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Polyisoprenylation potentiates the inhibitory and cell degenerative potency of sulfonyl fluorides towards polyisoprenylated methylated protein methyl esterase
Author(s) -
Aguilar Byron,
Amissah Felix,
Duverna Randolph,
Lamango Nazarius
Publication year - 2010
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.24.1_supplement.681.2
Subject(s) - pmsf , chemistry , stereochemistry , esterase , sulfonyl , enzyme , biochemistry , carboxylesterase , phenylmethylsulfonyl fluoride , active site , serine , organic chemistry , alkyl
Polyisoprenylated protein methyl transferase catalyses the esterification of polyisoprenylated proteins (PP) whereas polyisoprenylated methylated protein methyl esterase (PMPMEase) hydrolyses the ester bond. Significant changes in their enzymatic activity may alter PP function causing disease. Prior studies show that PMPMEase is Sus scrofa carboxylesterase, which hints at its susceptibility to serine protease inhibitors such as phenylmethylsulfonyl fluoride (PMSF). PMSF was used as a prototypical compound to develop high affinity specific inhibitors of PMPMEase. Pseudo first‐order kinetics revealed an over 680‐fold increase in k obs /[I] (M −1 s −1 ) values from PMSF (6), S‐ trans,trans ‐farnesyl (L‐28, 2000), to S‐ trans ‐geranylated (L‐23, 4100) 2‐thioethanesulfonyl fluorides. The compounds induced the degeneration of human neuroblastoma SH‐SY5Y cells with EC 50 values of 49, 130 and >1000 μM for L‐28, L‐23 and PMSF, respectively. The increase in affinity with the polyisoprenyl derivatization corroborates the observed substrate specificity and the reported hydrophobicity of the PMPMEase active site. These results suggest that (1) PMPMEase is a key enzyme for PP metabolism, (2) regulation of its activity is essential for maintaining cell viability, (3) abnormal activities may be involved in degenerative diseases and cancers and (4) its specific inhibitors may be useful in combating cancers.