Engineered CGL Enzymes for Cancer Metabolite Depletion
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Solution Overview
Problem
Current therapies lack irreversible cysteine/cystine degrading enzymes with properties suitable for human cancer treatment, as existing enzymes often fail to specifically degrade these amino acids, which are crucial for tumor growth and survival in cancers like prostate, small cell lung carcinomas, and glioblastomas.
Innovation Solution
Engineering primate cystathionine-gamma-lyase (CGL) enzymes with modified amino acids to enhance their catalytic efficiency and stability, allowing them to efficiently degrade both L-cystine and L-cysteine, thereby depriving tumors of essential metabolites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If native CGL enzymes are used, then the enzyme structure is simple and easy to produce, but the catalytic efficiency and stability are insufficient for human therapy
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the CGL enzyme sequence to alter its catalytic properties. Mutations at positions 59, 193, and 339 change the enzyme's substrate affinity and catalytic rate, transforming it into an effective therapeutic agent that degrades both L-cystine and L-cysteine with high efficiency while maintaining structural simplicity.
2Reliability
If enzymes are engineered to degrade both L-cystine and L-cysteine, then the therapeutic effectiveness against tumors is improved, but the enzyme design and production becomes more difficult
Solution Approach 1:
The patent uses parameter changes to expand the enzyme's substrate scope. By introducing specific mutations (E59T, C193S, E339V), the engineered CGL enzyme gains the ability to degrade both L-cystine and L-cysteine, providing comprehensive therapeutic coverage against tumors that rely on either amino acid for growth while maintaining feasibility for production.
3Productivity
If the enzyme catalytic activity is increased to deplete amino acids effectively, then the tumor killing effect is enhanced, but the enzyme may become less stable in serum
Solution Approach 1:
The patent applies parameter changes to simultaneously optimize both catalytic activity and serum stability. The triple mutation (E59T, C193S, E339V) not only enhances the enzyme's ability to degrade L-cystine and L-cysteine but also confers resistance to serum proteases, allowing the enzyme to maintain high activity in the complex in vivo environment.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified CGL enzymes demonstrate improved catalytic activity and stability, making them suitable for human cancer therapy by effectively depleting L-cystine and L-cysteine, thereby targeting and killing cancer cells with minimal toxicity to non-cancerous tissues.
Implementation Method 1
engineered primate cystathionine-gamma-lyase (CGL) enzymes with modified amino acids to enhance their catalytic efficiency and stability, allowing them to efficiently degrade both L-cystine and L-cysteine
Data Source
AI summary
Methods and compositions related to the engineering of a protein with L-cyst(e)ine degrading enzyme activity are described. For example, in certain aspects there may be disclosed a modified cystathionine-γ-lyase comprising one or more amino acid substitutions and capable of degrading L-cyst(e)ine. Furthermore, certain aspects of the invention provide compositions and methods for the treatment of cancer with L-cyst(e)ine using the disclosed proteins or nucleic acids.