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Allosteric inhibition of cobalt binding to albumin by fatty acids : implications for the detection of myocardial ischemia
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Lu, Jin, Stewart, Alan J., Sadler, P. J., Pinheiro, Teresa J. T. and Blindauer, Claudia A. (2012) Allosteric inhibition of cobalt binding to albumin by fatty acids : implications for the detection of myocardial ischemia. Journal of Medicinal Chemistry, Vol.55 (No.9). pp. 4425-4430. doi:10.1021/jm3003137
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WRAP_Pinheiro_495_JLu_Manuscript_JMedChem_revisions_02042012.pdf - Accepted Version Download (820Kb) | Preview |
Official URL: http://dx.doi.org/10.1021/jm3003137
Abstract
The biomarker "ischemia-modified albumin" (IMA), measured by the albumin-cobalt-binding assay (ACB assay), is the only FDA-approved biomarker for early diagnosis of myocardial ischemia. On the basis of the hypothesis that high levels of free fatty acids are directly responsible for reduction in cobalt binding by albumin, chemically defined model systems consisting of bovine serum albumin, Co(2+), and myristate were studied by isothermal titration calorimetry, (111)Cd NMR spectroscopy, and ACB assays. Significantly reduced Co(2+) binding to albumin, as demonstrated by an increase in the absorption of the Co-dithiothreitol adduct, elicited by adding ca. 3 mol equiv of myristate, was comparable to that observed in clinical ACB assays. Levels of free fatty acids are elevated during myocardial ischemia but also in other conditions that have been correlated with high IMA values. Hence, IMA may correspond to albumin with increased levels of bound fatty acids, and all clinical observations can be rationalized by this molecular mechanism.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Science > Chemistry Faculty of Science > Life Sciences (2010- ) |
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| Library of Congress Subject Headings (LCSH): | Allosteric regulation, Fatty acids, Reduction (Chemistry), Coronary heart disease -- Diagnosis, Cobalt, Albumins, Cooperative binding (Biochemistry) | ||||
| Journal or Publication Title: | Journal of Medicinal Chemistry | ||||
| Publisher: | American Chemical Society | ||||
| ISSN: | 0022-2623 | ||||
| Official Date: | 10 May 2012 | ||||
| Dates: |
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| Volume: | Vol.55 | ||||
| Number: | No.9 | ||||
| Page Range: | pp. 4425-4430 | ||||
| DOI: | 10.1021/jm3003137 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), BP (Firm), Royal Society (Great Britain), European Research Council (ERC) | ||||
| Grant number: | BB/D524516/1 (BBSRC) |
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