Drug binding to Sudlow's site I impairs allosterically human serum heme-albumin-catalyzed peroxynitrite detoxification.
Heme endows human serum albumin (HSA) with globin-like reactivity and spectroscopic properties. Here, the effect of chlorpropamide, digitoxin, furosemide, indomethacin, phenylbutazone, sulfisoxazole, tolbutamide, and warfarin on peroxynitrite isomerization to NO(3) (-) by ferric HSA-heme (HSA-heme-Fe(III)) is reported. Drugs binding to Sudlow's site I impair dose-dependently peroxynitrite isomerization by HSA-heme-Fe(III). The allosteric modulation of HSA-heme-Fe(III)-mediated peroxynitrite isomerization by drugs has been ascribed to the pivotal role of Tyr150, a residue that either provides a polar environment in Sudlow's site I or protrudes into the heme cleft (i.e., the fatty acid site 1, FA1), depending on ligand occupancy of either sites.
Ascenzi
Paolo
P
Department of Biology and Interdepartmental Laboratory for Electron Microscopy, University Roma Tre, Roma, Italy. ascenzi@uniroma3.it
Bolli
Alessandro
A
Gullotta
Francesca
F
Fanali
Gabriella
G
Fasano
Mauro
M
D000494:Allosteric Regulation; D000495:Allosteric Site; D002384:Catalysis; D005290:Ferric Compounds / Q000737:chemistry; D006418:Heme / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D030421:Peroxynitrous Acid / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D012709:Serum Albumin / Q000737:chemistry*; D013237:Stereoisomerism
D005290:Ferric Compounds; D004364:Pharmaceutical Preparations; D012709:Serum Albumin; D030421:Peroxynitrous Acid; D006418:Heme