Abali Emine Ercikan, Skacel Nancy E, Celikkaya Hilal, Hsieh Yi-Ching
Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903, USA.
Vitam Horm. 2008;79:267-92. doi: 10.1016/S0083-6729(08)00409-3.
Dihydrofolate reductase (DHFR) enzyme catalyzes tetrahydrofolate regeneration by reduction of dihydrofolate using NADPH as a cofactor. Tetrahydrofolate and its one carbon adducts are required for de novo synthesis of purines and thymidylate, as well as glycine, methionine and serine. DHFR inhibition causes disruption of purine and thymidylate biosynthesis and DNA replication, leading to cell death. Therefore, DHFR has been an attractive target for chemotherapy of many diseases including cancer. Over the following years, in order to develop better antifolates, a detailed understanding of DHFR at every level has been undertaken such as structure-functional analysis, mechanisms of action, transcriptional and translation regulation of DHFR using a wide range of technologies. Because of this wealth of information created, DHFR has been used extensively as a model system for enzyme catalysis, investigating the relations between structure in-silico structure-based drug design, transcription from TATA-less promoters, regulation of transcription through the cell cycle, and translational autoregulation. In this review, the current understanding of human DHFR in terms of structure, function and regulation is summarized.
二氢叶酸还原酶（DHFR）催化二氢叶酸还原生成四氢叶酸，该反应以烟酰胺腺嘌呤二核苷酸磷酸（NADPH）作为辅酶。嘌呤、胸苷酸、甘氨酸、蛋氨酸和丝氨酸的从头合成需要四氢叶酸及其一碳加合物。抑制DHFR会导致嘌呤和胸苷酸生物合成以及DNA复制受阻，从而导致细胞死亡。因此，DHFR一直是包括癌症在内的多种疾病化疗的理想靶点。在接下来的几年里，为了开发更有效的抗叶酸药物，人们利用各种技术对DHFR进行了深入研究，包括结构功能分析、作用机制、转录和翻译调控等方面。由于积累了大量相关信息，DHFR已被广泛用作酶催化的模型系统，用于研究基于计算机模拟结构的药物设计中的结构关系、无TATA盒启动子的转录、细胞周期中的转录调控以及翻译自调控。在这篇综述中，我们总结了目前对人DHFR在结构、功能和调控方面的认识。
