n-propargylglycine

n-propargylglycine (N-PPG) is an orally bioavailable, brain-penetrant, mechanism-based irreversible (suicide) inhibitor of proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (HYPDH/PRODH2). Developed by the Buck Institute for Research on Aging, this small molecule covalently modifies the enzyme-bound flavin adenine dinucleotide (FAD) cofactor and active site lysine, causing structural distortion and subsequent mitochondrial degradation of the target enzymes. By blocking PRODH and PRODH2, n-propargylglycine inhibits proline and 4-hydroxyproline catabolism, which suppresses the production of glyoxylate and downstream oxalate. This mechanism has shown therapeutic potential in preclinical models for the treatment of breast cancer (by inducing selective mitochondrial stress and synthetic lethality under hypoxia), neurodegenerative disorders such as Huntington's disease (by activating the mitochondrial unfolded protein response and inducing brain mitohormesis), and Primary Hyperoxaluria Type 2 (PH2) (by preventing calcium oxalate kidney stone formation and kidney failure).

Other names

2-(prop-2-yn-1-ylamino)acetic acidN-propargylglycine