Publications

• Carnitine biosynthesis in mammals.

  Vaz F.M., Wanders R.J.

  Carnitine is indispensable for energy metabolism, since it enables activated fatty acids to enter the mitochondria, where they are broken down via beta-oxidation. Carnitine is probably present in all animal species, and in numerous micro-organisms and plants. In mammals, carnitine homoeostasis is ... >> More

  Carnitine is indispensable for energy metabolism, since it enables activated fatty acids to enter the mitochondria, where they are broken down via beta-oxidation. Carnitine is probably present in all animal species, and in numerous micro-organisms and plants. In mammals, carnitine homoeostasis is maintained by endogenous synthesis, absorption from dietary sources and efficient tubular reabsorption by the kidney. This review aims to cover the current knowledge of the enzymological, molecular, metabolic and regulatory aspects of mammalian carnitine biosynthesis, with an emphasis on the human and rat. << Less

  Biochem J 361:417-429(2002) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase.

  Hulse J.D., Ellis S.R., Henderson L.M.

  Rat liver mitochondria were found to hydroxylate epsilon-N-trimethyl-L-lysine to produce beta-hydroxy-epsilon-N-trimethyl-L-lysine, an intermediate in carnitine biosynthesis. The hydroxylating system requires alpha-ketoglutarate, Fe2+, and ascorbate, but does not require NADPH nor NADH. No activit ... >> More

  Rat liver mitochondria were found to hydroxylate epsilon-N-trimethyl-L-lysine to produce beta-hydroxy-epsilon-N-trimethyl-L-lysine, an intermediate in carnitine biosynthesis. The hydroxylating system requires alpha-ketoglutarate, Fe2+, and ascorbate, but does not require NADPH nor NADH. No activity was found in the microsomal or soluble fractions of liver extracts. The hydroxylated alpha-amino acid was isolated and characterized by column chromatography using Dowex 50-H+ and Chelex 100-Cu2+ resins and by high voltage paper electrophoresis. The enzymatically produced beta-hydroxy-epsilon-N-trimethyl-L-lysine was shown to be periodate-sensitive and one periodation product was characterized as gamma-butyrobetaine aldehyde. The hydroxylated product was acted upon by crystalline serine transhydroxymethylase (EC 2.1.2.1) to yield gamma-butyrobetaine aldehyde and glycine. Conversion of about 40% of the epsilon-N-trimethyl-L-lysine to beta-hydroxy-epsilon-N-trimethyl-L-lysine was accomplished by this system with little or no further metabolism. << Less

  J Biol Chem 253:1654-1659(1978) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse.

  Malatesta M., Fornasier E., Di Salvo M.L., Tramonti A., Zangelmi E., Peracchi A., Secchi A., Polverini E., Giachin G., Battistutta R., Contestabile R., Percudani R.

  The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structures. By ... >> More

  The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structures. By screening AlphaFold-modeled vitamin B6-dependent enzymes, we find that a metric based on catalytically favorable conformations at the enzyme active site performs best (AUROC Score=0.84) in identifying genes associated with known reactions. Applying this procedure, we identify the mammalian gene encoding hydroxytrimethyllysine aldolase (HTMLA), the second enzyme of carnitine biosynthesis. Upon experimental validation, we find that the top-ranked candidates, serine hydroxymethyl transferase (SHMT) 1 and 2, catalyze the HTMLA reaction. However, a mouse protein absent in humans (threonine aldolase; Tha1) catalyzes the reaction more efficiently. Tha1 did not rank highest based on the AlphaFold model, but its rank improved to second place using the experimental crystal structure we determined at 2.26 Å resolution. Our findings suggest that humans have lost a gene involved in carnitine biosynthesis, with HTMLA activity of SHMT partially compensating for its function. << Less

  Nat Commun 15:3199-3199(2024) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.