TY - JOUR T1 - Structural and Conformational Analogues of L-Methionine as Inhibitors of the Enzymatic Synthesis of <em>S</em>-Adenosyl-L-Methionine. IV. Further Mono-, Bi- and Tricyclic Amino Acids JF - Molecular Pharmacology JO - Mol Pharmacol SP - 661 LP - 677 VL - 15 IS - 3 AU - JANICE R. SUFRIN AU - A. W. COULTER AU - PAUL TALALAY Y1 - 1979/05/01 UR - http://molpharm.aspetjournals.org/content/15/3/661.abstract N2 - A series of mono-, bi- and tricyclic amino acids was synthesized and examined for their ability to inhibit the enzymatic conversion of L-methionine to S-adenosyl-L-methionine by partially purified preparations of ATP:L-methionine S-adenosyltransferase (EC 2.5.1.6) of bakers’ yeast, Escherichia coli and rat liver. These studies are part of a program to define the topography of the amino acid binding site of these enzymes and to design selective inhibitors of potential chemotherapeutic value. The synthetic amino acids are structurally and conformationally related to 1-aminocyclopentane-1-carboxylic acid (cycloleucine), a highly effective inhibitor of S-adenosyl-L-methionine formation. They were designed to provide more precise information about the space-filling and conformational requirements for complementarity at the active sites of the enzymes. Cyclopentaneglycine, although less inhibitory than cycloleucine, has modest activity that is attributed to its conformational relationship to the highly active (1R,2R,4S)-isomer of 2-aminonorbornane-2-carboxylic acid. The (1R,2R,4S)-isomer of 2-amino-5,6-exo-trimethylenenorbornane-2-carboxylic acid appears to be a more potent inhibitor than its 2-aminonorbornane-2-carboxylic acid analogue. It is presumed that the 5,6-exo-trimethylene extension of the norbornane framework increases binding capacity because of positive hydrophobic interactions with the enzyme surface in this region. The most active enzyme inhibitor found in this study was (+)-2-aminobicyclo[2.1.1]hexane-2-carboxylic acid, which was even more potent than its close structural analogue, the active 2-aminonorbornane-2-carboxylic acid isomer. This enhancement of inhibitory activity may be a reflection of the size of the bridgehead angle of the bicyclo[2.1.1]hexane derivative which is almost 7° smaller than the corresponding bridgehead angle of the norbornane derivative, and apparently contributes to a more precise complementarity of the bicyclo[2.1.1]hexane amino acid at the surface of the enzyme. The idea that this internal bridgehead angle must not exceed a critical value if binding is to occur is further supported by the fact that the analogous isomer of 2-aminobicyclo[3.2.1]octane-2-carboxylic acid, which has an internal bridgehead angle 6° larger than the norbornane derivative, is inactive. Other amino acids which have contributed to the elucidation of the conformational requirements of the enzyme active site include 7-aminonorbornane-7-carboxylic acid, 3-aminonortricyclene-3-carboxylic acid, 1-amino-2,5-dimethylcyclopentane-1-carboxylic acid, 1-amino-3,4-dimethylcyclopentane-1-carboxylic acid and 3-aminobicyclo[3.2.0]heptane-3-carboxylic acid; the latter analogue possessed significant inhibitory activity. ACKNOWLEDGMENTS The authors are grateful to Mrs. Mary Karen Burch for skillful technical assistance; to Dr. C. Fenselau for the use of mass spectrometric facilities; and to Professors C. H. Robinson and G. R. Marshall for much wise advice and discussion. We wish to acknowledge once again the generosity of Drs. H. S. Tager and H. N. Christensen, Department of Biological Chemistry, University of Michigan, Ann Arbor for making available the four isomeric 2-aminonorbornane-2-carboxylic acids for which the results reported in reference (12) were obtained. ER -