Chaikuad Apirat, Fairweather Victoria, Conners Rebecca, Joseph-Horne Tim, Turgut-Balik Dilek, Brady R Leo
Department of Biochemistry, University of Bristol, United Kingdom.
Biochemistry. 2005 Dec 13;44(49):16221-8. doi: 10.1021/bi051416y.
Malaria caused by Plasmodium vivax is a major cause of global morbidity and, in rare cases, mortality. Lactate dehydrogenase is an essential Plasmodium protein and, therefore, a potential antimalarial drug target. Ideally, drugs directed against this target would be effective against both major species of Plasmodium, P. falciparum and P. vivax. In this study, the crystal structure of the lactate dehydrogenase protein from P. vivax has been solved and is compared to the equivalent structure from the P. falciparum enzyme. The active sites and cofactor binding pockets of both enzymes are found to be highly similar and differentiate these enzymes from their human counterparts. These structures suggest effective inhibition of both enzymes should be readily achievable with a common inhibitor. The crystal structures of both enzymes have also been solved in complex with the synthetic cofactor APADH. The unusual cofactor binding site in these Plasmodium enzymes is found to readily accommodate both NADH and APADH, explaining why the Plasmodium enzymes retain enzymatic activity in the presence of this synthetic cofactor.
间日疟原虫引起的疟疾是全球发病的主要原因，在罕见情况下会导致死亡。乳酸脱氢酶是疟原虫的一种必需蛋白质，因此是潜在的抗疟药物靶点。理想情况下，针对该靶点的药物应对两种主要疟原虫物种，即恶性疟原虫和间日疟原虫均有效。在本研究中，已解析出间日疟原虫乳酸脱氢酶蛋白的晶体结构，并将其与恶性疟原虫酶的等效结构进行了比较。发现这两种酶的活性位点和辅因子结合口袋高度相似，这使它们与人类对应物有所区别。这些结构表明，用一种通用抑制剂应能轻易实现对这两种酶的有效抑制。还解析出了这两种酶与合成辅因子APADH结合的晶体结构。发现这些疟原虫酶中不寻常的辅因子结合位点能够轻易容纳NADH和APADH，这解释了为何疟原虫酶在这种合成辅因子存在时仍保留酶活性。
