Chen S F, Perrella F W, Behrens D L, Papp L M
Du Pont Merck Pharmaceutical Company, Glenolden Laboratory, Pennsylvania 19036.
Cancer Res. 1992 Jul 1;52(13):3521-7.
The novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline- carboxylic acid sodium salt) was shown previously to be an inhibitor of dihydroorotate dehydrogenase, the fourth enzyme of the de novo pyrimidine biosynthetic pathway. Brequinar sodium inhibits the activity of this enzyme isolated from mammalian sources only but not those forms isolated from yeast or bacteria, which also use ubiquinone as the cofactor. Brequinar sodium also does not inhibit the activity of a soluble Zymobacterium oroticum dihydroorotate dehydrogenase which uses NAD+ as a cofactor. Brequinar sodium inhibits L1210 dihydroorotate dehydrogenase with mixed inhibition kinetics with respect to either the substrate (dihydroorotate) or the cofactor (ubiquinone Q6) with Ki' values in the 5-8 nM range. Our results suggest that brequinar sodium inhibits dihydroorotate dehydrogenase by binding to the enzyme at a unique site that is distinct from the dihydroorotate or the ubiquinone-binding site. This binding site appears to be unique to the mammalian enzyme, because brequinar sodium does not inhibit the yeast, Escherichia coli, or Z. oroticum forms of the enzyme.
新型抗癌候选药物布喹那钠（DuP 785、NSC 368390、6-氟-2-(2'-氟-1,1'-联苯-4-基)-3-甲基-4-喹啉羧酸钠盐）先前已被证明是二氢乳清酸脱氢酶的抑制剂，该酶是从头嘧啶生物合成途径中的第四个酶。布喹那钠仅抑制从哺乳动物来源分离的这种酶的活性，而不抑制从酵母或细菌中分离的酶的活性，酵母和细菌中的该酶也使用泛醌作为辅因子。布喹那钠也不抑制以NAD+作为辅因子的可溶性解脲支原体二氢乳清酸脱氢酶的活性。布喹那钠对底物（二氢乳清酸）或辅因子（泛醌Q6）以混合抑制动力学抑制L1210二氢乳清酸脱氢酶，其Ki'值在5-8 nM范围内。我们的结果表明，布喹那钠通过在与二氢乳清酸或泛醌结合位点不同的独特位点与酶结合来抑制二氢乳清酸脱氢酶。该结合位点似乎是哺乳动物酶所特有的，因为布喹那钠不抑制酵母、大肠杆菌或解脲支原体中的该酶形式。
