In silico protein structure analysis of nine deleterious NIT1 missense mutations identified in human cancers

NIT1 is a tumor suppressor which functions as a metabolite repair enzyme to process deaminated glutathione (dGSH). Missense variants in NIT1 were analyzed from the COSMIC database to assess their structural and functional consequences. Of 59 missense variants identified, nine were flagged as deleterious. Homology modeling onto the C. elegans NitFhit structure revealed two mechanistically distinct classes: active site mutations predicted to disrupt the conserved Glu-Lys-Cys (EKC) catalytic triad and surface mutations predicted to perturb the Nit1-Fhit interaction interface. This work provides a structural basis for understanding NIT1 loss of function in human cancer.