title: Potential inhibitors of collagen biosynthesis. 5,5-Difluoro-DL-lysine and 5,5-dimethyl-DL-lysine and their activation by lysyl-tRNA ligase.
abstract: The synthesis of lysine analogues wherein blocking groups are substituted at position 5, the site of hydroxylation by peptidyl lysine hydroxylase, is described. Thus, 5,5-difluorolysine (1) and 5,5-dimethylysine (2) were synthesized via a four- and six-step sequence, respectively, starting from ketone precursors. The propensity for these lysine analogues to be incorporated into procollagen protein in vivo was assessed by their ability to stimulate the lysine-dependent ATP-PPi exchange reaction in the presence of lysyl-tRNA ligase in vitro. The difluoro analogue 1 stimulated exchange, but at a Km (1.3 X 10(-3) M) 1000 times greater than that for lysine itself. The dimethyl analogue 2 did not stimulate exchange, but at high concentrations was a competitive inhibitor of lysine, with an apparent Ki of 1.6 X 10(-2) M. Thus, electronegative and/or bulky substituents at the 5 position of lysine cannot be tolerated by lysyl-tRNA ligase, and this position must be kept free in lysine analogues specifically designed to block collagen biosynthesis.
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D003864:Depression, Chemical; D007700:Kinetics; D007942:Leukemia, Experimental / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008250:Lysine-tRNA Ligase / Q000378:metabolism*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000037:antagonists & inhibitors; D011392:Proline / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003094:Collagen; D011392:Proline; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D000604:Amino Acyl-tRNA Synthetases; D008250:Lysine-tRNA Ligase; D008239:Lysine