N6-adenosine-methyltransferase catalytic subunit

Description of N6-adenosine-methyltransferase catalytic subunit

Introduction

N6 Adenosine Methyltransferase (METTL3) is a key enzyme responsible for the methylation of adenosine at the N6 position in RNA molecules. This modification, known as m6A, has been shown to play crucial roles in various biological processes such as RNA stability, splicing, translation, and cellular differentiation. In recent years, METTL3 has emerged as a potential drug target due to its involvement in diseases such as cancer, obesity, and neurological disorders. In this article, we will delve into the structure, activity, and potential applications of METTL3 as a drug target.

Structure of METTL3

METTL3 is a catalytic subunit of the m6A methyltransferase complex, which also includes METTL14 and WTAP. It contains a catalytic domain and a conserved SAM (S-adenosylmethionine) binding motif, essential for its methyltransferase activity. The crystal structure of METTL3 has been resolved, revealing a homodimeric structure with a central channel for RNA binding and a positively charged surface for interaction with the negatively charged RNA backbone. This unique structure allows METTL3 to specifically recognize and methylate adenosine residues in RNA molecules.

Activity of METTL3

METTL3 is primarily involved in the formation of m6A modification in RNA molecules, which is a reversible process regulated by other proteins such as demethylases and readers. The addition of m6A has been shown to affect various aspects of RNA metabolism, including RNA stability, translation, and splicing. METTL3 has been found to methylate a large number of transcripts, with a preference for those involved in RNA processing and translation. It has also been shown to play a crucial role in the regulation of gene expression and cellular differentiation.

Applications of METTL3 as a Drug Target

Given its essential role in RNA modification, METTL3 has emerged as a potential drug target for various diseases. In cancer, aberrant m6A modification patterns have been observed, with METTL3 being overexpressed in certain cancers such as acute myeloid leukemia and glioblastoma. Inhibiting METTL3 activity has been shown to reduce cancer cell proliferation and induce cell death, making it a promising target for anti-cancer therapies.

In addition to cancer, METTL3 has also been linked to obesity and metabolic disorders. Studies have shown that METTL3 plays a critical role in regulating adipogenesis and lipid metabolism. Inhibition of METTL3 has been shown to reduce adipogenesis and improve insulin sensitivity, making it a potential target for treating obesity and related metabolic disorders.

Furthermore, METTL3 has also been implicated in neurological disorders such as Alzheimer’s disease and depression. In Alzheimer’s disease, m6A modification has been found to be dysregulated, leading to altered gene expression and protein translation. Inhibition of METTL3 has been shown to improve cognitive function and reduce amyloid beta levels in Alzheimer’s disease mouse models. In depression, METTL3 has been found to be downregulated, and its inhibition has been shown to increase the expression of genes involved in neuroplasticity and synaptic function, potentially providing a new avenue for treating depression.

Conclusion

In summary, N6 Adenosine Methyltransferase catalytic subunit (METTL3) plays a crucial role in RNA modification and has emerged as a potential drug target for various diseases. Its unique structure and activity make it a promising target for developing novel therapies for cancer, obesity, and neurological disorders. Further research on the regulation and function of METTL3 is needed to fully understand its potential as a drug target.