Lecture #1. Done By : Rasha Rakan. Corrected by: Obadah Abubaker

Transcription

1 Lecture #1 Done By : Rasha Rakan Corrected by: Obadah Abubaker مالحظة: المكتوب باللون األسود هو ما كتب ف السال دات وما كتب باللون األزرق فهو كالم الدكتور أثناء المحاضرة وللذ ن قومون بتصو ر الش ت جعلنا كالم الدكتور بالخط المائل للتفر ق.

2 Specific objectives: 1.Hemoglobin and the Movement of Oxygen 1. The student must understand the process of oxygen binding, specifically; Oxygen binding and iron movement - deoxy versus oxygenated state Iron-oxygen binding Quaternary structure of deoxyhemoglobin Oxygen binding of myoglobin Oxygen binding of hemoglobin 2. The student must understand the concept of cooperativity, specifically; Cooperativity in hemoglobin's oxygen binding Quaternary changes on oxygen binding by hemoglobin T to R transition Sequential model of binding The effect of 2,3 BPG (is very important side product of glucose oxidation(glyculosis) and it is important to affect the function of ) رح تم شرحه ف ما بعد hemoglobin Binding of 2,3BPG to hemoglobin Oxygen binding and fetal hemoglobin 3.The student must understand molecular aspects of Bohr Effect, specifically; Effect of ph on oxygen affinity of hemoglobin Carbon dioxide and ph Carbon dioxide effects Carbamate formation Transport of CO 2 to lungs 4. The student must know some Hemoblobin Genetic Considerations; Sickled blood cells and hemoglobin fibers

3 Sickle cell traits and malaria Introduction: Animals Have Widely Varying Needs for Oxygen Demand for Oxygen Can Change in Seconds Basal Needs are Significant - Diffusion not Enough Exercise, Fight/Flight Add to the Need ATP Energy Produced Aerobically 15 Times More Efficiently Than Anaerobically Respiration versus Fermentation Efficient, Adaptable Oxygen Delivery is Necessary Hemoglobin No other protein can do the function of hemoglobin Function: Carrying O 2 to all the tissues of the body. Why isn t hemoglobin important to plants? because they don t move Hemoglobin delivers O 2 : 1. Fast 2. Where it s needed Myoglobin can t do that. Energy is produced by oxidation that needs oxygen delivered by hemoglobin. The delivery is adaptable: Changes with requirements, the concentration of CO 2 / H +, etc.

4 Quaternary Structure Interaction of multiple protein subunits Hemoglobin - 4 Subunits (α 2 β 2 ), 1 Heme Each, 1 O 2 Each, 1 Donut Hole Myoglobin - 1 Subunit, 1 Heme, 1 O 2 Each Dount Hole Structure 2α subunits + 2β subunits these are just names Quaternary structure: it s protein aggregation of more than one subunit. Subunits: polypeptides connected to each other non-covalently (via H-bonding, electrostatic charges, etc.) Polypeptide chains: polypeptides connected to each other covalently (via S-S bridges) each of these subunits) α and β) can contain the α helix or the β sheets as a secondary structure.

5 Structure and Function: Heme Prosthetic Group Ferrous Iron - Methemoglobin Won t Work Only Fe ++ Binds Oxygen Each of these subunits contain a Heme group Heme is also known as prosthetic group Fe in the heme must be in the ferrous state (Fe ++ ) It must stay in this state, because if it s oxidized to the ferric state (Fe +++ ) it won t bind to O 2. The Fe isn t oxidized when it binds to O 2, How? Hemoglobin prevents the oxidation of iron from ferrous to ferric upon O 2 binding to iron. Each subunit carries 1 O 2 Each hemoglobin carries 4 O 2

6 Edge-on View Attached to Remainder of Global Subunit Histidine s Movement Changes Global Unit s Shape Myoglobin and Hemoglobin Have the same primary, secondary and tertiary structures. Only hemoglobin has quaternary structure. That s why : 1. Hemoglobin Delivers O 2 2. Myoglobin Stores O 2 وهنا نستنتج أن ال structure determines function Dount Hole: it s where 2,3-BPG binds and does it s effect Heme one for each subunit 4 pyrole rings making protoporphyrin ring In the center of the ring Fe ++ : 1.4 bonds to N 2. 1 to the His 3. 1 to O 2 الحد د مرتبط بستة روابط كما هو موضح باألعلى *كل هالجزء فضل تركزو ف ه النو مش واضح*

7 Cooperativity No Oxygen )T-State( Affected by O 2 Binding )R-State)0 Fully Oxygenated (R-State( Entering Lungs Exiting Lungs Oxygen Bound Affected by O 2 Binding R-State Binding of the first O 2 favors binding of second, etc. - Cooperatively Cooperatively Important as Hemoglobin Rapidly Passes Through Lungs Hyperbolic Binding Curve At High O 2, Both Hold 100% As Curves Move to Right Less Affinity for Oxygen As Curves Move to Right Less Affinity for Oxygen Sigmoidal Binding Curve Myoglobin Better for Storing Oxygen Hemoglobin Better at Delivering Oxygen

8 Myoglobin & Hemoglobin Saturation Myoglobin ( hyperbolic curve) - at low O 2 concentration it holds more than hemoglobin at 27 mm Hg 95% is saturated Hemoglobin (sigmoidal curve) at 27 mm Hg 50% is saturated Myoglobin isn t affected by CO 2 /H + /2,3-BPG Cooperativity: Ferrous (Fe ++ ) binds to O 2 His connects between one of the heme group and its subunit Before binding to O 2 Fe is in the center After Binding to O 2 : 1. oxygen pulls Fe, Fe pulls His 2. His is attached to the rest of amino acids of that subunit, so it pulls them 3.The subunit is attached to the rest subunits so it changes them تحر ك ال Fe لمسافة قص رة جدا nanoscopic distance بسبب ارتباطها بال O 2 هذا س ؤثر بال structure of hemoglobin بالتال س حدث تغ ر ف ال function O 2 binds and effects the tertiary structure, therefor it effects the function هذا الذي حدث هو مفهوم ال cooperativity والذي حدث ف اله موغلوب ن وال حدث ف الم وغلوب ن النه متكون من subunit واحد فقط.

9 T & R states When hemoglobin reaches the lung, it is in the T state. -T state: a state that doesn t favor O 2 binding -R state: a state that favors O 2 binding T state O 2 binding Changes in the tertiary structure effecting the neighbor subunits R state Bohr Effect Less Oxygen Bound at Same Pressure Less Affinity More Affinity

10 Bohr Effect 1. ph physiological ph = 7.4 if the tissue is very active, the [H + ] will increase, H + will bind to hemoglobin and change the tertiary structure of the subunits and that causes the unloading of O 2 Increasing in [H + ] = Decreasing of ph = Decreasing Binding to O 2 (decreasing ino 2 affinity) 2. CO 2 it s a signal to hemoglobin that the tissue needs O 2 it will produce H +,(and also bind to hemoglobin) and H + changes the structure of hemoglobin unloads O 2

11 Active Metabolizing Tissues increasing in [H + ] + increasing in [CO 2 ] increasing in unloading of O 2 Protons bins at disassociated : 1. Carboxylic groups uncharged COOH 2. Amino groups Positively charged NH 4 + Once protons bind to them, positive charges or negative charges will come nearer to each other and that will produce electrostatic effect change in the tertiary structure بالتال بص ر ف unloading لل O 2