Abstract
Myocardial ischemia is difficult to diagnose effectively with still few well-defined biochemical markers for identification in advance, or in the absence of myocardial necrosis. “Ischemia-modified albumin” (IMA), a form of albumin displaying reduced cobalt-binding affinity, is significantly elevated in ischemic patients, and the albumin cobalt-binding (ACB) assay can measure its level indirectly. Elucidating the molecular mechanism underlying the identity of IMA and the ACB assay hinges on understanding metal-binding properties of albumin. Albumin binds most metal ions and harbours four primary metal binding sites: site A, site B, the N-terminal site (NTS), and the free thiol at Cys34. Previous efforts to clarify the identity of IMA and the causes for its reduced cobalt-binding capacity were focused on the NTS site, but the degree of N-terminal modification could not be correlated to the presence of ischemia. More recent work suggested that Co2+ ions as used in the ACB assay bind preferentially to site B, then to site A, and finally to the NTS. This insight paved the way for a new consistent molecular basis of the ACB assay: albumin is also the main plasma carrier for free fatty acids (FFAs), and binding of a fatty acid to the high-affinity site FA2 results in conformational changes in albumin which prevent metal binding at site A and partially at site B. Thus, this review advances the hypothesis that high IMA levels in myocardial ischemia and many other conditions originate from high plasma FFA levels hampering the binding of Co2+ to sites A and/or B. This is supported by biophysical studies and the co-association of a range of pathological conditions with positive ACB assays and high plasma FFA levels.
Highlights
Myocardial ischemia occurs due to restricted blood supply to the muscular tissue of the heart resulting in insufficient oxygen supply
Following our discovery of free fatty acids (FFAs)-mediated inhibition of zinc binding to albumin [21,22,23,24], we have demonstrated that the conformational changes that FFA-binding to albumin elicits in the protein is sufficient to cause reduced cobalt binding capacity [22,25]
Before considering cobalt binding in depth, we will briefly summarise the interactions of albumin with other d-block metal ions, with the exception of Cr3+, Fe3+, and Mn2+, which are preferentially transported by transferrin, another important metal ion transporter in blood plasma
Summary
Myocardial ischemia occurs due to restricted blood supply to the muscular tissue of the heart (myocardium) resulting in insufficient oxygen supply. While a plethora of cardiac biomarkers have been described for detecting the development of other acute coronary syndromes (ACS) [2,3], there are still few well-defined biochemical markers for identification of myocardial ischemia in advance, or in the absence of myocardial necrosis. One of these biomarkers is based on albumin, the most abundant protein in blood plasma. This review will present essential background information on metal ion-albumin interactions and discuss the molecular basis of FFA-mediated inhibition of metal (in particular Co2+) binding It will provide a clinical perspective to highlight how conclusions from biochemical/ bioinorganic investigations are reflected in patient data
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