Allosteric inhibition of cobalt binding to albumin by fatty acids: Implications for the detection of myocardial ischemia

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. Based on 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 BSA, Co2+, and myristate were studied by Isothermal Titration Calorimetry, 111Cd NMR spectroscopy, and ACB assays. Significantly reduced Co2+ binding to albumin, as demonstrated by an increase in absorption of the Co-dithiothreitol adduct, elicited by adding ca. 3 molar equivalents 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 rationalised by this molecular mechanism.