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Investigating the active site of human trimethyllysine hydroxylase.

Wang, Yali; Reddy, Y Vijayendar; Al Temimi, Abbas H K; Venselaar, Hanka; Nelissen, Frank H T; Lenstra, Danny C; Mecinovic, Jasmin.
Biochem J; 476(7): 1109-1119, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30898847
The biologically important carnitine biosynthesis pathway in humans proceeds via four enzymatic steps. The first step in carnitine biosynthesis is catalyzed by trimethyllysine hydroxylase (TMLH), a non-heme Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase, which catalyzes the stereospecific hydroxylation of (2S)-N ε-trimethyllysine to (2S,3S)-3-hydroxy-N ε-trimethyllysine. Here, we report biocatalytic studies on human TMLH and its 19 variants introduced through site-directed mutagenesis. Amino acid substitutions at the sites involved in binding of the Fe(II) cofactor, 2OG cosubstrate and (2S)-N ε-trimethyllysine substrate provide a basic insight into the binding requirements that determine an efficient TMLH-catalyzed conversion of (2S)-N ε-trimethyllysine to (2S,3S)-3-hydroxy-N ε-trimethyllysine. This work demonstrates the importance of the recognition sites that contribute to the enzymatic activity of TMLH: the Fe(II)-binding H242-D244-H389 residues, R391-R398 involved in 2OG binding and several residues (D231, N334 and the aromatic cage comprised of W221, Y217 and Y234) associated with binding of (2S)-N ε-trimethyllysine.
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