Nucleophilic stress through proline catabolism.

Within the proline metabolic pathway (Figure 2a), loss-of-function ALDH4A1 mutations result in the accumulation of its nucleophilic substrate pyrroline-5-carboxylate (P5C), which depletes the essential cofactor pyridoxal-5’-phosphate (PLP) through Knoevenagel condensation, causing selective cytotoxicity to cells of the central nervous system and connective tissue (Figure 2b). Conversely, biallelic mutations in ALDH18A1 result in proline auxotrophy and toxicity to the same tissue. We have identified a recurrent deletion that alters proline metabolism in ~15-55% of prostate, skin and central nervous system cancers (Figure 3c). This project focuses on developing chemical-proteomic and imaging based platforms to screen small molecule libraries for compounds that alter nucleophilic stress through proline metabolism (Figure 2d,e).

Figure 2: Proline metabolism and nucleophlic stress in IEM and cancer.