Hydrolysis esterases

Expt Intracellular diffusion/ bioconversion Esterase hydrolysis k (sec-1) Fraction metabolized Fraction not metabolized... 

R. Traverso, A. Moretto, M. Lotti, Human Serum A -Esterases. Hydrolysis of o,o-Dimethyl-2,2-dichlorovinyl Phosphate , Biochem. Pharmacol. 1989, 38, 671-676. 

The types of enzymes that bring about hydrolysis are hydrolase enzymes. Like most enzymes involved in the metabolism of xenobiotic compounds, hydrolase enzymes occur prominently in the liver. They also occur in tissue lining the intestines, nervous tissue, blood plasma, the kidney, and muscle tissue. Enzymes that enable the hydrolysis of esters are called esterases, and those that hydrolyze amides are amidases. Aromatic esters are hydrolyzed by the action of aryl esterases and alkyl esters by aliphatic esterases. Hydrolysis products of xenobiotic compounds may be either more or less toxic than the parent compounds. 

The phosphate products may be measured in urine as bioindicators of exposure to organophosphates. The product that is observed depends on whether or not oxidative desulfuration occurs prior to esterase hydrolysis of the molecules. These products have been studied in the urine of greenhouse workers exposed to three methyl organophosphate esters toclofos-methyl (Figure 18.9), feni-trothion (Figure 18.9), and omethoate, a phosphorothiolate compound (below)14 ... 

Articaine is an aminoamide that also contains an ester group, which is rapidly hydrolysed by plasma esterases. It is 4-methyl-3([2-(propylamino)propion-amido)]-2-thiophenecarboxylic acid, methyl ester hydrochloride. The thiophene group increases its lipid solubility while the ester group enables it to undergo plasma esterase hydrolysis as well as hepatic enzyme metabolism. Articaine is formulated as a 4% solution with adrenaline. It is the most widely used local anesthetic agent in dentistry in some parts of Europe. 

The onset of neuromuscular blockade typically occurs in 3-5 min of i.v. administration and lasts for 20-35 min. Higher doses will result in a longer duration of blockade. Pancuronium is eliminated primarily in bile and vecuronium undergoes hepatic and renal excretion. The recovery from blockade produced by atracurium is a result of metabolism by non-specific plasma esterases (hydrolysis) and spontaneous Hoffman degradation (spontaneous at body temperature and physiological pH), which is independent of renal or hepatic function and, therefore, unaffected by renal or hepatic disease (Plumb 1995). Atracurium does not accumulate. 

Vree, T.B., Dammers, E., Ulc, I., Horkovics-Kovats, S., Ryska, M. and Merkx, I. (2003) Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose. The Scientific Word Journal, 3,1332-1343. 

Bacillus sp. (Nitro-benzyl- esterases) Hydrolysis of polyethylene terephthalate) oligomers [61, 62]... 

As a rule, amides are more stable to esterase hydrolysis than are esters, and it is not surprising to find amides excreted largely unchanged. This fact has been exploited in developing the antiarrhythmic drug procainamide. Procaine is not useful because of its rapid esterase hydrolysis, ... 

Hydrolases Amidohydrolases Esterases Urease Acetylcholine esterase Hydrolysis reactions Urea Acetylcholine NH3, CO2 or H+ H +... 

Figure 24.12 Changes in rednced viscosity (o, ) and scattered light ( ) during the addition of CaCl2 to pectin solutions (polymer concentration 0.2gL 5 X 10 M CaCy. Role of the carboxyl group distribution (a) DE = 30 per cent blockwise distribution, obtained by pectin-esterase hydrolysis (b) DE = 30 per cent random distribution, obtained by alkaline hydrolysis. (Reproduced from Reference [92], with permission from John WUey Sons, Inc., on hehalf of...

An example of this is the formation of acetylcholine derivatives. Acetylcholine, a neurotransmitter in higher animals and human beings (E 3.2), is rapidly degraded by choline esterase. Hydrolysis of the synthetically prepared ester of choline with carbamic acid (carbachol) is, however, much slower, and the physiological action of carbachol therefore lasts much longer than that of acetylcholine. 

There continue to be reports of potential prodrugs of biologically-active nucleoside-5 -phosphates. The S-acetyl-2-thioethyl ester 137 of d4T has been prepared, and undergoes esterase hydrolysis in the cell. The same team have also made the analogous derivative of AZT. A series of aromatic aminoacid phosphoramidates of AZT have been described as have bis-ketol AZT monophosphates and 4-acyloxybenzyl bis(nucleosid-5 -yl) phosphates of AZT and ddl. Phosphodi- and tri-esters incorporating both AZT and a metal-com-... 

Lovastatin is rapidly metabolised, which is undesirable for any dmg likely to be chronically administered. In order to achieve once-daily dosing, steric hindrance around the ester carbonyl was increased by the introduction of an extra methyl group close to the ester bond in order to reduce the rate of esterase hydrolysis. This resulted in formation of simvastatin, a highly successful lipid-lowering agent. Simvastatin (like lovastatin) is inactive until metabolised in the liver to form its active metabolite mevinolinic acid (Fig. 8.48). Part of mevino-linic acid is stmcturally similar to the HMG portion of HMG-GoA, the substrate for HMG-CoA reductase, and hence competes with it for the active site of the enzyme. This reduces the amount of mevalonic acid which is produced. Mevalonic acid is a precursor of cholesterol. 

The extra methyl group led to enhanced selectivity at the muscarinic receptor and diminished activity at the nicotine receptor. Methacholine was designed to ensure stability against chemical hydrolysis, but the additional group appeared to provide hindrance to access of cholinesterase as well, and methacholine is three times more resistant to esterase hydrolysis than ACh. 

A number of papers describe techniques for the determination of choline esterase activity based on amperometric measurement of the product formed as a result of enzymatic hydrolysis. The oxidation potential of choline is too high to be electro-chemically oxidized directly. In this case, artificial (nonnative) choline esterase substrates are used. Thus, butyiyl or acetyl thiocholine forms thiocholine as a result of choline esterase hydrolysis. When the analyte is not present in the solution, the substrate acetylthiocholine is converted into thiocholine and acetic acid. Thiocholine is oxidized by the appUed voltage. In the presence of an inhibitor, conversion of acetylthiocholine is decreased or even null. Furthermore, the anodic oxidation current is inversely proportional to the concentration of pesticides in samples and the exposed time as well. The procedure of the preparation of an AChE biosensor and pesticide detection is shown in Fig. 13.4. 

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