Human carnitine biosynthesis proceeds via (2S,3S)-3-hydroxy-N^ε-trimethyllysine

Abstract

The stereochemistry of human trimethyllysine hydroxylase was determined to be (2S,3S)-3-hydroxy-N ε-trimethyllysine by comparison to asymmetrically synthesised (2S,3R)-3-hydroxy-N ε-trimethyllysine.

The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases

“…20). Comparison with a diastereomeric mixture of C3 hydroxylysine isomers and synthetic (2 S ,3 R )/(2 R ,3 S )-hydroxylysine standard27 identified (2 S , 3S )-hydroxylysine as the JMJD7-catalyzed product (Fig. 4b and Supplementary Fig.…”

“…C3, C4, and C5 hydroxylysine standards were synthesized or commercially obtained as described14. The synthesis of the (2 S ,3 R )/(2 R ,2 S )-3-hydroxylysine standard has been reported elsewhere27.…”

Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

“…The (2S,3S) stereochemistry of the TMLH-catalyzed product was established through both synthetic and NMR-based investigations ( Figure 2 ) [ 32 , 43 ]. The synthetic (2S,3S)-3-hydroxylysine and (2S,3R)-3-hydroxylysine were used as standards for comparison to the product formed in the presence of the recombinant TMLH.…”

Adventures in Defining Roles of Oxygenases in the Regulation of Protein Biosynthesis

“…As an aside it is notable that the role of TML in the carnitine biosynthesis pathway provides a potentially direct link between histone modification status (and, hence, epigenetics) and fatty acid metabolism. The stereochemistry of the BBOX and TMLH catalysed reactions are conserved with respect to the N ϵ ‐trimethyl‐ and carboxylate groups in their substrates, consistent with a common evolutionary origin. This proposal is supported by sequence analyses based on crystallographic studies on BBOX, which revealed a dimeric structure, and contrasts with the monomeric nature of IPNS/DAOCS subfamily oxygenases.…”

“…The small molecule starting point for carnitine biosynthesis is N ϵ ‐trimethyl lysine (TML) which is produced via protein degradation, likely substantially from N ‐methylated histones. Trimethyllysine hydroxylase (TMLH) catalyses ( 3S )‐hydroxylation of TML to give (2 S ,3 S )‐3‐hydroxy‐ N ϵ ‐trimethyllysine, which undergoes transformation to γ‐butyrobetaine, which further undergoes (3 R )‐hydroxylation as catalysed by γ‐butyrobetaine hydroxylase (BBOX) to give carnitine (Figure A). As an aside it is notable that the role of TML in the carnitine biosynthesis pathway provides a potentially direct link between histone modification status (and, hence, epigenetics) and fatty acid metabolism.…”