Acetyl choline esterase

Acid- and base-sensitive lipidated peptides can be selectively deprotected by enzymatic hydrolysis of choline esters.[13al Choline esters of simple peptides, but also of sensitive peptide conjugates like phos-phorylated and glycosylated peptides,1141 nucleopep-tides1151 and lipidated peptides,113,1631 can be cleaved with acetyl choline esterase (AChE) and butyryl choline esterase (BChE) under virtually neutral conditions with complete chemoselectivity. Acid-labile farnesyl groups and base-sensitive thioesters are not attacked. 

Quon et al. (1985) investigated the stability of esmolol in blood, plasma, red blood cells, and purified enzymes (human serum pseudocholinesterase, human and dog serum albumin, acetyl choline esterase, carbonic anhydrases A and B and human haemoglobin). Udata et al. (1999) studied the hydrolysis of propranolol ester prodrugs in purified acetylcholine esterase. 

Thus (+)-[Ni(phen)3]2+ and (+)-[Ru(phen)3]2+ are more toxic to mice by intraperitoneal injection (153) than are their enantiomers. As the mice exhibited symptoms of curare poisoning (24) which is thought to be due to inhibition of acetyl choline-esterase, the effects of some other complexes on this enzyme were studied. (—)-[Ru(bipy)3]2+ inhibits (153) this enzyme much more than does (- -)-[Ru(bipy)3]2+. However, the enantiomers of [Ru(bipy)3]2+ have equal toxicities to mice (153), and (+)-[Ru(phen)3]2+ is more readily absorbed from the intraperitoneal cavity than is (—)-[Ru(phen)3]2+.The configurations of (—)-[Ru(bipy)3]2+ and (+)-[Ru(phen)3]2+ have been said (44) to be identical on the basis of the physiological work outlined above, but this conclusion, resting as it does on physiological results which are of doubtful relationship to one another is very tenuous, and conflicts with other work (see p. 78). 

Figure 8.10 Acetylcholine Esterase, (a) Hydrolysis reaction catalyzed by acetyl choline esterase (AChE) (b) ribbon display structure of AChE Torpedo californica) (pdb lamn) illustrating crystallographic water molecules (oxygen red hydrogen white) plus sulphate ion and substrate analogue bound in catalytic site. Both these are rendered as CPK structures (red oxygen yellow sulphur grey carbon blue nitrogen).

Figure 8.14 Colourimetric assay. Acetyl Choline Esterase (AChE) assay system involving thio-acetylcholine that is hydrolyzed to thio-choline. This in turn combines with colourless reagent 5,5 -dithio-bis(nitrobenzoic acid) (DTNB) to form yellow coloured 5-thio-2-nitro-benzoic acid (TNB).

B Oxidative bioactivation of losartan C Methyienedioxy derivatives as bioprecursors of catechols D Site-specific delivery of the acetyl-choline-esterase reactivator 2-PAM to the brain... 

The activity of these biofunctional peptides is based on their inherent amino acid composition and sequence. The size of active sequences may vary from 2 to 20 amino acid residues, and many peptides are known to have multifunctional properties [89], e.g., peptides from the sequence 60-70 of P-casein show immunostimulatory, opioid, and angiotensin I converting enzyme (acetyl choline esterase [ACE]) -inhibitory activities. This sequence has been defined as a strategic zone [90,91]. The sequence is protected from proteolysis because of its high hydrophobicity and the presence of proline residues. Other examples of the multi-functionality of milk-derived peptides include the... 

Hydrolysis of the postsynaptically bound ACh. The most rapid step of the ACh metabolism is the enzymatic decomposition of ACh. Acetyl choline esterase (EC 3.1.1.7) is a very active enzyme. Rapid hydrolysis is the precondition of rapid recovery of the resting state after transmitting an impulse. 

Aceclidine exerts an inhibiting action on pseudo- and acetyl-choline-esterase but is 1,000-10,000 times less active than neostigmine methylsulphate. 

Quaternary ammonium salts with a single quaternary centre tend to be both water and fat soluble. Thus acetyl choline esterase inhibitor neostigmine bromide (Fig. 3.27) is both water soluble and moderately well absorbed from the GI tract, whereas polycationic quaternary amines such as gaUamine triethiodide (Fig. 3.27) are much less lipophilic and have to be administered by injection. Apart from the role of long-chain quaternary amines as disinfectants, most quaternary amine dmgs act on the cholinergic system either as acetyl choline esterase inhibitors or via direct actions on the acetyl choline receptor. 

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