Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 3. Modifications of the sugar portion of S-adenosylhomocysteine.

Structural analogs of S-ADENOSYL-L-HONOCYSTEINE (L-SAG), WITH MODIFICATION IN THE RIBCOSE PORTION OF THE MOLECULE, HAVE BEEN SYNTHESIZED AND THEIR ABILITIES TO INHIBIT CATECHOL O-METHYLTRANSFERECE(COMT), phenylethanolamine N-methltransferase (PNMT) histamine N-methyltransferase (HMT),and hydroxyindole o-methytransferase (HIOMT) have been investigated. From these studies it was concluded that, in general, the 2'-hydroxyl and 3'-hydroxyl groups of the ribcose moiety of SAH play crucial roles in the binding of this molecule to most methyltransferases. However several interesting exceptions to this strict structural specificity have been observed. While S-3'-DEOXY-ADENOSYL-L-HOMOCYSTEINE PRODUCED NO INHIBITION OF HMT and HIOMT, it produced strong inhibition of the transmethylation catalyzed by PNMT and COMT. Likewise, S-2'-DEOXYADENOSYL-L-HOMOCYSTEINE AND S-5'-(9-(arabinofuranosyl)adenyl)-l-homocysteine had little or no effect of COMT, HMT, and HIOMT but were potent inhibtors of PNMT. The significance of these data relative to the nature of the SAH binding sites and the potential inhibitors of PNMT. The significance of these data relative to the nature of the SAH binding sites and the potential for in vivo differential inhibition of methyltransferases will be discussed.