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Boston College
CHEM 4465

HEMOGLOBIN AND MYOGLOBIN I. OXYGEN CARRIERS A. Why do we need oxygen carriers? i. Cannot carry enough in blood to meet metabolic demand ii. Oxygen is very reactive – oxidizes iii. Oxygen cannot diffuse very easily (we have thick skin) B. Properties of a good oxygen carrier i. Binds oxygen at a high [O ] 2 ii. Doesn’t oxidize cellular components iii. Gives up oxygen on demand C. Hemoglobin and Myoglobin i. Cooperativity 1. Hemoglobin needs to have high affinity to bind O in the2lungs, but low affinity to unload to myglobin 2. Sigmoidal curve: represents weak-binding state at low P and st02ng- binding state at high P 02 ii. Hemes 1. The heme binds O not 2,e protein 2. Function of protein: provides crevice – keeps heme from oxidizing 2+ 3+ a. absence of protein: ferrous atom (Fe )  ferric state (Fe ) b. heme buried in hydrophilic environment of protein: O binding 2 does not result in oxidation 3. Heme structure a. Each polypeptide of protein is made from 8 residues  6 helices – A, B, C, D, E, F b. Fe has 6 coordinating bonds i. 4 bonds = nitrogens from tetrapyrrole ring system ii. 5 bond - Helix F binds to Fe at terminal Histidine * 5 bond = helix F8, residue 93 in Mb, molecule (His F8)* = proximal histidine residue 92 in the β-chain of Hb and th residue 87 in α-chain of Hb iii. 6 bond – deoxygenated: empty, histidine residue from ** 6 bond = helix E7, His 64 for Mb, His helix E** hovers; oxygenated: oxygen bonds here 63 in b-chain and 58 in a-chain c. Oxygen binds to Fe at 120° angle  easily removed II. MYOGLOBIN A. Physico-chemical properties i. 153 amino acids – single polypeptide chain ii. Very compact: globular structure  little empty space for solution to get in iii. Tertiary structure: 8 alpha helices (A-H), 4 helices terminated by proline residues iv. About 75% is in alpha helical structure v. Polar side chains on outside of protein  interact with solution vi. Myoglobin = storage protein  mainly in skeletal muscle vii. High O a2finity – does not change with concentration viii. Monomer  no cooperativity B. Oxygen binding to Mb i. θ = (pO2)/(p50 + pO2) 1. θ= fraction of Mb sites bound to O2 2. p50 = O2 partial pressure for half-saturation ii. θ /(1- θ) = pO2/p50 1. take logs of this equation  linear graph  no cooperativity III. HEMOGLOBIN A. Structure i. Primary, secondary and tertiary structures are same as Mb Differences in Hb and Mb - Mb is a storage ii. More than 1 subunit  quaternary structure: protein – binds O2 1. 2  and 2  subunits; cooperativity in binding and release of O2 avidly, dissociates slowly a.  subunits: 146 residues, identical (same gene) - Mb is not b. : 141 residues, differ by 1 or 2 genes cooperative 2. In urea, Hb dissolves into dimers of /- - interaction is stronger - Mb is 1 polypeptide than - or - 3. Tetramer is globular molecule: spherical iii. Subunits are 2.5nm apart  cooperativity is not due to heme-heme interaction; affinity of O2 varies with concentration (also with pH, CO2, 2,3 biphos. - see c) B. Conformational states i. Deoxy/Oxy Hemoglobin 1. Deoxy: molecule is very rigid, large cavity in center 2. Oxy: when exposed to O2,molecule loosens, rotates, cavity becomes smaller ii. Graph – sygmoidal curve  logs of affinity: 2 tangents – when 1 O2 bound, 4 th nd rd th O2 bound  demonstrates cooperativity – 2 binds 9x faster, 3 36x, 4 100x iii. Salt bridges of Hb – 1. charge-charge interactions between termini and other residues in deoxy state: a. C terminus of 2 (146 His) with Asp of 2, helix C of 1 (Lys40) b. 1 and 2 have same interactions (due to symmetry) c. N term of 1 with C term of 2; C term of 1 with N term of 2 d. C term of 1 with Asp126 of 2; inverse e. Tyr140 of 1 h bonds to COOH of Val93 of 1; also in  2. When O2 binds, these interactions are disrupted and Hb relaxes, permitting sliding and rotating to assume oxy conformation iv. Geometric explanation 1. Hemes are dome-shaped
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