Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target

详细信息    查看全文

• 作者：Sudaratana R. Krungkrai¹ ; Jerapan Krungkrai² ; ^{jerapan.k@chula.ac.th" class="auth_mail" title="E-mail the corresponding author} ; ^{jerapan.k@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Malaria ; Plasmodium falciparum ; Pyrimidine biosynthetic pathway ; Drug target ; Drug development ; Chemotherapy
• 刊名：Asian Pacific Journal of Tropical Medicine
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：9
• 期：6
• 页码：525-534
• 全文大小：1477 K

文摘

Malaria is a major cause of morbidity and mortality in humans. Artemisinins remain as the first-line treatment for Plasmodium falciparum (P. falciparum) malaria although drug resistance has already emerged and spread in Southeast Asia. Thus, to fight this disease, there is an urgent need to develop new antimalarial drugs for malaria chemotherapy. Unlike human host cells, P. falciparum cannot salvage preformed pyrimidine bases or nucleosides from the extracellular environment and relies solely on nucleotides synthesized through the de novo biosynthetic pathway. This review presents significant progress on understanding the de novo pyrimidine pathway and the functional enzymes in the human parasite P. falciparum. Current knowledge in genomics and metabolomics are described, particularly focusing on the parasite purine and pyrimidine nucleotide metabolism. These include gene annotation, characterization and molecular mechanism of the enzymes that are different from the human host pathway. Recent elucidation of the three-dimensional crystal structures and the catalytic reactions of three enzymes: dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5′-monophosphate decarboxylase, as well as their inhibitors are reviewed in the context of their therapeutic potential against malaria.