Multi-site inhibition of human plasma cholinesterase by cationic phenoxazine and phenothiazine dyes

Kucukkilinc T., Ozer I.

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, cilt.461, sa.2, ss.294-298, 2007 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 461 Sayı: 2
  • Basım Tarihi: 2007
  • Doi Numarası: 10.1016/j.abb.2007.02.029
  • Dergi Adı: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.294-298
  • Anahtar Kelimeler: acetylcholinesterase, butyrylcholinesterase, meldola blue, methylene blue, multi-site inhibition, nile blue, plasma cholinesterase, AMINO-ACID-RESIDUES, HUMAN BUTYRYLCHOLINESTERASE, ALZHEIMERS-DISEASE, ACETYLCHOLINESTERASE, BINDING, AGGREGATION, SELECTIVITY, ANTIDOTE, SITES, GORGE
  • Hacettepe Üniversitesi Adresli: Evet

Özet

Two cationic phenoxazine dyes, meldola blue (MB) and nile blue (NB), and the structurally related phenothiazine, methylene blue (MethB), were found to act as complex inhibitors of human plasma cholinesterase (butyrylcholinesterase, BChE). Studied at 25 OC, in 100 mM MOPS buffer (pH 8.0), with butyrylthiocholine as substrate, the kinetic pattern of inhibition indicated cooperative I binding at 2 sites. Intrinsic K ' values ( equivalent to [I](0.5)(2) extrapolated to [S] = 0) for MB, NB and MethB were 0.64 +/- 0.05, 0.085 +/- 0.026 and 0.42 +/- 0.04 mu M, respectively. Under the same experimental conditions the dyes acted as single-occupancy, hyperbolic-mixed inhibitors of electric eel acety1cholinesterase (AChE), with Ki = 0.035 +/- 0.010, 0.026 +/- 0.0034 and 0.017 +/- 0.0063 mu M (for MB, NB, MethB); alpha (coefficient of competitive interaction) = 1. 8-2.4 and beta (coefficient of noncompetitive interaction) = 0. 15-0.28. The complexity of the BChE inhibitory effect of phenoxazine/phenothiazine dyes contrasted with that of conventional ChE inhibitors which cause single-occupancy (n = 1), competitive or mixed inhibition in both AChE and BChE and signaled novel modes of ligand interaction at (or remote from) the active site gorge of the latter enzyme. (C) 2007 Elsevier Inc. All rights reserved.