Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin

Human serum albumin (HSA) participates to heme scavenging, in turn HSA–heme binds gaseous diatomic ligands at the heme–Fe-atom. Here, the effect of abacavir and warfarin on denitrosylation kinetics of HSA–heme–Fe(II)–NO (i.e., koff) is reported. In the absence of drugs, the value of koff is (1.3 ± 0.2) × 10−4 s−1. Abacavir and warfarin facilitate NO dissociation from HSA–heme–Fe(II)–NO, the koff value increases to (8.6 ± 0.9) × 10−4 s−1. From the dependence of koff on the drug concentration, values of the dissociation equilibrium constant for the abacavir and warfarin binding to HSA–heme–Fe(II)–NO (i.e., K = (1.2 ± 0.2) × 10−3 M and (6.2 ± 0.7) × 10−5 M, respectively) were determined. The increase of koff values reflects the stabilization of the basic form of HSA–heme–Fe by ligands (e.g., abacavir and warfarin) that bind to Sudlow’s site I. This event parallels the stabilization of the six-coordinate derivative of the HSA–heme–Fe(II)–NO atom. Present data highlight the allosteric modulation of HSA–heme–Fe(II) reactivity by heterotropic effectors.