The observation that S-adenosylhomocysteine (SAH) inhibits S-adenosylmethionine (SAM)-dependent methyltransferases and that our sugar-modified SAH analogs (2'-deoxy-SAH, 3'-deoxy-SAH, S-AraAH) were potent inhibitors, while Coward's cyclopentyl SAH analogs were nearly inactive against catechol O-methyltransferase (COMT) (suggesting the 1',4'-oxygen bridge's role in binding/conformation), led us to synthesize and reexamine Saristeromycinyl-L-homocysteine (SAmH) as a SAM-dependent methyltransferase inhibitor. We prepared SAmH from aristeromycin via a two-step synthesis (5'-chloro-5'-deoxyaristeromycin intermediate reacting with L-homocystine) with a 56% yield (superior to Coward's method). SAmH was a potent competitive inhibitor of SAM-dependent methyltransferases including COMT, phenylethanolamine N-methyltransferase (PNMT), histamine N-methyltransferase (HMT), and hydroxyindole O-methyltransferase (HIOMT). Notably, SAmH (Kis = 7.50 ± 0.62 μM) inhibited PNMT significantly more potently than SAH (29.0 ± 2.84 μM). Contrary to Coward's report, 1.5 mM SAmH inhibited COMT by 71%. SAmH converted to Saristeromycinyl-L-methionine-methyl-¹⁴C (SAmM-¹⁴CH₃) was a good substrate for these enzymes (Km/Vmax comparable to SAM). Conclusions: The 1',4'-oxygen bridge is not required for binding to these enzymes; the N-glycosidic linkage is not essential for SAH's active conformation. PNMT's tolerance to SAH sugar modifications supports designing specific inhibitors by leveraging methyltransferases' SAH binding site specificity differences.