Allosteric Inhibition of Cobalt Binding to Albumin by Fatty Acids: Implications for the Detection of Myocardial Ischemia

• Published in: Journal of medicinal chemistry 2012-05, Vol.55 (9), p.4425-4430
• Main Authors: Lu, Jin, Stewart, Alan J, Sadler, Peter J, Pinheiro, Teresa J. T, Blindauer, Claudia A
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Binding, Competitive; Biomarkers - analysis; Calorimetry; Cattle; Cobalt - chemistry; Cobalt - metabolism; Humans; Magnetic Resonance Spectroscopy; Myocardial Ischemia - diagnosis; Myocardial Ischemia - metabolism; Myristic Acid - chemistry; Myristic Acid - metabolism; Serum Albumin, Bovine - chemistry; Serum Albumin, Bovine - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3003137

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, 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 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.