Chan Cheryl, Goh Liuh Ling, Sim Tiow-Suan
Department of Microbiology, National University of Singapore, 5 Science Drive 2, MD4A, Singapore 117597, Singapore.
FEMS Microbiol Lett. 2005 Aug 15;249(2):315-21. doi: 10.1016/j.femsle.2005.06.024.
Falcipain-2A, the cysteine protease of Plasmodium falciparum has been proposed as a good drug target. This study evaluated the suitability of Plasmodium berghei as the animal model and reports the first functional expression and characterization of the falcipain-2A orthologue, berghepain-2. Comparative studies revealed that the orthologues exhibited different biochemical properties. Berghepain-2 demonstrated optimal activity at a narrower pH optima of 5.5-6 and a lack of preference for substrates with leucine at position 2. Mutagenesis studies revealed roles for residues Val63 and Arg230 of berghepain-2 in contributing to its distinctive biochemical properties. This warrants re-evaluation of employing P. berghei as the murine model for the in vivo screening of falcipain-2A inhibitors. More importantly, these findings stress the underlying importance of establishing the functionality of relevant genes of P. falciparum with concomitant relevance to its murine counterpart prior to its use as the animal model for the screening of potential antimalarials.
恶性疟原虫的半胱氨酸蛋白酶Falcipain-2A已被认为是一个良好的药物靶点。本研究评估了伯氏疟原虫作为动物模型的适用性，并报道了Falcipain-2A直系同源物berghepain-2的首次功能性表达及特性。比较研究表明，这些直系同源物表现出不同的生化特性。Berghepain-2在较窄的最适pH值5.5 - 6时表现出最佳活性，且对第2位为亮氨酸的底物无偏好。诱变研究揭示了berghepain-2的Val63和Arg230残基在形成其独特生化特性中的作用。这使得有必要重新评估将伯氏疟原虫用作体内筛选Falcipain-2A抑制剂的小鼠模型。更重要的是，这些发现强调了在将恶性疟原虫用作筛选潜在抗疟药的动物模型之前，确定其相关基因功能及其与小鼠对应基因相关性的根本重要性。
