Turner Robert T, Loy Jeffrey A, Nguyen Chan, Devasamudram Thippeswamy, Ghosh Arun K, Koelsch Gerald, Tang Jordan
Protein Studies Program, Oklahoma Medical Research Foundation and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Biochemistry. 2002 Jul 9;41(27):8742-6. doi: 10.1021/bi025926t.
Memapsin 1 is closely homologous to memapsin 2 (BACE), or beta-secretase, whose action on beta-amyloid precursor protein (APP) leads to the production of beta-amyloid (A beta) peptide and the progression of Alzheimer's disease. Memapsin 2 is a current target for the development of inhibitor drugs to treat Alzheimer's disease. Although memapsin 1 hydrolyzes the beta-secretase site of APP, it is not significantly present in the brain, and no direct evidence links it to Alzheimer's disease. We report here the residue specificity of eight memapsin 1 subsites. In substrate positions P(4), P(3), P(2), P(1), P(1)', P(2)', P(3)', and P(4)', the most preferred residues are Glu, Leu, Asn, Phe, Met, Ile, Phe, and Trp, respectively, while the second preferred residues are Gln, Ile, Asp, Leu, Leu, Val, Trp, and Phe, respectively. Other less preferred residues can also be accommodated in these subsites of memapsin 1. Despite the broad specificity, these residue preferences are strikingly similar to those of human memapsin 2 [Turner et al. (2001) Biochemistry 40, 10001-10006] and thus pose a serious problem to the design of differentially selective inhibitors capable of inhibiting memapsin 2. This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well. Several possible approaches to overcome this problem are discussed.
膜天冬氨酸蛋白酶1与膜天冬氨酸蛋白酶2（β-分泌酶）密切同源，后者作用于β-淀粉样前体蛋白（APP）会导致β-淀粉样蛋白（Aβ）肽的产生以及阿尔茨海默病的进展。膜天冬氨酸蛋白酶2是目前开发治疗阿尔茨海默病抑制剂药物的靶点。尽管膜天冬氨酸蛋白酶1能水解APP的β-分泌酶位点，但它在大脑中含量不高，且没有直接证据表明它与阿尔茨海默病有关。我们在此报告了8个膜天冬氨酸蛋白酶1亚位点的残基特异性。在底物位置P(4)、P(3)、P(2)、P(1)、P(1)'、P(2)'、P(3)'和P(4)'，最优先选择的残基分别是Glu、Leu、Asn、Phe、Met、Ile、Phe和Trp，而第二优先选择的残基分别是Gln、Ile、Asp、Leu、Leu、Val、Trp和Phe。其他不太优先选择的残基也可容纳在膜天冬氨酸蛋白酶1的这些亚位点中。尽管特异性较宽泛，但这些残基偏好与人类膜天冬氨酸蛋白酶2的偏好惊人地相似[特纳等人（2001年）《生物化学》40, 10001 - 10006]，因此给设计能够抑制膜天冬氨酸蛋白酶2的差异选择性抑制剂带来了严重问题。这一困难通过以下发现得到证实：几种有效的膜天冬氨酸蛋白酶2抑制剂也能有效抑制膜天冬氨酸蛋白酶1。本文讨论了几种可能克服这一问题的方法。
