REGULATION OF PROTEIN KINASES AND THEIR SUBSTRATES

蛋白激酶是参与在细胞水平上控制几乎所有生理过程的重要调节酶。人类基因组被认为含有大约1500种蛋白激酶来控制这些过程。这些酶将磷酸基团添加到靶蛋白，以可逆的方式改变其功能，蛋白磷酸酶去除磷酸基团。本项目主要研究代谢应激敏感蛋白激酶AMP活化蛋白激酶及其底物。在高能量需求期间，如剧烈运动或由饥饿或缺血引起的营养应激，AMP活化的蛋白激酶负责关闭需要能量的代谢途径并加速代谢，包括葡萄糖摄取和脂肪酸代谢，以恢复细胞能量水平。AMP活化的蛋白激酶调节控制胆固醇和脂质（脂肪酸）合成的关键酶以及内皮NO合酶，内皮NO合酶是血压和血小板活性的关键调节剂。由于这些原因，它在心血管疾病中具有潜在的重要性。AMP活化的蛋白激酶似乎也负责运动诱导的葡萄糖摄取，并且已知运动有助于恢复老年发病或II型糖尿病患者的葡萄糖控制。由于AMP激活的蛋白激酶加速脂肪酸代谢，因此它也可能在肥胖中起作用。虽然许多因素被认为与心血管疾病、糖尿病和肥胖有关，但AMP活化蛋白激酶是与澳大利亚最重要疾病相关的关键代谢调节酶。了解AMP活化蛋白激酶的结构和功能以及编码这种酶的基因是一个重要的目标。

Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP activated protein kinase and its substrates. During periods of high energy demand such as vigorous exercise or nutrient stress induced by starvation or ischaemia the AMP activated protein kinase is responsible for shutting down energy requiring metabolic pathways and accelerating metabolism including glucose uptake and fatty acid metabolism to restore cellular energy levels. The AMP activated protein kinase regulates key enzymes in the control of cholesterol and lipid (fatty acid) synthesis as well as endothelial NO synthase, a key regulator of blood pressure and platelet activity. For these reasons it is potentially important in cardiovascular disease. The AMP activated protein kinase also appears responsible for exercise induced glucose uptake and it is known that exercise helps restore glucose control in age onset or type II diabetic patients. Since the AMP acitivated protein kinase accelerates fatty acid metabolism it may also have a role in obesity. While many factors are thought to be involved in cardiovascular disease, diabetes and obesity the AMP activated protein kinase is a key metabolic regulatory enzyme relevant to the most important diseases in Australia. Understanding the structure and function of the AMP activated protein kinase as well as the genes that encode this enzyme is an important goal.