2Y1K

STRUCTURE OF HUMAN BUTYRYLCHOLINESTERASE INHIBITED BY CBDP (12H SOAK): PHOSPHOSERINE ADDUCT

Summary for 2Y1K

• Entry DOI: 10.2210/pdb2y1k/pdb
• Related: 1EHO 1EHQ 1KCJ 1P0I 1P0M 1P0P 1P0Q 1XLU 1XLV 1XLW 2J4C 2WID 2WIF 2WIG 2WIJ 2WIK 2WIL 2WSL 2XMB 2XMC 2XMD 2XMG 2XQF 2XQG 2XQI 2XQJ 2XQK
• Descriptor: CHOLINESTERASE, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (9 entities in total)
• Functional Keywords: hydrolase, inhibition, aging
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 62654.43

Authors

Carletti, E.,Colletier, J.P.,Nachon, F.,Weik, M. (deposition date: 2010-12-08, release date: 2011-06-29, Last modification date: 2023-12-20)

Primary citation

Carletti, E.,Schopfer, L.M.,Colletier, J.P.,Froment, M.T.,Nachon, F.,Weik, M.,Lockridge, O.,Masson, P.
Reaction of Cresyl Saligenin Phosphate, the Organophosphorus Agent Implicated in Aerotoxic Syndrome, with Human Cholinesterases: Mechanistic Studies Employing Kinetics, Mass Spectrometry, and X-Ray Structure Analysis.
Chem.Res.Toxicol., 24:797-, 2011

PubMed Abstract: Aerotoxic syndrome is assumed to be caused by exposure to tricresyl phosphate (TCP), an antiwear additive in jet engine lubricants and hydraulic fluid. CBDP (2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one) is the toxic metabolite of triortho-cresylphosphate, a component of TCP. Human butyrylcholinesterase (BChE; EC 3.1.1.8) and human acetylcholinesterase (AChE; EC 3.1.1.7) are irreversibly inhibited by CBDP. The bimolecular rate constants of inhibition (k(i)), determined under pseudo-first-order conditions, displayed a biphasic time course of inhibition with k(i) of 1.6 × 10(8) M(-1) min(-1) and 2.7 × 10(7) M(-1) min(-1) for E and E' forms of BChE. The inhibition constants for AChE were 1 to 2 orders of magnitude slower than those for BChE. CBDP-phosphorylated cholinesterases are nonreactivatable due to ultra fast aging. Mass spectrometry analysis showed an initial BChE adduct with an added mass of 170 Da from cresylphosphate, followed by dealkylation to a structure with an added mass of 80 Da. Mass spectrometry in (18)O-water showed that (18)O was incorporated only during the final aging step to form phospho-serine as the final aged BChE adduct. The crystal structure of CBDP-inhibited BChE confirmed that the phosphate adduct is the ultimate aging product. CBDP is the first organophosphorus agent that leads to a fully dealkylated phospho-serine BChE adduct.

PubMed: 21438623
DOI: 10.1021/TX100447K

Experimental method

X-RAY DIFFRACTION (2.5 Å)