Grobelny D, Poncz L, Galardy R E
Department of Biochemistry, University of Kentucky, Lexington 40536.
Biochemistry. 1992 Aug 11;31(31):7152-4. doi: 10.1021/bi00146a017.
The hydroxamic acid HONHCOCH2CH(i-Bu)CO-L-Trp-NHMe, isomer 6A (GM 6001), inhibits human skin fibroblast collagenase with Ki of 0.4 nM using the synthetic thiol ester substrate Ac-Pro-Leu-Gly-SCH(i-Bu)CO-Leu-Gly-OEt at pH 6.5. The other isomer, 6B, which has the opposite configuration at the CH2CH(i-Bu)CO alpha-carbon atom, has a Ki of 200 nM for this enzyme. GM 6001 is one of the most potent inhibitors of human skin fibroblast collagenase yet reported. GM 6001 has a Ki of 20 nM against thermolysin and Pseudomonas aeruginosa elastase. Isomer 6B has a Ki of 7 nM against thermolysin and 2 nM against the elastase. 6A and 6B are the most potent hydroxamate inhibitors reported for these bacterial enzymes. The pattern of inhibition for all three enzymes suggests that isomer 6A is the (R,S) compound, stereochemically analogous to the L,L-dipeptide, and isomer 6B is the (S,S) compound, analogous to the DL-dipeptide. The tolerance of the D configuration by thermolysin and the elastase allows these inhibitors to discriminate between the human and bacterial enzymes simply by inversion of configuration at the CH2CH(i-Bu)CO alpha-carbon atom. Substitution of the potential metal liganding groups carboxylate and hydrazide for the hydroxamate group yields much weaker inhibitors for all three enzymes.
异羟肟酸HONHCOCH2CH(i-Bu)CO-L-Trp-NHMe，异构体6A（GM 6001），在pH 6.5条件下，使用合成硫醇酯底物Ac-Pro-Leu-Gly-SCH(i-Bu)CO-Leu-Gly-OEt时，对人皮肤成纤维细胞胶原酶的抑制常数Ki为0.4 nM。另一种异构体6B，在CH2CH(i-Bu)CO α-碳原子处具有相反的构型，对该酶的抑制常数Ki为200 nM。GM 6001是迄今报道的人皮肤成纤维细胞胶原酶最有效的抑制剂之一。GM 6001对嗜热菌蛋白酶和铜绿假单胞菌弹性蛋白酶的抑制常数Ki为20 nM。异构体6B对嗜热菌蛋白酶的抑制常数Ki为7 nM，对弹性蛋白酶的抑制常数Ki为2 nM。6A和6B是报道的对这些细菌酶最有效的异羟肟酸抑制剂。对所有三种酶的抑制模式表明，异构体6A是(R,S)化合物，立体化学上类似于L,L-二肽，异构体6B是(S,S)化合物，类似于DL-二肽。嗜热菌蛋白酶和弹性蛋白酶对D构型的耐受性使得这些抑制剂只需在CH2CH(i-Bu)CO α-碳原子处反转构型，就能区分人源和细菌源的酶。用潜在的金属配位基团羧酸盐和酰肼取代异羟肟酸基团，会产生对所有三种酶抑制作用弱得多的抑制剂。
