title: Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI).
abstract: 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) is observed as a minor contaminant in caramel food colourings (E 150c). Feeding experiments with rodents have revealed a significant lymphopenic effect that has been linked to the presence of THI in these food colourings. Pyridoxal kinase inhibition by THI has been suggested, but not demonstrated, as a mode of action as it leads to lowered levels of pyridoxal-5'-phosphate, which are known to cause lymphopenia. Recently, THI was also shown to inhibit sphingosine-1-phosphate lyase causing comparable immunosuppressive effects and derivatives of THI are being developed for the treatment of rheumatoid arthritis in humans. Interestingly, sphingosine-1-phosphate lyase activity depends on pyridoxal-5'-phosphate, which in turn is provided by pyridoxal kinase. This report shows that THI does inhibit pyridoxal kinase with competitive and mixed-type non-competitive behaviour towards its two substrates, pyridoxal and ATP, respectively. The corresponding inhibition constants are in the low millimolar range.
authors.affiliation: Pharmaceutical Chemistry I, Pharmaceutical Institute , University of Bonn, Bonn , Germany and.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Elsinghorst
authors.forename: Martino L
authors.initials: ML
authors.lastname: di Salvo
authors.forename: Alessia
authors.initials: A
authors.lastname: Parroni
authors.forename: Roberto
authors.initials: R
authors.lastname: Contestabile
mesh_terms: D005505:Food Coloring Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D015394:Molecular Structure; D011731:Pyridoxal Kinase / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
chemical_list: D005505:Food Coloring Agents; D007093:Imidazoles; C049929:2-acetyl-4(5)-tetrahydroxybutylimidazole; D011731:Pyridoxal Kinase
keywords: Caramel food colourings; THI; pyridoxal kinase; sphingosine-1-phosphate lyase