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Studies with S‐alkylated cysteine methyl esters suggest carboxylesterase 1 may be polyisoprenylated methylated protein methyl esterase
Author(s) -
Lamango Nazarius Saah,
Koikov Leonid N,
Duverna Randolph
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1008.8
Subject(s) - chemistry , esterase , carboxylesterase , cysteine , alkylation , stereochemistry , serine , biochemistry , prenylation , enzyme , catalysis
An estimated 2% of eukaryotic proteins are S‐polyisoprenylated on a terminal cysteine. The terminal ‐COOH is esterified by isoprenyl carboxyl methyl transferase (ICMT). The methyl esters are hydrolyzed by serine esterases in the only reversible step of the pathway. While ICMT has been well studied, the esterases have received little attention. We purified and identified a liver esterase, which like ICMT has an ER‐retention signal. This “promiscuous” esterase, so‐called because of its large and flexible active site and repertoire of substrates, is better known for its (pro)drugs and xenobiotics metabolism. If its endogenous substrates are polyisoprenylated proteins (PP) as suggested by earlier preliminary studies with farnesylated substrates, it will show a higher affinity for S‐farnesylated (C15) and S‐geranylgeranylated (C20). A series of chromophoric S‐alkylated substrates ranging from C2 to C‐20 were synthesized. Enzyme kinetics revealed an increase in affinity (Km values) for ethyl (505±63 μM), prenyl (294±25 μM), geranyl (87±12 μM), t,t ‐farnesyl (29±2.2 μM) and all t ‐geranylgeranyl (15±2.7 μM). Since the C15 and C20 modifications occur in proteins, the results with the latter two substrates suggest that PP may constitute the endogenous substrates of this esterase, with the “promiscuous” features designed to accommodate the polypeptides bearing the polyisoprenylated methylated cysteine.