Protein Chemistry 3 Lecture Notes PDF

Field of Medicine Medicine and surgery program Lecture : PROTEIN CHEMISTRY 3 Dr : Moataz Maher Date : 10 /2024 Objectives: By the end of this lecture, the student will be able to: 1. Identify important examples of globular proteins 2. Identify the relation between hemoglobin structu...

Field of Medicine Medicine and surgery program Lecture : PROTEIN CHEMISTRY 3 Dr : Moataz Maher Date : 10 /2024 Objectives: By the end of this lecture, the student will be able to: 1. Identify important examples of globular proteins 2. Identify the relation between hemoglobin structure and its function 3. Compare between hemoglobin and myoglobin  1. Globular Proteins Globular proteins are folded to a more or less spherical shape. a.They tend to be soluble in water or in salt solutions b.Most of their polar side chains are on the outside and interact with the aqueous environment by hydrogen bonding c.Most of their non-polar side chains are buried inside d.Most of them have substantial sections of α-helix and β-sheet Example: myoglobin and hemoglobin  1a. Myoglobin (Structure) The first protein for which a complete 3- dimensional structure was determined. a. It is a single polypeptide chain of 153 amino acids b.It contains 8 regions of α-helix (A-H); no regions of β-sheet c.Most polar side chains are on the surface while Myoglobin non-polar side chains are folded to the interior. d.It contains one heme group in the hydrophobic pocket.  1a. Myoglobin (Properties) 1. It exists as a monomer (has only tertiary structure). 2. Each monomer contains a heme prosthetic group [It is formed of a protoporphryin ring bound to Fe2+ atom. 3. It Can only bind one oxygen (O2) per monomer 4.The normal physiological [O2] at the muscle is high enough to saturate O2 binding of myoglobin (It has high binding affinity to O2). 5. It acts as an oxygen storage protein in muscle. 6. It releases O2 when oxygen concentrations are very low.  1b. Hemoglobin (Hb) a.A tetramer of two α-chains (141 amino acids each) and two β-chains (146 amino acids each). b.Each chain is formed of 8 helices c. Each chain has 1 heme group. d. Each heme subunit contains ONE Fe2+. e. Hemoglobin can bind up to FOUR molecules of O2  1b. The Heme group Heme is formed of a Heterocyclic ring [Protoporphyrin] and iron. Under normal condition, the iron must be in the Fe2+ ferrous form [Fe2+] or reduced state. In the ferrous (Fe2+) from , Iron can form two additional bonds, they are called the fifth and sixth coordination sites. Heme 1b. The Heme group -The 5th coordination site is occupied by the imidazole ring of a histidine residue from the globin (proximal histidine in F helix) that binds directly to the Fe2+ of heme. - In deoxyhemoglobin, the 6th coordination site remains unoccupied and in oxyhemoglobin it binds the oxygen molecule.  1b. The Heme Group Each heme subunit (ONE in myoglobin and FOUR in hemoglobin) binds ONE molecule of O2 +. Under normal condition, the iron must be in the Fe2+ form (ferrous) or reduced form. Conversion between ferric (Fe3+) and ferrous (Fe2+) forms gives heme its function as an acceptor and donor of electrons. Loss of electrons= oxidation Gain of electrons= reduction Heme-Fe2+  1b. Hemoglobin (Hb) Strong Hydrophobic interactions Weak ionic/ hydrogen bonds Globin chain Hb Globin chains  1b. Hemoglobin (Properties) 1. At the 4ry level, Hemoglobin is composed of two identical dimers, (αβ)1 and (αβ)2. α and β chains in each dimer are held tightly together by strong hydrophobic interactions, while weak ionic and hydrogens bonds occur between the αβ dimers. 2. Contains 4 heme groups, so up to 4 O2 can be bound 3. Its physiological role is a carrier/transporter of oxygen from the lungs to the rest of the body, therefore its oxygen binding affinity is much lower than that of myoglobin. 4. If the Fe2+ becomes oxidized to Fe3+ by chemicals or oxidants, oxygen can no longer bind, it is called Methemoglobin.  