Purification and Cloning of the GTP Cyclohydrolase I Feedback Regulatory Protein, GFRP

Milstien, Sheldon; Jaffe, Howard; Kowlessur, Devanand; Bonner, Tom I.

doi:10.1074/jbc.271.33.19743

Cited by 87 publications

(82 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…After 72-h postfertilization, however, GTP cyclohydrolase I activity does not correlate with the onset of rapid production of pteridine pigments. In mammalian cells, various cytokines and growth factors regulate the activity of GTP cyclohydrolase I at the transcriptional or post-transcriptional level (55)(56)(57), through post-translational modification by hyperphosphorylation (58) or by association with a feedback regulatory protein (59). Research is under way into the regulation of GTP cyclohydrolase I activity during the development of the zebrafish and in particular to explain why this activity starts to decrease at around 72-h postfertilization, which coincides with the production of xanthophore pteridine pigments.…”

Section: Discussionmentioning

confidence: 99%

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Ziegler¹,

McDonald²,

Heßlinger³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

In the zebrafish, the peripheral neurons and the pigment cells are derived from the neural crest and share the pteridine pathway, which leads either to the cofactor tetrahydrobiopterin or to xanthophore pigments. The components of the pteridine pattern were identified as tetrahydrobiopterin, sepiapterin, 7-oxobiopterin, isoxanthopterin, and 2,4,7-trioxopteridine. The expression of GTP cyclohydrolase I activity during the first 24-h postfertilization, followed by 6-pyruvoyl-5,6,7,8-tetrahydropterin synthase and sepiapterin reductase, suggest an early supply of tetrahydrobiopterin for neurotransmitter synthesis in the neurons and for tyrosine supply in the melanophores. At 48-h postfertilization, sepiapterin formation branches off the de novo pathway of tetrahydrobiopterin synthesis. Sepiapterin, via 7,8-dihydrobiopterin and biopterin, serves as a precursor for the formation of 7-oxobiopterin, which may be further catabolized to isoxanthopterin and 2,4,7-trioxopteridine. Neither 7,8-dihydrobiopterin nor biopterin is a substrate for xanthine oxidoreductase. In contrast, both of these compounds are oxidized at C-7 by a xanthine oxidase variant form, which is inactivated by KCN, but is insensitive to allopurinol. The oxidase and the dehydrogenase form of xanthine oxidoreductase as well as the xanthine oxidase variant have specific developmental patterns. It follows that GTP cyclohydrolase I, the formation of sepiapterin, and the xanthine oxidoreductase family control the pteridine pathway in the zebrafish.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Ziegler¹,

McDonald²,

Heßlinger³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Determination of GTPCH Activity-GTPCH activity was measured essentially as described previously (24). In brief, to 30 l of lysate were added 5 l of 0.5 M Tris-HCl (pH 7.4), 5 l of 10 mM dithiothreitol, 5 l of 10 mg/ml bovine serum albumin, and 5 l of 10 mM GTP.…”

Section: Methodsmentioning

confidence: 99%

“…In some cell types, BH 4 inhibits GTPCH activity through the action of the GFRP, which forms a complex with GTPCH (24,30). Thus, cytokine-induced decreases in GFRP activity or expression might lead to an increase in GTPCH activity, and result in higher levels of BH 4 .…”

Section: Tnf-␣ But Not Ceramide Up-regulates Bhmentioning

confidence: 99%

Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-α

Vann¹,

Twitty²,

Spiegel³

et al. 2000

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Synthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH 4 ), a required cofactor for inducible nitric-oxide synthase (iNOS) activity, is usually coordinately regulated with iNOS expression. In C6 glioma cells, tumor necrosis factor-␣ (TNF-␣) concomitantly potentiated the stimulation of nitric oxide (NO) and BH 4 production induced by IFN-␥ and interleukin-1␤. Expression of both iNOS and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the BH 4 biosynthetic pathway, was also markedly increased, as were their activities and protein levels. Ceramide, a sphingolipid metabolite, may mediate some of the actions of TNF-␣. Indeed, we found that bacterial sphingomyelinase, which hydrolyzes sphingomyelin and increases endogenous ceramide, or the cell permeable ceramide analogue, C 2 -ceramide, but not C 2 -dihydroceramide (N-acetylsphinganine), significantly mimicked the effects of TNF-␣ on NO production and iNOS expression and activity in C6 cells. Surprisingly, although TNF-␣ increased BH 4 synthesis and GTPCH activity, neither BH 4 nor GTPCH expression was affected by C 2 -ceramide or sphingomyelinase in IFN-␥-and interleukin-1␤-stimulated cells. It is likely that increased BH 4 levels results from increased GTPCH protein and activity in vivo rather than from reduced turnover of BH 4 , because the GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, blocked cytokine-stimulated BH 4 accumulation. Moreover, expression of the GTPCH feedback regulatory protein, which if decreased might increase GTPCH activity, was not affected by TNF-␣ or ceramide. Treatment with the antioxidant pyrrolidine dithiocarbamate, which is known to inhibit NF-B and sphingomyelinase in C6 cells, or with the peptide SN-50, which blocks translocation of NF-B to the nucleus, inhibited TNF-␣-dependent iNOS mRNA expression without affecting GTPCH mRNA levels. This is the first demonstration that cytokine-stimulated iNOS and GTPCH expression, and therefore NO and BH 4 biosynthesis, may be regulated by discrete pathways. As BH 4 is also a cofactor for the aromatic amino acid hydroxylases, discovery of distinct mechanisms for regulation of BH 4 and NO has important implications for its specific functions.

show abstract

“…Nevertheless, we observed only a relatively modest (3-to 4-fold) increase in tissue BH4 levels in GCH-Tg mice, in the setting of a 5-to 10-fold increase in total GTPCH mRNA levels. This suggests that the activity of transgenic GTPCH may be regulated posttranscriptionally or posttranslationally, for example, by GTPCH feedback regulatory protein (34).…”

Section: Figurementioning

confidence: 99%