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PDBsum entry 1qxe
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Oxygen storage/transport
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PDB id
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1qxe
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for the potent antisickling effect of a novel class of five-Membered heterocyclic aldehydic compounds.
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Authors
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M.K.Safo,
O.Abdulmalik,
R.Danso-Danquah,
J.C.Burnett,
S.Nokuri,
G.S.Joshi,
F.N.Musayev,
T.Asakura,
D.J.Abraham.
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Ref.
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J Med Chem, 2004,
47,
4665-4676.
[DOI no: ]
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PubMed id
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Abstract
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Naturally occurring five-membered heterocyclic aldehydes, including
5-hydroxymethyl-2-furfural, increase the oxygen affinity of hemoglobin (Hb) and
strongly inhibit the sickling of homozygous sickle red blood (SS) cells. X-ray
studies of Hb complexed with these compounds indicate that they form Schiff base
adducts in a symmetrical fashion with the N-terminal alphaVal1 nitrogens of Hb.
Interestingly, two cocrystal types were isolated during crystallization
experiments with deoxygenated Hb (deoxyHb): one crystal type was composed of the
low-affinity or tense (T) state Hb quaternary structure; the other crystal type
was composed of high-affinity or relaxed state Hb (with a R2 quaternary
structure). The R2 crystal appears to be formed as a result of the aldehydes
binding to fully or partially ligated Hb in the deoxyHb solution. Repeated
attempts to crystallize the compounds with liganded Hb failed, except on rare
occasions when very few R state crystals were obtained. Oxygen equilibrium, high
performance liquid chromatography (HPLC), antisickling, and X-ray studies
suggest that the examined heterocyclic aldehydes may be acting to prevent
polymerization of sickle hemoglobin (HbS) by binding to and stabilizing liganded
Hb in the form of R2 and/or various relaxed state Hbs, as well as binding to and
destabilizing unliganded T state Hb. The proposed mechanism may provide a
general model for the antisickling effects of aldehyde containing small
molecules that bind to N-terminal alphaVal1 nitrogens of Hb. The examined
compounds also represent a new class of potentially therapeutic agents for
treating sickle cell disease (SCD).
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