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From Proteopedia

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Hemoglobin 1qxd

Introduction

Individuals with Sickle Cell Anemia, or Sickle Cell Disease, contain a mutated form of hemoglobin, the oxygen binding protein found in red blood cells. Mutated hemoglobin causes normal disk-shaped red blood cells to become sickle-shaped. These sickle cells are fragile, deliver less oxygen to the body's tissues, and clog small blood vessels and capillaries, which results in a variety of adverse symptoms and detrimental complications. Some of these symptoms include abdominal and bone pain, breathlessness, fatigue, and rapid heart rate. Over time, irreversible tissue damage leads to the failure of many organ systems.

Sickle Cell Disease results from a single point mutation in the Hemoglobin amino acid sequence. Normal Hb contains a hydrophilic glutamate residue at position 6 of the beta strand, whereas in HbS, this residue has been changed to a hydrophobic valine residue. . The mutation region of one HbS molecule will then bind to a region defined by β Phe85 and β Leu88 in the Heme pocket of another HbS molecule via noncovalent hydrophobic interactions.. The subsequent polymerization of HbS molecules leads to the sickling of red blood cells.

The cooperative binding of oxygen leads to a conformation change in hemoglobin from the tense, or T state, to the R, or relaxed state. Recently, studies have shown that multiple relaxed Hb conformers exist, such as the R2, RR2, and R3 states.It has been proven that sickling only occurs with the deoxygenated T-state Hb, and it is therefore desirable to explore ways in which allosteric equilibrium can be shifted toward the R- conformation. Compounds that achieve such an equilibrium shift are therefore being sought. Vanillin, a food flavoring compound, as well as the furanic aldehyde compounds 5-hydroxymethyl-2-furfural (5HMF), 5-methyl-2-furfural (5MF), 5-ethyl-furfural (5EF), and furfural (FUF) all exhibit such antisickling properties and are nontoxic to humans. These compounds are therefore promising candidates for potential SCD drug treatments. It will later be seen that these compounds bind and stabilize the R2 conformation.

Overall Structure

Ordinary human hemoglobin is a tetramer of globular protein subunits: two α chains and two β chains. Both the α and β subunits are identical, and form two identical αβ dimers, which in turn form a dimer to create the complete structure of hemoglobin. Each of the subunits consists largely of alpha helices, with 8 in both the α and β chains and short, non-helical residue sequences binding them. In total, each α chain contains 141 residues, and each β chain contains 146.

The structure of sickle hemoglobin is identical to that of healthy hemoglobin, save for the substitution of a single residue within the β chains. The sixth residue in each chain, a glutamic acid, has been changed to a valine, resulting from a single point mutation. This mutation doesn't actually lead to any interference with the bonding interactions that lend hemoglobin its quaternary structure, and doesn't lead to structural changes within the hemoglobin or the β chain. It does, however, allow for hydrophobic interactions between separate hemoglobin proteins, leading to the polymerization of Hb molecules that causes sickling.

Each of the four globular domains within hemoglobin contains a heme group, the non-protein components that allow hemoglobin to bind to oxygen. Each heme group consists of an iron ion bound within four cyclically bonded pyrrole molecules, referred to as a whole as a porphyrin ring. Each pyrrole molecule consists of a heterocyclic ring of four carbons and one nitrogen, with the nitrogen from each ring bound to the Fe ion at the heme group's center. Each heme group is anchored in place in its respective subunit primarily by a histidine sidechain; a nitrogen atom in the imidazole ring on the sidechain anchors to the iron ion in the heme group, and the propanoate groups attached to the porphyrin ring are held in place by hydrophobic interaction with the hydrophobic residues within the subunit.

Binding Interactions

five-membered heterocyclic aldehydes inhibits sickling of homozygous sickle red blood cells and increases oxygen affinity of Hemoglobin

R state: N terminal αVall interactions Sites: α1ser131OG 1Thr134OG1 α2ser138OG

R2 state: N terminal αVall Sites: α2ser138OG

T state: N terminal αVall Sites: αTyr140OH - hydrogen bonding

Additional Features

oxygen is bound to iron in a heme group through ion-induced dipole forces

Heme made up of protoprophyrin with 4 linked pyrrole rings with a central Fe 2+ ion. Iron ion is coordinated to side chain of a histidine residue in myoglobin. An oxygen atom from O2 binds to a open coordination site with iron. When oxygen is bound to iron, iron moves into plane of prophyrin. T and R state depends on the amount of oxygen sites are bound to iron. R state refers to when oxygen is bound to sites, while T state reflects unbounded oxygen to oxygen binding sites.

Oxygen is bound to iron until it is ready to be released in tissue.

Hemoglobin is made of 4 monomers

Heretocyclic aldehydes increase oxygen affinity of hemoglobin strongly inhibit the sickling of homozygous sickle red blood they do this by readily passing through serum albumin and RBC membrane and then forming a Schiff-base adduct with intracellular oxy- and deoxyHbS. Heterocyclic aldehydes decreased sickle-cell hemoglobin polymerization by destabilizing the low-affinity T state, which in turn caused a shift in the sickle-cell hemoglobin allosteric equilibrium toward the high-affinity R state form. These heterocyclic aldehydes may be acting to prevent polymerization of sickle hemoglobin by binding to and stabilizing liganded hemoglobin in the form of R2 and/or various relaxed state hemoglobin, as well as binding to and destabilizing unliganded T state hemoglobin.

(note to other members, I'm not sure what else i can say for additional features)

Credits

Introduction - Ryan Colombo

Overall Structure - Will Yarr

Drug Binding Site - Jacqueline Pasek-Allen

Additional Features - Joey Nguyen

References