Developing novel chemical probes to interrogate the allosteric mechanism of MTHFR and explore its therapeutic potential

叶酸和蛋氨酸循环是细胞存活的关键代谢途径。亚甲基四氢叶酸还原酶代表了这些循环之间的关键调节联系，因此对一系列疾病产生了强烈的影响。MTHFR功能的丧失或降低会导致一种称为同型半胱氨酸尿症的危及生命的代谢紊乱，而另一方面，在某些癌症(如前列腺癌)中观察到MTHFR的过度表达。通过化学合成、生物物理分析、电子对接和结晶学的组合方法，该项目希望开发概念验证化学探针来调节MTHFR，并探索两者的治疗潜力，抑制和激活酶。

The folate and methionine cycles are critical metabolic pathways for cell survival. The enzyme MTHFR represents a key regulatory connection between these cycles, hence exerting a strong influence on an array of diseases. Loss or reduced MTHFR function results in a life-threatening metabolic disorder called homocystinuria whilst on the other hand, overexpression of MTHFR has been observed in certain cancers (e.g. prostate). Through combined approaches of chemical synthesis, biophysical assays, in silico docking and crystallography, this project looks to develop proof of concept chemical probes to modulate MTHFR and explore the therapeutic potential of both, inhibiting and activating the enzyme.