TY - JOUR
T1 - Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin
AU - Ascenzi, Paolo
AU - Imperi, Francesco
AU - Coletta, Massimo
AU - Fasano, Mauro
PY - 2008/5/2
Y1 - 2008/5/2
N2 - 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.
AB - 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.
KW - Abacavir
KW - Allostery
KW - Drug-dependent denitrosylation kinetics
KW - Ferrous nitrosylated human serum heme-albumin
KW - Warfarin
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U2 - 10.1016/j.bbrc.2008.02.077
DO - 10.1016/j.bbrc.2008.02.077
M3 - Article
C2 - 18307975
AN - SCOPUS:40849114506
VL - 369
SP - 686
EP - 691
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -