Journal article
Molecular Crowding Limits the Role of Fetal Hemoglobin in Therapy for Sickle Cell Disease
Journal of molecular biology, v 347(5), pp 1015-1023
2005
PMID: 15784260
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The dominant assumption central to most treatments for sickle cell anemia has been that replacement of sickle hemoglobin (HbS) by fetal hemoglobin (HbF) would have major clinical benefit. Using laser photolysis, we have measured polymerization kinetics including rates of homogeneous and heterogeneous nucleation on mixtures of 20% and 30% HbF with HbS. We find that the present model for polymerization, including molecular crowding, can accurately predict the rates of such mixtures, by using the single assumption that no significant amount of HbF enters the polymer. The effects of replacing HbS by HbF on the rates of polymer formation are found to be significantly lower than previous measurements appeared to indicate because the impact of the replacement is also highly dependent on the total hemoglobin concentration. This is because the molecular crowding of non-polymerizing HbF offsets substantially the effects of decreasing the concentration of HbS concentration, an effect that increases with concentration. Most strikingly, the demonstrated benefit of hydroxyurea therapy in slowing the kinetics of intracellular polymerization cannot be primarily due to enhanced HbF, but must have some other origin, which could itself represent a promising therapeutic approach.
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Details
- Title
- Molecular Crowding Limits the Role of Fetal Hemoglobin in Therapy for Sickle Cell Disease
- Creators
- Maria Rotter - Department of Physics, Drexel Univesity, Philadelphia, PA 19104, USAAlexey Aprelev - Department of Physics, Drexel Univesity, Philadelphia, PA 19104, USAKazuhiko Adachi - Children's Hospital of Philadelphia, Division of Hematology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAFrank A Ferrone - Department of Physics, Drexel Univesity, Philadelphia, PA 19104, USA
- Publication Details
- Journal of molecular biology, v 347(5), pp 1015-1023
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000228111800012
- Scopus ID
- 2-s2.0-15244361470
- Other Identifier
- 991014878138204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology