Porcin liver esterase (PLE) belongs to a family of carboxylesterases (EC 3.1.1.1) (Musidlowska & Bornscheuer 2003, p. 1139). Carboxylesterases often differ in their immunological, genetic and biochemical properties and have different functions depending on the part of the organism they are expressed. The enzyme is isolated from pigs’ hepatic tissues and is constituted of three major subunits: the alpha, beta and gamma subunits that exist in trimeric form (Musidlowska & Bornscheuer 2003, p. 1139). The general roles of carboxylesterases include the detoxification of xenobiotics since they can effectively degrade a wide range of exogenous compounds like amides, thoiesters and esters. The degradation of these latter compounds, esters, has significantly been exploited in drug delivery systems.
While PLE hydrolyzes esters and this property has been used in the delivery of pro-drugs, the enzyme expresses a varying range of stereoselectivity in its substrates and acts on a number of compounds such as a diesters of mesocycloalkane-1,2-dicarboxylic acid. However, one of the most striking features of PLE is that hydrolysis reaction catalyzed by PLE is strictly stereospecific for S-centre esters for cyclobutanyl-and cyclopropanyl-substrates (Jones1990, p. 1445). However, PLE is always stereospecific for the R-centre when it comes to the cyclohexanyl diesters. The ability of PLE to hydrolyze esters was studied through the use of PLE recombinant gamma subunit and was found to have similar activity with proline-β-naphthylamidase and proline intestinal carboxylesterase (PICE) also from the liver of pigs.
PLE cleaves a number of esters although no natural compounds have been identified to be cleaved by PLE (Bonneau, et al 1996, p. 357). The exploitation of this property has been of success in the delivery of natural compounds such as prostaglandin E1. PLE is able to cleave the methyl ester moiety in the prostaglandin while maintaining the integrity of the rest of the molecule (Shim 1989, p.33). However, for these drugs molecules to be cleaved off the ester in them have to fit exactly into the active sites and this shows a high degree of specificity. An example of such agents that can be delivered as pro-drugs is dimethylfumarate and ethylhydrogenfumarate in the forms of zinc, calcium and magnesium salts (Werdenberg, et al 2003, p. 259). These drugs can be delivered as esters (mono and diesters) of fumaric acid to enhance stability against hepatic and intestinal hydrolysis and increase permeability.
Bibliography
- Bonneau, PR, Martin, R, Lee, T, Sakowicz, R, Martichonok, V, Hogan, JK, Gold, M & Jones, JB 1996, “Enzymes in organic synthesis. Present and future, Journal of Brazil Chemical Society, vol.7, no.5, pp. 357-369
- Jones, JB 1990, Esterases in organic synthesis: present and future, Pure & Applied Chemistry, vol. 62, no. 7, pp. 1445-1448
Musidloswska-Person, A & Bornscheuer 2003 UT, Recombinant porcine intestinal carboxylesterase: cloning from the pig live esterase gene by site directed mutagenesis, functional expression and characterization, Protein Engineering, vol.16, no. 12, pp. 1139-1145 - Shim, YK, Shim, J, Cho, YS & Kim, WJ 1989, “Enzymatic hydrolysis of β-lactam esters by PLE”, Bulletin of Korean Chemical Society, vol.10, no. 1, pp. 33-34.
- Werdenberg, D, Joshi, R, Wolffram, S, Merkle, HP & Langguth, P 2003, “Presystematic metabolism and intestinal absorption of antipsoriatic fumaric acid esters”, Biopharmaceutics & Drug Disposition, vol. 24, pp. 259-273
