Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 5. Role of the asymmetric sulfonium pole in the enzymic binding of S-adenosyl-L-methionine

Abstract

The configuration at the asymmetric sulfonium pole of S-adenosyl-L-methionine (SAM) necessary for optimal enzymatic binding and methyl donation has been elucidated in this study. For the transmethylations catalyzed by catechol O-methyltransferase, phenylethanolamine N-methyltransferase, histamine N-methyltransferase, and hydroxyindole O-methyltransferase, it was demonstrated that only the natural (-) enantiomer of SAM was active as a methyl donor. The corresponding (+)-SAM, which was prepared by enzymatic resolution of synthetic (+/-)-SAM, was shown to be inactive as a methyl donor in these enzymatic reactions. The (+)-SAM was found, however, to be a potent inhibitor of each of these enzyme-catalyzed transmethylations. These results suggest that the (+) enantiomer offers a nonproductive configuration for the methyl-transfer reaction itself; however, this configuration fails to hamper enzymatic binding. These results are discussed relative to the geometric requirements necessary for the methyl-transfer reaction and the requirements for enzymatic binding.

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

“…His work in this area quickly expanded into the design and synthesis of inhibitors of other methyltransferases, including histamine N-methyltransferase, [29][30][31] indole ethylamine N-methyltransferase, 32 t-RNA methyltransferases, 33 phenylethanolamine N-methyltransferase (PNMT), 34-47 protein carboxyl methytransferase [48][49][50][51][52] and viral mRNA methyltransferases. [53][54][55][56] The development of PNMT inhibitors and protein carboxyl methyltransferase arose from fruitful collaborations with fellow KU faculty members Professors Gary Grunewald and Charles O. Rutledge, respectively.…”

“…52,[57][58][59][60][61][62][63][64] These broad-spectrum methyltransferase inhibitors were found to also block viral mRNA methyltransferases, which are critical for translation of viral proteins in infected cells. Ron's 1980 publication of a Perspective article in the Journal of Medicinal Chemistry on AdoMet-dependent methyltransferases as potential therapeutic targets 65 established him as a broad thinker in this important area of investigation and directly inspired a young graduate student (now-Professor Michael Wolfe) in the Department of Medicinal Chemistry at KU to join Ron's research group to do the research for his Ph.D. dissertation.…”

Yeast, Plants, Worms, and Flies Use a Methyltransferase to Metabolize Age-Damaged (R,S)-AdoMet, but What Do Mammals Do?

“…4 AdoMet can exist in two diastereoisomeric states with respect to its sulfonium ion. 5,6 The S configuration (S,S)-AdoMet is the only form that is produced enzymatically, as well as the only form used in almost all biological methylation reactions 5,[7][8][9][10] Under physiological conditions, however, the sulfonium ion can spontaneously racemize to the R form, producing (R,S)-AdoMet. 5 As of yet, (R,S)-AdoMet has no known physiological function and may inhibit cellular reactions.…”

Homocysteine Methyltransferases Mht1 and Sam4 Prevent the Accumulation of Age-damaged (R,S)-AdoMet in the Yeast Saccharomyces cerevisiae

“…(R,S)-AdoMet forms from the inversion of the configuration of the sulfonium center of the molecule from S to R. The full extent of (R,S)-AdoMet toxicity is still unknown. In addition to simply taking up valuable cell space, it has been shown to lead to the production of cellular inhibitors (21,22) as well as to directly inhibit some methyltransferase reactions (23). At least one of the latter inhibitory effects, however, is still controversial (24).…”