Endostatin Mutant ATPase Activity Enhancement
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Solution Overview
Problem
Native endostatin's ATPase activity is negatively related to its anti-tumor activity, limiting its effectiveness in inhibiting angiogenesis and tumor growth, as evidenced by decreased activity in mutants with lower ATPase activity.
Innovation Solution
Identification of an auxiliary ATP-binding motif in endostatin, Val-Leu-Cys-Ile-Glu, and strategic mutations in the Walker A and B motifs to enhance ATPase activity, resulting in ES mutants with increased anti-angiogenesis and anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native endostatin is used to inhibit angiogenesis and tumor growth, then anti-tumor activity is achieved, but ATPase activity limits its effectiveness
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the ATP-binding motifs (Walker A and Walker B motifs) of endostatin to alter its ATPase activity. By changing the chemical parameters of the protein structure through site-directed mutagenesis, the invention achieves enhanced anti-tumor activity while controlling the energy-related ATPase parameter.
Solution Approach 2:
The patent applies local quality by making specific localized changes to the ATP-binding motifs rather than modifying the entire protein structure. The mutations are concentrated in the Walker A (GXXGXXK) and Walker B (h E) motifs, which are specific local regions responsible for ATP binding and hydrolysis, thereby improving overall anti-tumor activity through targeted local modifications.
2Reliability
If ATPase activity is increased to enhance anti-angiogenesis activity, then inhibition of endothelial cell migration is improved, but energy consumption increases
Solution Approach 1:
The patent optimizes the relationship between ATPase activity and anti-angiogenesis function by changing the amino acid parameters in the ATP-binding motifs. The mutations are designed to achieve the optimal balance where enhanced inhibition of endothelial cell migration is accomplished with controlled energy consumption, rather than simply maximizing ATPase activity.
Solution Approach 2:
The patent creates multiple mutant variants of endostatin with different amino acid substitutions in the ATP-binding motifs. These copies (mutants) allow selection of the optimal variant that achieves the desired anti-angiogenesis activity with appropriate energy consumption characteristics, rather than relying on a single protein structure.
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
ES mutants with elevated ATPase activity demonstrate significantly improved inhibition of endothelial cell migration and tumor growth, offering enhanced therapeutic potential for angiogenesis-related diseases like tumors, obesity, and insulin resistance.
Implementation Method 1
ATPase, also named as adenosine triphosphatase, is a class of enzymes which can catalyze the hydrolysis of ATP to release energy
Implementation Method 2
ATPase, also named as adenosine triphosphatase, is a class of enzymes which can catalyze the hydrolysis of ATP
Data Source
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Figure 2(A)~2(C)
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AI summary
Provided is a mutant of an endostatin. The mutant has improved ATPase activity and improved activity of inhibiting angiogenesis and inhibiting tumors. Further provided is use of the mutant in treatment of angiogenesis related diseases such as tumors.