University of the Northern Philippines Biochemistry LC3A Hemoglobin PDF

COURSE OUTLINE I. Introduction II. Hemoglobin Vs Myoglobin III. Structure And Function A. Cooperativity B. Bohr Effect C. Bohr Effect And Co2 D. 2,3 Bpg...

COURSE OUTLINE I. Introduction II. Hemoglobin Vs Myoglobin III. Structure And Function A. Cooperativity B. Bohr Effect C. Bohr Effect And Co2 D. 2,3 Bpg Figure 1: Structure of Hemoglobin and Myoglobin E. 2,3 Bpg And Oxygen Binding F. 2,3 Bpg And Smoking IV. Movement Of Co2 III.STRUCTURE AND FUNCTION V. Carbon Monoxide And Heme VI. Fetal Hemoglobin VII. Sickle Cell Anemia Heme prosthetic group Ferrous iron — Methemoglobin won't work HEMOGLOBIN Only Fe2+ binds oxygen. I. 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 Figure 2: Heme and Hemoglobin Structure In fight and flight, the hormones and the different cells are working more to provide more energy in an emergency situation. ATP energy produced aerobically is 15 times more efficient than anaerobically — respiration versus fermentation. Efficient, adaptable oxygen delivery is necessary. Figure 3: Structure of Deoxygenated and Oxygenated Hemoglobin II. HEMOGLOBIN VS MYOGLOBIN HEMOGLOBIN Hemoglobin is a protein consisting of four subunits: two alpha and two beta subunits. Each subunit can carry one molecule of oxygen, allowing hemoglobin to transport a Figure 4: Structure of Deoxygenated and Oxygenated blood. total of four oxygen molecules. The heme Entering and exiting the lungs. group within hemoglobin contains a ferrous ion, for oxygen binding. Binding of the first O2 favors binding of the second, etc. — cooperatively MYOGLOBIN Cooperativity is important as hemoglobin Myoglobin consists of a single subunit rapidly passes through lungs. that can only bind one oxygen molecule When oxygen binds to the ferrous ion in hemoglobin, a conformational change Remember that only ferrous ions would be able to occurs, which enhances the ability of the bind to oxygen. Otherwise, like if it is in ferric, ferric remaining subunits to bind oxygen. This iron 3+, it would not be able to bind to oxygen. phenomenon is referred to as cooperativity. BIOCHEMISTRY LC 3A: HEMOGLOBIN DR. ESPIRITU, A. DATE: 08/28/2024 Hemoglobin can exist in two The graphs show the saturation of conformations: the tense (T) state, which is myoglobin and hemoglobin illustrate their less flexible and does not facilitate oxygen binding affinities for oxygen. Myoglobin binding, and the relaxed (R) state, which displays a hyperbolic curve, indicating its enables easier binding and release of high affinity for oxygen even at low oxygen. concentrations, whereas hemoglobin When deoxygenated hemoglobin (in the T shows a sigmoidal curve, which reflects its state) moves to the lungs, where there is a cooperative binding behavior. high concentration of oxygen, the first oxygen molecule that binds triggers a B. BOHR EFFECT conformational change, making it easier Factors affecting oxygen binding include for the other subunits to also bind oxygen. the Bohr effect, which relates to the pH of This results in a rapid saturation of the environment. In more acidic conditions hemoglobin with oxygen as it passes (lower pH), hemoglobin has a lower affinity through the lungs. for oxygen because active cells produce Myoglobin, which is primarily used for more hydrogen ions, necessitating oxygen storage in muscle cells, myoglobin increased oxygen delivery. does not undergo the same cooperativity. Instead, it binds oxygen with high affinity and only releases it under low oxygen conditions, making it ideal for storage purposes. A. COOPERATIVITY Figure 9 and 10: Fractional O2 Sat and PO2 Figure 5: Myoglobin vs. Hemoglobin Figure 6: Hemoglobin vs. Myoglobin Figure 11: O2 Saturation Figure 7: Hemoglobin vs Myoglobin PREPARED BY: BATCH 2028 1D 2 BIOCHEMISTRY LC 3A: HEMOGLOBIN DR. ESPIRITU, A. DATE: 08/28/2024 Protons can bind to hemoglobin. Protons change hemoglobin's shape. Reshaped hemoglobin loses oxygen. Rapidly metabolizing tissues release protons. Rapidly metabolizing tissues get more oxygen from hemoglobin. As demonstrated in the Bohr effect graph, a decrease in pH shifts the oxygen binding curve to the right, indicating that Figure 13: Structure of 2,3 Biphosphoglycerate hemoglobin releases more oxygen to active tissues. E. 2,3 BPG AND OXYGEN BINDING C. BOHR EFFECT AND CO2 Acid favors release of O2 from hemoglobin. CO2 favors release of O2 from hemoglobin. Acid and CO2 are released by rapidly metabolizing tissues. Figure 14: 2,3 BPG and Oxygen Binding Rapidly metabolizing cells produce acid. Rapidly metabolizing cells release CO2. Rapidly metabolizing cells release 2,3 BPG. Figure 12: Tissue Oxygen and Lung Oxygen All favor O2 release from hemoglobin, so rapidly metabolizing cells get more O2. Carbon dioxide also influences oxygen release: it What would you expect on the oxygen does bind to hemoglobin, but not to the heme binding curve? Would it shift to the right or group; instead, it binds to other sites on the shift to the left with increased levels of hemoglobin molecule, facilitating oxygen unloading 2,3-BPG? It would shift to the right. This is in tissues with high carbon dioxide concentrations. due to the fact that active