# Structural and functional modulation of human kynurenine aminotransferase I enhances selenium-driven redox metabolism for cancer therapy

## TL;DR

Scientists modified an enzyme to improve how cancer cells process a selenium compound, making it more effective at killing cancer cells.

## Contribution

The study introduces enzyme modifications that significantly boost selenium compound metabolism and anticancer effects.

## Key findings

- Mutants Y101H and F278A increased both transamination and β-elimination activity of hKYAT1.
- D126L mutation favored β-elimination and induced redox stress-driven cytotoxicity.
- Enhanced MSC metabolism led to apoptosis and histone acetylation in cancer cells.

## Abstract

Se-methylselenocysteine (MSC) is a redox-active selenium-containing amino acid with notable anticancer potential, requiring enzymatic activation for cytotoxicity. Human kynurenine aminotransferase 1 (hKYAT1) catalyzes MSC through transamination and β-elimination pathways, generating β-methylselenopyruvate and methylselenol, both of which induce oxidative stress and epigenetic modulation. To enhance MSC metabolism and its therapeutic efficacy, we performed site-directed mutagenesis targeting three critical hKYAT1 residues: Tyr101, Asp126, and Phe278. These mutants, along with wild-type hKYAT1, were expressed in hepatocellular carcinoma cell lines HepG2 and Huh7, and their impact on enzymatic activity, cytotoxic effects, apoptosis and chromatin remodeling were evaluated. Several mutations significantly enhanced MSC metabolism, with Y101H and F278A increasing both transamination and β-elimination activity, and D126L favoring β-elimination. These modifications led to a five-to 30-fold increase in MSC-induced cytotoxicity compared to wild-type hKYAT1. Additionally, mutant hKYAT1 expression altered histone deacetylase (HDAC) profiles, increased histone H4 acetylation, and activated apoptotic signaling through caspase cleavage and cytochrome c release. Collectively, our findings demonstrate that rational engineering of hKYAT1 can potentiate MSC metabolism and amplify its anticancer effects, offering a promising enzyme-targeting strategy for selenium-based cancer therapies.

Image 1

•Rational engineering of hKYAT1 altered its catalytic balance between transamination and β-elimination.•Mutants Y101H and F278A enhanced dual activity towards Se-methylselenocysteine (MSC).•D126L selectively favoured β-elimination and induced redox stress–driven cytotoxicity.•Enhanced MSC metabolism by hKYAT1 mutants led to apoptosis and histone acetylation in cancer cells.•Findings support hKYAT1 as a tuneable metabolic node for selenium-based cancer therapy.

Rational engineering of hKYAT1 altered its catalytic balance between transamination and β-elimination.

Mutants Y101H and F278A enhanced dual activity towards Se-methylselenocysteine (MSC).

D126L selectively favoured β-elimination and induced redox stress–driven cytotoxicity.

Enhanced MSC metabolism by hKYAT1 mutants led to apoptosis and histone acetylation in cancer cells.

Findings support hKYAT1 as a tuneable metabolic node for selenium-based cancer therapy.