草酰乙酸脱羧酶钠离子泵的结构和功能研究

草酰乙酸脱羧酶钠离子泵属于一个独特的钠离子主动泵家族。该家族的成员由多个亚基构成，催化羧基从底物向生物素的转移，并利用生物素脱羧产生的自由能驱动钠离子跨细胞膜的转运。在多种微生物中，草酰乙酸脱羧酶钠离子泵维持跨细胞膜的钠离子浓度梯度。细胞利用该钠离子浓度梯度驱动营养物质转运、ATP合成等重要能量代谢过程。多种致病微生物依赖草酰乙酸脱羧酶钠离子泵在人体细胞内存活。本课题组在研究能量代谢关键蛋白质尤其是以生物素为中间载体的羧基转移酶家族成员方面有较多的积累，也在近期解析了草酰乙酸脱羧酶钠离子泵跨膜亚基的结构。在本项目中，我们将结合结构和功能研究手段，研究草酰乙酸脱羧酶钠离子泵利用底物脱羧驱动钠离子跨膜转运的详细机制。本研究将丰富对化学能驱动的物质跨膜转运的认识、及对含有草酰乙酸脱羧酶钠离子泵的物种的能量代谢的理解，也可为防治依赖该钠离子泵的致病微生物的感染提供新思路。

The oxaloacetate decarboxylase (OAD) sodium pump belongs to a unique family of primary sodium transporters. Members in this family are membrane-integrated complexes. They catalyze the carboxyl-transfer from their substrates to biotin, and subsequently utilize the free energy derived from biotin decarboxylation to drive sodium transport across the cell membrane. In many microorganisms, OAD is critical for maintaining the sodium gradient across the cell membrane, which is utilized by the cell to drive nutrient intake, ATP synthesis and other essential energy metabolism processes. A number of pathogenic microorganisms rely on OAD for survival inside the human cell. We have long been interested in the structure and function of proteins essential for energy metabolism, especially enzymes that utilize biotin to catalyze carboxyl-transfer reactions. Recently, we have determined the structure of the membrane-integrated subunits of OAD. In this project, we will combine structural and biochemical/biophysical techniques to study how substrate decarboxylation by OAD drives sodium transport across the cell membrane. Our study will provide novel insights into substrate transport across the cell membrane driven by chemical energies, the energy metabolism of OAD-containing organisms, and could provide a starting point to develop novel treatments for pathogenic OAD-containing microorganisms.