A recent study co-first-authored by Dr P. Maheswaran of the Department of Pharmacy has been published in the prestigious journal Nucleic Acids Research, offering significant new mechanistic insights into the function of the human fat mass and obesity-associated (FTO) enzyme, a key regulator of RNA modification.
The research examines how FTO acts on N⁶-methyladenosine (m⁶A), one of the most abundant and biologically significant RNA modifications. While FTO has long been described as an RNA demethylase, the study demonstrates that its catalytic activity fundamentally differs from the prevailing view. Through the combined use of mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, the authors show that FTO primarily catalyses the hydroxylation of m⁶A to form an N⁶-hydroxymethyladenosine (hm⁶A) intermediate, rather than directly generating demethylated adenosine.
This mechanism contrasts sharply with that of other human AlkB family enzymes, including ALKBH5, ALKBH2, and ALKBH3, which directly demethylate the methyl group. These findings establish FTO as mechanistically distinct within the AlkB enzyme family and suggest that its biological effects may be mediated through hm⁶A modification rather than conventional demethylation.
By refining the molecular understanding of FTO activity, the study provides a more accurate framework for interpreting epitranscriptomic regulation and its relevance to development and disease. The article is published as open access, enabling wide dissemination of the findings to the international research community.