title: Control of lysyl oxidase activity through site-specific deuteration of lysine.
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-d(2)-lysine is oxidised by LOX at substantially lower rate, with apparent deuterium effect on V(max)/K(m) as high as 4.35 ± 0.22. Lys is an essential nutrient, so dietary ingestion of D(2)Lys and its incorporation via normal Lys turnover suggests new approaches to mitigating LOX-associated pathologies.
authors.affiliation: Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117871, Russia.
authors.forename: Nikolay B
authors.initials: NB
authors.lastname: Pestov
authors.forename: Irina A
authors.initials: IA
authors.lastname: Okkelman
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Shmanai
authors.forename: Alaksiej L
authors.initials: AL
authors.lastname: Hurski
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Shchepinov
mesh_terms: D000818:Animals; D003903:Deuterium / Q000737:chemistry; D007553:Isotope Labeling; D007700:Kinetics; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D010084:Oxidation-Reduction; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012756:Sheep; D013379:Substrate Specificity
chemical_list: D011994:Recombinant Proteins; D003903:Deuterium; D008249:Protein-Lysine 6-Oxidase; D008239:Lysine