Targeting Disease-Linked Metalloenzymes Involved in RNA Metabolism

RNA plays a critical role in the central dogma of molecular biology by bridging genetic information transfer from DNA to protein. Therefore, RNA metabolism involving RNA synthesis through transcription, RNA posttranscriptional modifications, and RNA processing is tightly regulated and significantly impacts gene expression patterns. Many of these processes are catalyzed by metalloenzymes. Dysregulation of metalloenzymes involved in RNA metabolism at different stages of the RNA life cycle is associated with the progression of various diseases, including cancer. Therefore, several of these metalloenzymes are actively being investigated as targets for drug discovery. In this chapter, we will discuss selected metalloenzymes that are involved in RNA metabolism such as RNA modifications, editing, and processing. We will first focus our discussion on several RNA-modifying enzymes belonging to the AlkB subfamily of ferrous iron and 2-oxoglutarate-dependent oxygenases, including the fat mass and obesity-associated protein (FTO), AlkB homologue 5 (ALKBH5), and AlkB homologue 3 (ALKBH3). While FTO and ALKBH5 are responsible for catalyzing the oxidation of N6-methyladenosine (m 6 A), ALKBH3 oxidizes N1-methyladenosine (m 1 A)-modified RNA. We will then discuss the adenine deaminases acting on RNAs (ADARs), which are RNA-editing enzymes that catalyze the conversion of adenosine to inosine. Finally, we will summarize the work on CPSF73, an endonuclease involved in pre-mRNA 3 ′ -end processing. For each enzyme, we have attempted to cover the biochemistry of each selected metalloenzyme, highlighting its involvement in various diseases. We have also detailed how their structural investigations guided the currently known inhibition strategies involving small molecule inhibitors. We conclude this chapter with information gleaned from the reported inhibitor discovery efforts on these RNA metalloenzymes while briefly commenting on the potential strategies that could be useful for future drug discovery initiatives.