Other Serine Hydrolases

Other serine hydrolases such as cholinesterases, carboxylesterases, lipases, and fl-lactamases of classes A, C, and D have a hydrolytic mechanism similar to that of serine peptidases [25-27], The catalytic mechanism also involves an acylation and a deacylation step at a serine residue in the active center (see Fig. 3.3). All serine hydrolases have in common that they are inhibited by covalent attachment of diisopropyl phosphorofluoridate (3.2) to the catalytic serine residue. The catalytic site of esterases and lipases has been less extensively investigated than that of serine peptidases, but much evidence has accumulated that they also contain a catalytic triad composed of serine, histidine, and aspartate or glutamate (Table 3.1). 

Diisopropylfluorophosphate, in contrast to its action on other serine hydrolases, has only a slight inhibitory effect on alkaline phosphatase in the range 1-10 ml (76, 113). 

LPL is a glycoprotein (8% by weight carbohydrate) with a native molecular weight of around 100 000 Da and a monomer subunit of about 50 000 Da (Kinnunen et al., 1976). Senda et al. (1987) calculated the molecular weight of the unglycosylated form as 50 548 Da based on the cDNA encoding it. LPL has a serine at the active site, located in a beta turn in the enzyme, similar to that at the active site of other serine hydrolases (Reddy et al., 1986). 

Since OPs inhibit serine hydrolases such as AChE by phosphorylating them, it follows that OPs are potential inhibitors of all other serine hydrolases. This means that OPs can be used as synergists, notably for the pyrethroids that are detoxified by ester hydrolysis, and OP-containing mixture have proven successful in several cases (34.) The usefulness of these mixtures can be prolonged by using them in rotations with other mixtures and/or insecticides. 

Another early discovery was that CALB accepts H202 as nucleophile to produce peroxycarboxylic acids from esters or carboxylic acids (perhydrolysis activity can also be found in other serine hydrolases) [46, 47]. The in situ formed peracid can subsequently be used to epoxidize an alkene by (non-enzymatic) Prileshajev epoxidation. Hence, oleic acid incubated with CALB and H202 will produce 9,10-epoxyoctadecanoic acid [48]. Other alkenes can be epoxidized by H202 and a catalytic amount of carboxylic acid (and CALB) (Scheme 13.2) [49],... 

Other pancreatic enzymes, like phospholipase A2, amylase, trypsin, chymo-trypsin and liver-esterase, are not blocked by lipstatin. Though, it is known that tetrahydrolipstatin also inhibits other serine-hydrolases such as stomach-lipase and pancreas-carboxylic-ester lipase. [253]... 

---