Research Topics, Division of Biological Chemistry, Biocentre, Innsbruck Medical University
Molecular biology of tetrahydrobiopterin biosynthetic enzymes
Tetrahydrobiopterin is formed by three biosynthetic enzymes from guanosine triphosphate (GTP), i.e GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase. We have shown that cytokines regulate the first step of this biosynthesis, by inducing GTP cyclohydrolase I (1) and repressing its feedback regulatory protein (2). Neopterin derivatives accumulate in human cells and in particular in human macrophages due to a low activity of the second enzyme of the pathway, 6-pyruvyol tetrahydropterin synthase (1). The mechanistic basis of this is selective skipping of exon 3 of this enzyme in the splicing process which is particularly effective in human macrophages (3) in which tetrahydrobiopterin is undetectable. GTP cyclohydrolase I is induced by cytokines in alternatively spliced RNAs, and coexpression of the spliced truncated forms of this enzyme cause decrease in activity and protein, presumably by accelerated decay (4).
(1) Werner ER, Werner-Felmayer G, Fuchs D, Hausen A, Reibnegger G, Yim JJ, Pfleiderer W, Wachter H (1990) Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1 and T 24 cells. GTP-cyclohydrolase I is stimulated by interferon-gamma, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase are constitutively present. J Biol Chem 265:3189-3192
(2) Werner ER, Bahrami S, Heller R, Werner-Felmayer G (2002) Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. J Biol Chem 277:10129-10133
(3) Leitner KL, Meyer M, Leimbacher W, Peterbauer A, Hofer S, Heufler C, Müller A, Heller R, Werner ER, Thoeny B, Werner-Felmayer G (2003) The low tetrahydrobiopterin biosynthetic capacity of human monocytes is caused by exon skipping in 6-pyruvoyl tetrahydropterin synthase. Biochem J 373:681-688
(4) Pandya MJ, Golderer G, Werner ER, Werner-Felmayer G (2006) Interaction of human GTP cyclohydrolase I with its splice variants. Biochem J 400:75-80