muscle cells produce more acid, more carbon dioxide, Carbon dioxide, when dissolved in the and, consequently, more 2,3-BPG. The blood, forms carbonic acid, and this 2,3-BPG binds in the “donut hole” of process is crucial for transporting CO2 hemoglobin, rather than at the heme sites from tissues to the lungs for exhalation. where oxygen binds. When it binds to this hole, it locks hemoglobin in the T state D. 2,3 BPG (tense state). Bisphosphoglycerate As the levels of 2,3-BPG increase, along By-product of glycolysis with the production of carbon dioxide and Exercising muscle cells rapidly use acidity in the environment, the oxygen glycolysis binding curve shifts to the right. This Exercising muscle cells produce acid, CO2, means a lower affinity of hemoglobin for and 2,3 BPG oxygen, resulting in rapidly metabolizing Highly active cells produce more 2,3-BPG cells gaining access to more oxygen. Binds in hole of donut Locks hemoglobin in T-state PREPARED BY: BATCH 2028 1D 3 BIOCHEMISTRY LC 3A: HEMOGLOBIN DR. ESPIRITU, A. DATE: 08/28/2024 F. 2,3 BPG AND SMOKING oxygen-carrying capacity of the blood 2,3 BPG big concern for smokers because it competes with oxygen for the same binding site. This creates an Blood of smokers has high levels of 2,3 additional challenge for smokers, as the BPG presence of carbon monoxide diminishes Hemoglobin gets locked in T-state in the ability of hemoglobin to transport passage through lungs oxygen. Oxygen carrying capacity of blood reduced Carbon monoxide levels are also higher in smokers. Figure 15: Structure of 2,3 Biphosphoglycerate Figure 17: Oxymyoglobin and Mb:CO Complex Structure Carbon monoxide can easily bind to the heme group and competes with oxygen for VI. FETAL HEMOGLOBIN binding. This is why carbon monoxide is poisonous. Carbon monoxide forms as a byproduct of inefficient burning of fuels, for The body makes different globins over instance, in fuel-burning appliances like time. stoves. Most variations centered on birth Fetal Hemoglobin Mostly α2γ2 IV. MOVEMENT OF CO2 Figure 18: Percentage of Total Globin Synthesis Fetal hemoglobin can't bind to 2,3 BPG. Mostly remains in R-state Figure 16: Movement of CO2 V. CARBON MONOXIDE AND HEME An additional histidine is present at the heme iron site. Reduces affinity to CO, but does not eliminate it. Carbon monoxide in cigarette smoke Note that CO2 does not bind to heme, nor do protons. When carbon monoxide binds to hemoglobin, it reduces the Figure 19: O2 Saturation PREPARED BY: BATCH 2028 1D 4 BIOCHEMISTRY LC 3A: HEMOGLOBIN DR. ESPIRITU, A. DATE: 08/28/2024 Fetal hemoglobin is different; it has a different composition from adult hemoglobin. The body produces various globins throughout development. Fetal hemoglobin is primarily in the form of alpha 2 gamma 2. Over time, the gamma subunits are replaced by beta subunits as fetal development progresses. 2,3-BPG does not affect the oxygen-carrying capacity of the blood because fetal hemoglobin has a higher Figure 22: Sickled Cells in the Capillaries affinity for oxygen, which leads to a leftward shift in the oxygen binding curve. This characteristic allows the fetus to WHY SICKLE CELL ANEMIA SO WIDESPREAD? effectively extract oxygen from the WHY HAS IT NOT BEEN SELECTED AGAINST? maternal bloodstream. VII. SICKLE CELL ANEMIA Sickle cell anemia is a genetic disease affecting hemoglobin. Multiple forms — mutation of Glu to Val at position #6 most common Red blood cells lose rounded shape and form sickles. Figure 23: Incidence of Sickle Cell Anemia and Malaria Shape change happens in low O2 Benefit of sickle cell mutation for conditions — exercise heterozygotes Change caused by polymerization of No benefit to homozygous recessive or hemoglobin dominant The most common form involves the substitution of glutamic acid with valine at a 6th position, causing red blood cells to lose their rounded shape and form a sickle shape, particularly under low oxygen conditions, such as during exercise or in the presence of an infection. These sickle-shaped cells tend to get stuck in smaller blood vessels, leading to complications. Figure 20: Structure of Sickle Cells Despite the challenges posed by sickle cell anemia, it remains widespread and has not been eliminated through evolution. The highest incidence of sickle cell anemia occurs in Africa and regions with a high prevalence of malaria. The evolutionary implication here is that individuals with sickle cell trait (heterozygotes) may have a selective advantage in these regions because the abnormal shape of their red blood cells makes them less susceptible to malaria parasites, which infect red blood cells. While sickle cell anemia may pose Figure 21: Red Blood Cells in the Capillaries challenges for homozygous individuals (those with two copies of the sickle cell gene), it offers a protective benefit for PREPARED BY: BATCH 2028 1D 5 BIOCHEMISTRY LC 3A: HEMOGLOBIN DR. ESPIRITU, A. DATE: 08/28/2024 heterozygous carriers. Thus, the presence of sickle cell trait provides an evolutionary advantage in malaria-endemic areas, highlighting a fascinating example of natural selection and adaptation. Reference(s): 1. Dr. A. Espiritu (2024). Lecture and Powerpoint Presentation. PREPARED BY: BATCH 2028 1D 6