results of a shift to the right: P50 is shifted to a higher value of oxygen pressure → affinity decreases ( more oxygen is required to achieve 50% saturation) → facilitate delivery of oxygen Availability of 2,3-Bisphosphoglycerate(BPG) ● ● Binds to deoxy-Hb and stabilizes the T form (in tissues), bind to the two β chains When oxygen bind to Hb BPG is released (in the lung) High altitude and O2 affinity Important At high altitude : ● RBC number increases (compensatory mechanism) ● Hb Conc. increases ● BPG increases to decrease the affinity in the tissues (facilitate unloading), the saturation in the lungs didn’t decrease by much due to high PO2 Thus increases O2 delivery to tissues 2,3 BPG levels rise 01 In hypoxia and high altitude 02 03 This decrease O2 affinity of Hb 04 High altitude and O2 affinity Important High O2 affinity (left shift) is due to ● Alkalosis ● High levels of HbF (in thalassaemia) ● Multiple transfusion of 2,3-DPG depleted blood (2,3-DPG = 2,3-BPG) the anticoagulant found in blood transfusion bag deplete 2,3-DPG Know which factors shift the curve to the left and to the right Extra (IMP) Shift to left Shift to right ↑ pH ↓ pH ↓ DPG ↑ DPG ↓ Temperature ↑ Temperature ↓ P50 ↑ P50 ↑ Abnormal Hb - Other types of Hb Fetal hemoglobin HbF HbA2 HbA1C Major hemoglobin found in fetus and newborn Appears shortly before birth High level in patients with diabetes mellitus Tetramer with two α and two 𝜸 (gamma) chains Composed of two α and two δ (delta) globin chains Two α and two β , like in normal HbA - Higher affinity for O2 than HbA -Transfer O2 from maternal to fetal circulation across placenta -Increased in individuals with thalassemia Constitute ~ 2% of total Hb & remains constant throughout life. - HbA undergoes non-enzymatic glycosylation - glycosylation depends on plasma glucose level In the first curve you just need to know in the 1st trimester (the first 3 months of pregnancy) the major form of globins chains are zeta chains not the alpha chains, but in the 2nd trimester the alpha chains increase and becomes the major form. In the second curve the gamma chains start to appear in the second trimester and becomes the major form until the birth, after the birth the beta chains become the major form. In other word the reaction will happen by Presence of HbA with glucose in blood. Quiz MCQs Q1:Which of the following is NOT bound to the heme group of hemoglobin? A- Histidine B- Nitrogen C- Oxygen D- Sulfur Q2: which of the following is irreversible? A- carboxy Hb B- sulf Hb C- met Hb D- none of them Q3: HbA2 is composed of ? A- two α and two δ globin chains B- two α and two 𝜸 (gamma) chains C- four α globin chains D- Two α and two β globin chains Q4: Which of the following is NOT a feature of T-form of hemoglobin? A- movement of diner is constrained B- low oxygen affinity C- Abundant 2,3-BPG D- Oxygenated form of Hb Q5: Which of the following is NOT an allosteric effector? A- Availability of 2,3- BPG B- PCO C- PO2 D- PH of environment Q6: which of the following shift the curve to the right? A- ↑PH B- ↓DPG C- ↓Temperature D- ↑DPG Answers:Q1-D, Q2- B, Q3- A, Q4- D, Q5- B, Q6-D SAQ Q: Enumerate the factors that cause Left shift of the Oxygen Dissociation Curve A: 1- Inc. pH, Alkalosis, dec. Protons 2- Dec. Temperature 3- Dec. P50 4- Dec. 2,3-BPG 5- Abnormal Hb 6- High levels of HbF Members board Team Leaders Raghad Alhamid Remas Aljeaidi Mohammed Alqutub Team Members Leen Alduaij Zeyad Alotaibi Sultan Almishrafi Wafa Alakeel Mohammed Alarfaj Juwan Al Musma Madawi Alhussain Nazmi A Alqutub Wasan Alanazi Leen K Althunayan Faisal Alshowier Aishah boureggah Dana A Alkheliwi Osama Almashjari Mansour Alotaibi Aldanah Abdullah Nazmi M Alqutub Salma Alsaadoun Layan Al-Ruwaili Fahad Mobeirek Areej Alquraini Sarah Alajaji Waad alqahtani Special Thanks to Aleen Alkulyah for the Design! [email protected]