Sandbox Reserved 426
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===Introduction=== | ===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. <scene name='Sandbox_Reserved_426/Glu6_residue_of_hb/3'>Glu 6 Residue of normal Hemoglobin</scene>. 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. | |
| - | Structural tension of T state attributed to interdimer salt bridges and hydrogen bonds, and the binding of 2,3-biphosphoglycerate (BPG) | ||
| - | + | 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, and are therefore promising candidates for potential SCD drug treatments. | |
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| - | <Structure load='1qxd' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | ||
| - | Red blood cells containing these polymerized HbS T-state molecules become sickle-shaped. These sickle-shaped cells block small capilaries, cause severe pain, and lead to tissue damage. | ||
| - | + | <Structure load='1qxd' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | |
===Overall Structure=== | ===Overall Structure=== | ||
Revision as of 17:26, 24 March 2012
| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
Contents |
YourMacromolecule
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, and are therefore promising candidates for potential SCD drug treatments.
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Overall Structure
Hemoglobin is a tetramer composed of two αβ dimers.
The majority of Hb consists of alpha helices, with each of the α and β domains containing 8 alpha helices and no beta strands.
Each α chain contains 141 residues, and each β chain contains 146.
Each of the four globular domains within hemoglobin contains a heme group, which consists of an iron ion bound within four cyclically bonded pyrrole molecules, and is bound to hemoglobin via a histidine sidechain.
The point mutation responsible for this altered form of hemoglobin changes a glutamic acid residue in both beta subunits to a valine, resulting in hydrophobic interactions between separate Hb molecules, but no major structural changes on an individual basis.
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
(note to other members, I'm not sure what else i can say for additional features for hemogloblin) the structure itself is already described, those things that arent heme groups are the 5 member heterocyclic aldehydes)
Credits
Introduction - Ryan Colombo
Overall Structure - Will Yarr
Drug Binding Site - Jacqueline Pasek-Allen
Additional Features - Joey Nguyen
