Aminopropyltransferases: Mechanistic Studies and the Synthesis of Specific Inhibitors
We have studied the mechanism of enzyme-catalyzed alkyl transfer reactions by a variety of methods including non-enzymic model reactions, steady-state kinetics, and stereochemistry. In this brief paper, the results of our earlier work on catechol O-methyltransferase (COMT, E.C. 220.127.116.11) and more recent work on putrescine aminopropyltransferase (PAPT, E.C. 18.104.22.168, sometimes referred to as spermidine synthase) will be reviewed. These investigations have resulted in the demonstration that each of these alkyltransferases catalyze a reaction which proceeds via a ternary complex involving the enzyme and both nucleophilic and electrophilic substrates. In addition, the demonstration of general base catalysis in related model reactions, provides chemical precedent for the involvement of this type of catalysis by basic residues of the enzyme. The mechanistic conclusions have allowed us to design and synthesize several mechanism-based inhibitors which exhibit great potency and specificity for individual alkyltransferases1.
KeywordsTernary Complex Purine Nucleoside Polyamine Biosynthesis Sulfonium Salt Electrophilic Substrate
Unable to display preview. Download preview PDF.
- 1.J. K. Coward, Mechanism-Based Inhibitors of Alkyltransferases, in: “Biological Methylation and Drug Design,” R. T. Borchardt, C. R. Creveling, and P. M. Ueland, eds., Humana Press, Clifton, New Jersey (1986).Google Scholar
- 5.J. K. Coward, Inhibition of Intracellular Methyl Transfer and Aminopropyl Transfer Reactions by Analogs of Substrates, Products and Transition States, in: “Design of Enzyme Inhibitors as Drugs,” M. Sandier and H. J. Smith, eds., Oxford university Press, Oxford (1988).Google Scholar
- 6.G. R. Orr, D. W. Kullberg, G. Pontoni, P. C. Prabhakaran, S. J. Gould, and J. K. Coward, The Synthesis of Chirally Deuterated S-Adenosylmethylthiopropylamines and Spermidines. Elucidation of the Stereochemical Course of Putrescine Aminopropyltransferase (Spermidine Synthase), J. Amer. Chem. Soc. 110: 5791 (1988).CrossRefGoogle Scholar
- 7.R. J. Miller, A. Kuliopulos, and J. K. Coward, The Synthesis of p-Nitrothioanisoles and N-Methyl-p-Nitroanilines Containing Stereochemically Defined Neighboring Nucleophiles, J. Org. Chem. in preparation.Google Scholar
- 9.P. M. Woster, A. Y. Black, K. J. Duff, J. K. Coward, and A. E. Pegg, Synthesis and Biological Evaluation of S-Adenosyl-1, 12-diamino-3-thio-9-azadodecane, A Multisubstrate Adduct Inhibitor of Spermine Synthase, J. Med. Chem. submitted.Google Scholar
- 11.E. Yau and J. K. Coward, manuscript in preparation.Google Scholar