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L-Lysine α-Oxidase: Enzyme with Anticancer Properties.

ABSTRACT: L-lysine α-oxidase (LO), one of L-amino acid oxidases, deaminates L-lysine with the yield of H₂O₂, ammonia, and α-keto-ε-aminocaproate. Multiple in vitro and in vivo studies have reported cytotoxic, antitumor, antimetastatic, and antitumor activity of LO. Unlike asparaginase, LO has a dual mechanism of action: depletion of L-lysine and formation of H₂O₂, both targeting tumor growth. Prominent results were obtained on murine and human tumor models, including human colon cancer xenografts HCT 116, LS174T, and T47D with maximum T/C 12, 37, and 36%, respectively. The data obtained from human cancer xenografts in immunodeficient mice confirm the potential of LO as an agent for colon cancer treatment. In this review, we discuss recently discovered molecular mechanisms of biological action and the potential of LO as anticancer enzyme.

SUBMITTER: Lukasheva EV

PROVIDER: S-EPMC8618108 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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L-Lysine α-Oxidase: Enzyme with Anticancer Properties.

Lukasheva Elena V EV Babayeva Gulalek G Karshieva Saida Sh SS Zhdanov Dmitry D DD Pokrovsky Vadim S VS

Pharmaceuticals (Basel, Switzerland) 20211022 11

L-lysine α-oxidase (LO), one of L-amino acid oxidases, deaminates L-lysine with the yield of H2O2, ammonia, and α-keto-ε-aminocaproate. Multiple in vitro and in vivo studies have reported cytotoxic, antitumor, antimetastatic, and antitumor activity of LO. Unlike asparaginase, LO has a dual mechanism of action: depletion of L-lysine and formation of H2O2, both targeting tumor growth. Prominent results were obtained on murine and human tumor models, incl ...[more]

PMID: 34832852

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Project description:Recombinant urate oxidase (UOX, E.C.1.7.3.3) is an important therapeutic enzyme used in preventing and treating chemotherapy-induced hyperuricemia and severe gout. However, UOX use is limited due to the poor stability and short plasma half-life. To solve this problem, we designed three PASylated variants of Aspergillus flavus UOX with different PAS sequences at the C- or N-terminus. The genes of native and PASylated variants (UOX-PAS20, PAS24-UOX, and UOX-PAS100) were designed and produced in Escherichia coli strain BL21 (DE3). The expressed recombinant native and PASylated enzymes were compared in terms of biophysical properties, kinetics parameters, and pharmacokinetics behavior using standard methods. PASylation of UOX with PAS100 polymer caused a 1.24-fold reduction in K m to 52.61 μM, and a 3.87-fold increase in K cat/K m for uric acid compared to the native variant. UOX-PAS100 retained its activity in different temperatures (20-55 °C); however, other variants lost nearly 50% of their original activity at 55 °C. UOX-PAS100 exhibited a 1.78-fold increase in hydrodynamic radius and a 1.64-fold larger apparent molecular size in comparison to the native UOX. Circular dichroism (CD) spectroscopy demonstrated that the addition of the PAS tag does not change the secondary structure of the fusion enzyme. The tryptophan fluorescence emission spectra for PASylated enzymes showed a significant modification in the conformational state of UOX by the PAS polymer presence. UOX-PAS100 retained 89.0% of the original activity following 72 h incubation in the presence of plasma at 37 °C. However, only about 61.0%, 57.0%, 50.0%, and 52.0% of activity from PAS24-UOX, UOX-PAS20, native UOX, and rasburicase (Fasturtec, Italy) remained, respectively, at the identical time. UOX-PAS100 had an increased biological half-life (8.21 h) when compared with the rasburicase (3.12 h) and native UOX (2.87 h) after being injected into a rat. Having considering everything, our results suggest that the UOX-PAS100, an A. flavus UOX fused with a C-terminally 100 amino acid PAS-residue, is a proper candidate with enhanced biological activity and extended plasma half-life for clinical therapy in patients suffering from hyperuricemia.

Dataset Information

L-Lysine α-Oxidase: Enzyme with Anticancer Properties.

Publications

L-Lysine α-Oxidase: Enzyme with Anticancer Properties.

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