药学前沿大讲堂第二十七讲（2009.3.3）-Studies of Cholesterol Biosynthesis and Fatty Acid Metabolism for Medicine Development
Studies of Cholesterol Biosynthesis and Fatty Acid Metabolism for Medicine Development
讲座题目：Studies of Cholesterol Biosynthesis and Fatty Acid Metabolism for Medicine Development
主 讲 人：Ding Li Department of Biology and ChemistryCity University of Hong Kong
主 持 人：黄志纾 副院长 中山大学药学院
Cardiovascular disease is a leading cause of death for people in China and many other countries. The disease is closely related with high cholesterol level, therefore, inactivation of the enzymes involved in mevalonate pathway of cholesterol biosynthesis is one major method for treating cardiovascular disease. The mevalonate pathway has also been reported as a drug target for treatment of cancer and bacteria infection. The mevalonate pathway contains several enzymes including thiolase, mevalonate kinase (MK), phosphomevalonate kinase (PMK), mevalonate 5-diphosphate decarboxylase (MDD), and farnesyl pyrophosphate synthase (FPPS). Several investigators have suggested the involvement of these enzymes as important regulatory steps in the biosynthesis of cholesterol. We synthesized and studied a variety of multifunctional enzyme inhibitors in mevalonate pathway, which can inactivate several enzymes simultaneously. The inhibition of two or more consecutive enzymes in a pathway using a combined drug treatment can block the pathway much more effectively than a single inhibitory drug therapy with fewer side effects.
The degradation of saturated fatty acids occurs in a sequence of four reactions referred to as the β-oxidation cycle. The partial fatty acid oxidation (pFOX) inhibition has been reported as a therapy for non-insulin dependent diabetes mellitus (NIDDM) and chronic stable angina. We overexpressed in E. coli, and purified several enzymes involved in fatty acid oxidation, including mitochondrial trifunctional protein (MTP), acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase. A variety of natural or synthetic substrate analogs were synthesized and studied through enzyme incubations, which increased our understanding of these enzymes and provided potential drug candidates for treating related diseases.
主讲人简介：李丁，男，1967年2月9日出生于中国山西省阳泉市。现为香港城市大学生物化学系副教授。1989年北京大学化学系本科毕业。1995年美国明尼苏达大学化学系获博士学位。1995年-2000年在美国哈佛大学化学系和德州农工大学化学系进行博士后研究工作。2000年-2002年在香港城市大学生物化学系担任助理教授。2002年至今在香港城市大学生物化学系担任副教授。在J. Am. Chem. Soc.，Org. Lett.等SCI杂志上发表文章41篇。