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Control of lysyl oxidase activity through site-specific deuteration of lysine |
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| Authors: | Pestov Nikolay B Okkelman Irina A Shmanai Vadim V Hurski Alaksiej L Giaccia Amato J Shchepinov Mikhail S |
| Affiliation: | a Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117871, Russia b Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, ul. Surganova, 13, Minsk 220072, Belarus c Radiation Oncology Department, Stanford University School of Medicine, Stanford, CA 93025, USA d Retrotope Inc., 12133 Foothill Lane, Los Altos Hills, CA 94022, USA |
| Abstract: | Lysyl oxidase (LOX) is implicated in several extracellular matrix related disorders, including fibrosis and cancer. Methods of inhibition of LOX in vivo include antibodies, copper sequestration and toxic small molecules such as β-aminopropionitrile. Here, we propose a novel approach to modulation of LOX activity based on the kinetic isotope effect (KIE). We show that 6,6-d2-lysine is oxidised by LOX at substantially lower rate, with apparent deuterium effect on Vmax/Km as high as 4.35 ± 0.22. Lys is an essential nutrient, so dietary ingestion of D2Lys and its incorporation via normal Lys turnover suggests new approaches to mitigating LOX-associated pathologies. |
| Keywords: | BAPN, β-aminopropionitrile LOX, lysyl oxidase MAO, monoamine oxidase KIE, kinetic isotope effect DVK, deuterium isotope effect on Vmax/Km DV, deuterium isotope effect on Vmax SSAO, semicarbazide-sensitive amine oxidase |
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