STRUCTURE ACTIVITY STUDIES ON THE RETINAL ROD OUTER SEGMENT ISOPRENYLATED PROTEIN METHYLTRANSFERASE

Structure-activity studies were performed on the retinal rod outer segment isoprenylated protein methyltransferase that transfers a methyl group from S-adenosylmethionine (AdoMet) to the carboxyl group of isoprenylated (farnesylated or geranylgeranylated) cysteine residues. This methyltransferase enzyme has been shown to methylate N-acetyl-S-farnesyl-L-cysteine (L-AFC, 1) and S-(farnesyl-3-thio)propionic acid (FTP, 2). It is shown here that the enzyme does not enzymatically process D-AFC (8), although D-AFC (8) is a mixed-type inhibitor of the enzyme. Small modifications in the FTP (2) structural series generally lead to inactive substrates. For example, neither the cis- nor the trans-acrylate derivatives of FTP (2) are substrates of the enzyme, but both are inhibitors of it. Alkyl substitutions at the 3-position of FTP (2), moreover, lead to inhibitors of the methyltransferase. Substituents at the 2-position of FTP (2), as in 2-methyl-S-(farnesyl-3-thio)propionic acid (MFTP, 28) or S-farnesyl-2-(thiomethyl)acrylic acid (FTMA, 31), produce active substrates. Modifications at the carboxyl moiety produce neither substrates nor inhibitors of the enzyme. The conclusion from this and earlier studies is that the methyltransferase is selective for an isoprenylated thiopropionate moiety. Small deviations from this minimally essential structure lead to the abolition of substrate activity.