Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00261
Keywords
Carnitine; isothermal titration calorimetry; trimethyllysine; dioxygenase
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Funding
- European Regional Develop-ment Fund
- Latvian Institute of Organic Synthesis
- [1.1.1.1/20/A/009]
- [IG-2022-04]
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This study reports a new method for analyzing the binding of TMLD substrate analogues to the enzyme, providing insight into the substrate selectivity of TMLD.
epsilon-Trimethyllysine dioxygenase (TMLD) is a nonheme Fe(II) and alpha-ketoglutarate dependent oxygenase that catalyzes the stereospecific hydroxylation of epsilon-trimethyl-L-lysine (TML) to beta-hydroxy-TML during the first step of L-carnitine biosynthesis. Targeting TMLD with inhibitors is a viable strategy for the treatment of cardiovascular diseases. Herein, we report a methodology for isothermal titration calorimetry analysis of TMLD substrate analogue binding to the enzyme. Despite the high structural similarity of the tested compounds, two different binding mechanisms (enthalpy- and entropy-driven) were observed, giving insight into the ligand (substrate) selectivity of TMLD. We demonstrate that the method allows distinguishing a natural substrate-like binding mode, which correlates with the ability of the compounds to serve as substrates in the TMLD catalytic reaction.
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