Arginine deiminase pathway (ADI pathway) (ADI pathway)

The Arginine Deiminase (ADI) pathway is a three-enzyme catabolic system found in various bacteria, archaea, and some anaerobic eukaryotes, such as Giardia intestinalis and Trichomonas vaginalis [3, 12]. It is composed of three key enzymes: arginine deiminase (ArcA), ornithine carbamoyltransferase (ArcB), and carbamate kinase (ArcC), which together convert L-arginine into ornithine, ammonia, and carbon dioxide while generating ATP [2, 15]. In many human pathogens, this pathway serves as a critical virulence factor by providing energy under anaerobic conditions and neutralizing acidic environments through ammonia production, which supports the survival of antibiotic-tolerant biofilms [2, 19, 21]. Clinically, the pathway is exploited through the administration of pegylated arginine deiminase (ADI-PEG 20), a biopharmaceutical agent that depletes systemic arginine to treat arginine-auxotrophic cancers, such as melanoma and hepatocellular carcinoma [20, 22]. These tumors cannot synthesize endogenous arginine due to a deficiency in argininosuccinate synthetase 1 (ASS1), making them uniquely sensitive to arginine deprivation [15, 20]. While the enzyme itself is used as a therapeutic drug in oncology, the genetic components of the pathway in bacteria are investigated as targets for novel anti-biofilm and antimicrobial agents to sensitize resistant infections to treatment [6, 19].

Other names

Arginine dihydrolase pathwayADI systemarc operonArginine deiminase system

Enzymatic depletion of systemic L-arginine to induce metabolic starvation, autophagy, and apoptosis in arginine-auxotrophic cancer cells [15, 20, 22]; Suppression of bacterial energy production (ATP) and ammonia-mediated pH regulation to disrupt biofilm maintenance and acid stress tolerance in pathogens [2, 6, 19, 21].