Xanthine derivatives inhibit FTO in an L-ascorbic acid-dependent manner

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The fat-mass-and-obesity-associated protein (FTO) is an N-methyladenosine (m6A) demethylase implicated in various biological processes.
• Identifying specific inhibitors of FTO activity is crucial for understanding its function and developing therapeutic strategies.

Purpose of the Study:

• To identify novel inhibitors of FTO's m6A demethylase activity.
• To explore the mechanism of inhibition and identify key components for designing FTO-specific inhibitors.

Main Methods:

• Activity-based high-throughput screening was employed using the m6A-sensitive ribonuclease MazF.
• The inhibitory effects of identified compounds, including xanthine derivatives, on FTO were evaluated.

Main Results:

• Xanthine derivatives were identified as inhibitors of FTO's m6A demethylase activity.
• Pentoxifylline demonstrated L-ascorbic acid concentration-dependent inhibitory activity against FTO.
• This represents an unprecedented mode of FTO inhibition.

Conclusions:

• L-ascorbic acid is a critical factor in the inhibitory mechanism of pentoxifylline against FTO.
• L-ascorbic acid serves as a promising key for the rational design of FTO-specific inhibitors.