Next generation of cancer treatments by the in-depth study of the enzyme ω-amidase.

ω-Amidase is an enzyme in the human body that has implications in numerous forms of cancer including triple-negative breast cancer, castration resistant prostate cancer, non-small cell lung cancer, pancreatic cancer and many others. All cancers that rely heavily on the amino acid glutamine or asparagine for survival can potentially be destroyed by disruption of ω-amidase survival pathways.

Utilizing ω-amidase, the glutaminase II pathway converts L-glutamine to α-ketoglutarate, a major nutrient for cells in the well-known Krebs cycle (also known as the tricarboxylic acid cycle or the TCA, cycle). Inhibitors of an alternative α-ketoglutarate producing pathway are currently in clinical trials as anti-cancer agents. Therefore, specific drugs targeting the glutaminase II pathway alone, or perhaps in combination with current inhibitors, may provide a new treatment for severe cancers.

Glutaminase II Pathway

In addition to the glutaminase II pathway, many cancers have a high requirement for asparagine due, in part, to a lack of two enzymes responsible for asparagine production: asparagine synthetase and asparaginase. Therefore, for many cancers, asparagine is conditionally essential, meaning it must be made by an alternative ω-amidase utilizing asparaginase II pathway. (Figure Below) This is especially true for acute lymphoblastic leukemia (ALL). 

Asparaginase II Pathway

Another major role of ω-amidase in mammals is the interconnection of the asparaginase II and the glutaminase II pathways. In the asparaginase II pathway (upper red box), asparagine is transaminated with a suitable α-keto acid producing α-ketosuccinamate (KSM) and the corresponding amino acid. KSM is a substrate of ω-amidase, generating the important TCA cycle intermediate oxaloacetate. In the glutaminase II pathway (lower, pink box), glutamine is transaminated with a suitable α-keto acid, producing the corresponding amino acid and α-ketoglutaramate (KGM), which is also a substrate of ω-amidase, generating the important TCA cycle intermediate α-ketoglutarate. Aspartate is generated by 1) the hydrolysis of asparagine, the asparaginase I reaction, upper, left, purple box or 2) transamination of oxaloacetate with glutamate in a reaction catalyzed by aspartate aminotransferase. Aspartate is converted back to asparagine by the action of glutamine-dependent asparagine synthetase. 

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