2. Hemoglobin Function Oxygen Transport Following oxygenation, a considerable structural conformational change occurs in Hb. - Oxygenation rotates the a1b1 dimer in relation to a2b2 dimer about 15°. - Hb changes from the T R T-state (Taut) R-state (relax) Deoxyhemoglobin Oxyhemoglobin 2. Hemoglobin Function 2. Hemoglobin Function  2. Hemoglobin Function Hemoglobin main role is acting as carrier/ transporter of oxygen from the lungs to the rest of the body. Role of the globin chain: The globin surrounds the heme as it helps in the following: 1. It provides proximal histidine that binds to Fe2+ and the distal histidine that stabilizes oxygen binding. 2. The heme alone interacts with oxygen so that the Fe2+ becomes oxidized to Fe3+ and no longer binds oxygen. Presence of globin chain help in reversible oxygen binding to Hb. (Fe3+ does bind oxygen, but because of it's higher oxygen affinity it does not release it well, which means that it cannot effectively oxygenate tissue)  3. Comparison between Myoglobin & Hemoglobin Structural similarities: 1.The amino acid sequences of myoglobin and hemoglobin are similar but not identical. 2.Their polypeptide chains fold in a similar manner 3. Both are localized in the cell cytosol.  3. Comparison between Myoglobin & Hemoglobin Hemoglobin Myoglobin Found in mature erythrocytes Found in muscles A multi-subunit tetrameric A monomeric protein. proteins It is an oxygen transport protein It is an oxygen storage protein It binds and releases oxygen It binds oxygen tightly and releases when the tissues require it when oxygen concentrations are oxygen (O2 affinity lower). very low (O2 affinity higher). Carries CO2. It can’t carry CO2.  Blood doping Blood doping is an illicit method of improving athletic performance by artificially boosting the blood's ability to bring more oxygen to muscles. In many cases, blood doping increases the amount of hemoglobin in the bloodstream, increasing hemoglobin allows higher amounts of oxygen to reach and fuel an athlete's muscles. This can improve stamina and performance, particularly in long-distance events, such as running and cycling. Blood doping is banned by the International Olympic Committee and other sports organizations. Types of Blood Doping The three widely used types of blood doping are: 1. Blood transfusions 2. Injections of erythropoietin (EPO) 3. Injections of synthetic oxygen carriers 1a) Autologous transfusion. This involves a transfusion of the athlete's own blood, which is drawn and then stored for future use. 1b) Homologous transfusion. In this type of transfusion, athletes use the blood of someone else with the same blood type. 2. EPO injections. EPO is a hormone produced by the kidney. It regulates the body's production of red blood cells. In medical practice, EPO injections are given to stimulate the production of red blood cells. For example, a synthetic EPO can be used to treat patients with anemia related to chronic or end- stage kidney disease. Athletes using EPO do so to encourage their bodies to produce higher than normal amounts of red blood cells to enhance performance. 3. Synthetic oxygen carriers have a legitimate medical use as emergency therapy. It is used when a patient needs a blood transfusion but:  human blood is not available  there is a high risk of blood infection  there isn't enough time to find the proper match of blood type.  Risks of Blood Doping By increasing the number of red blood cells, blood doping causes the blood to thicken. This thickening forces the heart to work harder than normal to pump blood throughout the body. As a result, blood doping raises the risk of: 1. Blood clot 2. Heart attack 3. Stroke  SUMMARY - Important globular proteins include hemoglobin and myoglobin - The structure of hemoglobin helps in its function as oxygen transporter - Comparison between myoglobin and hemoglobin regarding their structure and function show the differences and similarities between both protein in relation to their function  Video link: (57) Hemoglobin R T State Howard Hughes Institute with Narration - YouTube Reference: – Lippincott's Illustrated Reviews: Biochemistry, 7th Edition. Chapter 3.