Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R, 2S, 3R)-1, 2, 3, 4-tetrahydroxybutyl)imidazole (THI). (3rd June 2014)

• Record Type: Journal Article
• Authors: Elsinghorst, Paul W.; di Salvo, Martino L.; Parroni, Alessia; Contestabile, Roberto
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 30:Number 2(2015:Apr.)
• Page Start: 336
• Page End: 340
• Publication Date: 2014-06-03
• Subjects: Caramel food colourings -- pyridoxal kinase -- sphingosine-1-phosphate lyase -- THI; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2014.915396
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 2-Acetyl-4-((1 R, 2 S, 3 R )-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.