University:
Kentucky State University
Course:
BIO 318 | Hematology
Academic year:

2020
Views:

49

Pages:

30
Author:

slypery5hy

Quaternary Structure • Quaternary (4°) structure: the association of polypepetide monomers into multisubunit proteins (dimer, trimer, tetramer, etc) – examples we will see in this course Globular Protein Subunits Alcohol dehydrogenase 2 Triosephosphate isomerase 2 Aldolase 3 Hemoglobin 2+2 Lactate dehydrogenase 4 Pyruvate kinase 4 Insulin 2 Sheet Note #1 Collagen is an example on a secondary structure Myoglobin is an example on a tertiary structure Hemoglobin is an example on a quaternary structure *Key enzymes are composed of multiple subunits )regulation/activation ( The two alpha chains ALONE have NO FUNCTION .same thing for the two beta chains Each heme group carry one oxygen molecule Oxygen Binding of Hb – Hb is a tetramer of two -chains (141 amino acids each) and two -chains (153 amino acids each); 22 – each chain has 1 heme group; hemoglobin can bind up to 4 molecules of O2 – binding is cooperative; when one O2 is bound, it becomes easier for the next O2 to bind (positive cooperativity) – the function of hemoglobin is to transport oxygen while myoglobin*s function is to store oxygen – the structure of oxygenated Hb (loaded) is different from that of unoxygenated Hb (unloaded) – H+, CO2, Cl-, and 2,3-bisphosphoglycerate (BPG) affect the ability of Hb to bind and transport oxygen #Once one oxygen molecule is united the rest will follow Loaded & unloaded hemoglobin forms The distance between the two beta chains is shorter in the loaded form Oxygen Binding of Hb Hyperbolic curve Sigmoidal curve Sheet Note #2 Myoglobin has a higher affinity for o2. So when o2 has a very small consentration myoglobin will be fully saturated While hemoglobin has less affinity than myoglobin. So pressure of o2 must be high (for example 25 or 27) to reach half saturation of hemoglobin Oxygen Binding of Hb • The effect of pH on the oxygen-binding ability of Hb is called the Bohr effect as pH decreases (more acidic), oxygen is released – Hb has lower affinity to O2 under  [H+] (under high production of acids) CO2 promotes release of O2 fromHbo2 • carbonic anhydrase This happen in lungs CO 2 + H 2 O H2 CO 3 H2 CO 3 H2co3 is a weak acid H+ + HCO 3 - Oxygen Binding of Hb The Bohr effect Oxygen Binding of Hb Summary of the Bohr effect Actively Metabolizing Muscle Lungs + Higher pH than actively Lower pH due to production of H Such as lactic acid.pyruvate acid…etc metabolizing tissue Hemoglobin binds O2 2 Hemoglobin releases O2 + Hemoglobin releases H + Hemoglobin binds H Hemoglobin (Hb) • Hemoglobin in blood is bound to BPG – interaction is electrostatic, between negative charges on BPG and positive side chains (e.g., Lys, Arg) of hemoglobin – BPG promotes O2 dissociation – Hb stripped of BPG remains saturated with O2 O- O C H C OPO 3 2 - CH2 OPO 3 2 2,3-Bisphos phoglycerate (BPG) @BPG unit with beta chain & make a decrease o2 affinity With BPG decrease o2*s binding to Hb Without BPG o2 fully saturated Fetal Hemoglobin, Hb F – has a higher affinity for O2 than maternal Hb A – structure is 2g2 – binds less strongly to BPG than does Hb A Oxygen binding capacity of Hb F Adaptation to High Altitude • Physiologic changes that accompany prolonged exposure to high altitude include an increase in the number of erythrocytes and in their concentrations of hemoglobin and of BPG. • Elevated BPG lowers the affinity of HbA for O2 (decreases P50), which enhances release of O2 at the tissues. CO the silent killer SHEET CO is colour less CO competitive with o2 And it has 200 times more affinity than o2 So CO has the proiority To unit with Hb BIOMEDICAL IMPLICATIONS Myoglobinuria • Following massive crush injury, myoglobin released from damaged muscle fibers colors the urine dark red. • Myoglobin can be detected in plasma following a myocardial infarction. Anemias • Anemias, reductions in the number of red blood cells or of hemoglobin in the blood, can reflect impaired synthesis of hemoglobin (eg, in iron deficiency; or impaired production of erythrocytes (eg, in folic acid or vit.B12 def.) Glycosylated Hemoglobin (HbA1c) When blood glucose enters the erythrocytes it glycosylates the amino group of lysine residues and the amino terminals of hemoglobin. The fraction of hemoglobin glycosylated, normally about 5%, is proportionate to blood glucose concentration. Since the half-life of an erythrocyte is typically 60 days, the level of glycosylated hemoglobin (HbA1c) reflects the mean blood glucose conc.over the preceding 6–8 weeks. Measurement of HbA1c therefore provides valuable information for management of diabetes mellitus. 20% OF PEOPLE(IN GENERAL) SUFFER FROM DIABETES 37% OF ADULTS SUFFER FROM DIABETES Hemoglobin (HbS) • In sickle cell, Val replaces the β6 Glu of HbB, creating a “sticky patch” that has a complement on deoxyHb (but not on oxyHb). • DeoxyHbS polymerizes at low O2 concentrations, forming fibers that distort erythrocytes into sickle shapes. • Alpha and beta thalassemias are anemias that result from reduced production of α and β subunits of HbA, respectively SHEET IF the both parents are carriers the possibility is 50% To get a child with sickle cell disease Factors Directing Folding • Noncovalent interactions, such as – hydrogen bonding between polar side chains, e.g., Ser and Thr – hydrophobic interaction between nonpolar side chains, e.g., Val and Ile – electrostatic attraction between side chains of opposite charge, e.g., Lys and Glu – electrostatic repulsion between side chains of like charge, e.g., Lys and Arg, Glu and Asp • Formation of disulfide (-S-S-) covalent bonds between side chains of cysteines Denaturation • Denaturation: the unfolding of the protein the loss of biological activity • Native protein (active) denatured protein (inactive) • Denaturation can be brought about by 1. Heat 2. Large changes in pH, which alter charges on side chains, e.g., -COO- to -COOH or -NH+ to -NH 3. Detergents such as sodium dodecyl sulfate (SDS) which disrupt hydrophobic interactions 4. Urea or guanidine HCL, which form H-bonds with protein that are stronger than those within the protein disrupt H-bonding 5. Mercaptoethanol, which reduces disulfide bonds.

Lecture Hemoglobin

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