Certain tumors have a unique dependency on L-Methionine (L-Met) and have a lower tolerance towards the lack of L-Met than normal human cells, creating an exploitable weakness for potential therapeutics. Depletion of L-Met by methionine-g-lyase from Pseudomonas putida (pMGL) in various animal models inhibits tumor growth. However, pMGL produces a strong immune response due to its bacterial source, is unstable in serum, and has no human homologue. Recently, the Georgiou lab has engineered human cystathionine-g-lyase  (hCGL), an enzyme with high sequence similarity to pMGL, altering its substrate specificity to yield a novel human methioninase enzyme. Modifications to the active site of hCGL were made based on structural phylogenies, leading to L-Met degradation. Our goal is to further optimize methioninase activity by creating libraries of modified hCGL variants. Variants with high activity will be identified, sequenced and studied kinetically, yielding a further optimized enzyme that can be studied in vivo.

Degradation of methionine by modified cystathionine-gamma-lyase as a novel cancer therapeutic

245th National Meeting (2013)

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