Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1, and T 24 cells. GTP-cyclohydrolase I is stimulated by interferon-gamma, and 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase are constitutively present.
Interferon-gamma induces tetrahydrobiopterin biosynthesis in human cells and cell lines. Macrophages are peculiar in the formation of large amounts of neopterin derivatives as compared to tetrahydrobiopterin (Werner, E. R., Werner-Felmayer, G., Fuchs, D., Hausen, A., Reibnegger, G., and Wachter, H. (1989) Biochem J. 262, 861-866). Here we compare the impact of interferon-gamma treatment on activities of GTP-cyclohydrolase I (EC 3.5.4.16), 6-pyruvoyl tetrahydropterin synthase, and sepiapterin reductase (EC 1.1.1.153) in human peripheral blood-derived macrophages, normal dermal fibroblasts, THP-1 myelomonocytic cells, and the T 24 bladder transitional-cell carcinoma line. Upon interferon-gamma treatment, GTP-cyclohydrolase I activity is increased 7- to 40-fold, whereas 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase activities, which are constitutively present in all four investigated cells, remain unchanged. In fibroblasts and T 24 cells GTP cyclohydrolase I activity is the rate-limiting step of tetrahydrobiopterin biosynthesis. In macrophages and in THP-1 cells, however, the induced GTP cyclohydrolase I activity is higher than the 6-pyruvoyl tetrahydropterin synthase activity, leading to the accumulation of neopterin and neopterin phosphates.
Werner
E R
ER
Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Werner-Felmayer
G
G
Fuchs
D
D
Hausen
A
A
Reibnegger
G
G
Yim
J J
JJ
Pfleiderer
W
W
Wachter
H
H
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000619:Aminohydrolases / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002460:Cell Line; D004926:Escherichia coli / Q000201:enzymology; D005347:Fibroblasts / Q000201:enzymology; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D008264:Macrophages / Q000201:enzymology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D019761:Phosphorus-Oxygen Lyases; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000201:enzymology
D011994:Recombinant Proteins; D001708:Biopterins; D007371:Interferon-gamma; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D010744:Phosphoric Monoester Hydrolases; D000619:Aminohydrolases; D006136:GTP Cyclohydrolase; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase; C003402:sapropterin