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.
Department of Biology and Interdepartmental Laboratory for Electron Microscopy, University Roma Tre, Roma, Italy. ascenzi@uniroma3.it
Paolo
P
Ascenzi
Alessandro
A
Bolli
Francesca
F
Gullotta
Gabriella
G
Fanali
Mauro
M
Fasano
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