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Publikācija: Mapping the Active Site of Epsilon-Trimethyllysine Hydroxylase

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Nosaukums oriģinālvalodā Mapping the Active Site of Epsilon-Trimethyllysine Hydroxylase
Pētniecības nozare 3. Medicīnas un veselības zinātnes
Pētniecības apakšnozare 3.1. Medicīnas bāzes zinātnes, tai skaitā farmācija
Autori Diāna Zeļencova
Edvards Liepiņš
Atslēgas vārdi TMLH, NMR, in silico, molecular modelling
Anotācija dioxygenase located in the submitochondrial matrix. This enzyme is crucial for the stereospecific oxidation of ε-trimethyllysine (TML) to β-hydroxytrimethyllysine (HTML) – the first step in the biosynthesis of L-carnitine. It is proposed that the regulation of enzymatic activity of TMLH may have more potent cardioprotective effect than meldonium (clinically used anti-ischemia drug) that is an inhibitor of γ-butyrobetaine hydroxylase (GBBH) – the final step of the L-carnitine production. Due to failure of the crystallographic methods there is still lack of information about the structure of the TMLH and especially about its active site. In this work we applied in silico and in vitro methods to design the possible active site of TMLH. The structure of the TMLH was modelled using homology modelling approach based on the closest homolog – GBBH (used as template). However, the overall similarity between both enzymes was slightly below 30%. Thus, various modelling software were tested, and the resulting structures were optimized during molecular dynamics simulations. This approach gave the insights into possible enzyme fold. Next, the NMR protein-ligand binding experiments (T1ρ, waterLOGSY and ST1D) and the enzymatic assay (reaction monitored by 1D 1H-NMR) revealed some crucial structure-activity relationships (SAR) that in combination with molecular docking and previous in silico data allowed to construct estimated active site of TMLH.
DOI: 10.21767/2471-8084-C1-009
Atsauce Zeļencova, D., Liepiņš, E. Mapping the Active Site of Epsilon-Trimethyllysine Hydroxylase. No: 10th Edition of International Conference on Structural Biology: Biochemistry and Molecular Biology Journal, Spānija, Barcelona, 15.-16. marts, 2018. Barcelona: 2018, 51.-51.lpp. ISSN 2471-8084. Pieejams: doi:10.21767/2471-8084-C1-009
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