Rescuing the Function of Mutated Isocitrate Dehydrogenase

Abstract

Isocitrate dehydrogenase (IDH1), an enzyme involved in the conversion of isocitrate into α-ketoglutarate, is an important enzyme in the citric acid cycle—a primary source of energy for the human body. A mutation in IDH1 disrupts its structure and overall functionality, leading to the high probability of developing aggressive brain tumors. In order to assess and repair this impairment, two synthetic binders, or FABs, were used to determine the effect on the activity of mutant IDH1. Comparison of the activities of these two different FABs revealed to what degree the activity of this enzyme was restored. The wild-type activity for IDH1 is greater than the activity of the mutant enzyme without the presence of any FABs. With the presence of FAB4, the activity was increased a significant degree. In comparison, FAB5 exhibits an opposite effect on the activity of the enzyme, lowering the enzyme’s activity considerably. FAB4 helped to bring the activity of mutated IDH1 closer to that of wild-type IDH1; from this result, it’s possible that FAB4 has the potential to lead to the development of a potential therapeutic agent.