Tetrahydrobiopterin Biosynthetic Pathway and Deficiency

Niederwieser, A.; Curtius, Hans−Christoph

doi:10.1159/000469220

Cited by 20 publications

(4 citation statements)

References 17 publications

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“…Diaminohydroxypyrimidine (DAHP), an inhibitor of GTP cyclohydrolase (26,27), the first enzyme in de novo BH 4 biosynthetic pathway (25,28,29), did not alter the serum withdrawal effect on DNA fragmentation (Fig. 1C).…”

Section: Bhmentioning

confidence: 96%

Tetrahydrobiopterin Enhances Apoptotic PC12 Cell Death following Withdrawal of Trophic Support

Anastasiadis

Jiang

Bezin

et al. 2001

Journal of Biological Chemistry

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(6R)-Tetrahydro-L-biopterin (BH 4 ) is the rate-limiting cofactor in the production of catecholamine and indoleamine neurotransmitters and is also essential for the synthesis of nitric oxide by nitric-oxide synthase. We have previously reported that BH 4 administration induces PC12 cell proliferation and that nerve growth factor-or epidermal growth factor-induced PC12 cell proliferation requires the elevation of intracellular BH 4 levels. We show here that BH 4 accelerates apoptosis in undifferentiated PC12 cells deprived of serum and in differentiated neuron-like PC12 cells after nerve growth factor withdrawal. Increased production of catecholamines or nitric oxide cannot account for the enhancement of apoptosis by BH 4 . Furthermore, increased calcium influx by exogenous BH 4 administration is not involved in the BH 4 proapoptotic effect. Our data also argue against the possibility that increased oxidative stress, due to BH 4 autoxidation, is responsible for the observed BH 4 effects. Instead, they are consistent with the hypothesis that BH 4 induces apoptosis by increasing cell cycle progression. Elevation of intracellular BH 4 during serum withdrawal increased c-Myc (and especially Myc S) expression earlier than serum withdrawal alone. Furthermore, N-acetylcysteine and the cyclin-dependent kinase inhibitor olomoucine ameliorated the BH 4 proapoptotic effect. These data suggest that BH 4 affects c-Myc expression and cell cycle-dependent events, possibly accounting for its effects on promoting cell cycle progression or apoptosis.Apoptotic cell death is important for normal nervous system development, where neurons that make proper connections and receive sufficient trophic support survive, whereas neurons that are deprived of trophic support die via apoptosis (for a review, see Ref. 1). The requirement for neurotrophic support is thought to continue in mature neurons (for a review, see Ref.2). During normal aging and in Parkinson's disease (PD), 1 nigrostriatal dopamine neurons preferentially degenerate. The etiology of this selective cell loss remains unknown. Local availability of trophic factors is able to protect cells from degeneration in animal models of PD (3-6), suggesting that lack of trophic support could contribute to the observed neurodegeneration in normal aging and in PD. Furthermore, morphological characteristics of apoptotic cell death have been reported in brain sections from PD patients (7, 8), but the involvement of apoptosis in PD is still controversial.PC12 cells have been extensively used as a model of catecholaminergic neurons in culture as well as for the study of neuronal apoptotic death. Naive (undifferentiated) PC12 cells grown in the presence of serum undergo apoptosis upon serum withdrawal (9 -11). Furthermore, PC12 cells that become neuronally differentiated and postmitotic following prolonged incubation with NGF undergo apoptosis upon NGF and serum withdrawal (9, 10). Undifferentiated PC12 cell death upon serum withdrawal has been linked to an inappropriate progression through th...

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Section: Bhmentioning

confidence: 96%

Tetrahydrobiopterin Enhances Apoptotic PC12 Cell Death following Withdrawal of Trophic Support

Anastasiadis

Jiang

Bezin

et al. 2001

Journal of Biological Chemistry

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“…There is also a very small amount of a 6-PTP reductase that reduces the 2‘-oxo group of 6-PTP. Its scarcity is evident from the 50000-fold purification from human liver to homogeneity that has been reported . SR and this aldol reductase are the only enzymes not yet associated with a form of HPA or PKU.…”

Section: Pterin Biochemistrymentioning

confidence: 99%

Pterin-Dependent Amino Acid Hydroxylases

1996

Chem. Rev.

315

385

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“…In contrast to the original report of a single form of GTP cyclohydrolase I mRNA in rat liver 2 , we have detected two mRNA species of 1.2 and 3.8 kilobases in rat liver and other tissues 23 ' 25 • The relative abundance of these mRNAs varied, with the short form predominant in the liver and the long form the major species in the pineal gland, adrenal gland, brainstem and hypothalamic neurons maintained in culture. This heterogeneity in GTP cyclohydrolase I mRNA may reflect alternative splicing of pre-mRNA, alternative transcription initiation sites or multiple polyadenylation signals and may help to explain the disparate range of sizes reported for the subunit form of mammalian GTP cyclohydrolase f 6 • 27 • 28 • 29 • Although these apparent structural differences might suggest otherwise, the possibility of two distinct GTP cyclohydrolase I genes is unlikely because mutations that eliminate GTP cyclohydrolase I enzyme activity and BH4 biosynthesis in man 30 and mouse 31 would have to involve simultaneous loss of both genes. It remains to be determined whether these apparent differences in GTP cyclohydrolase I protein are related to the two forms of mRNA which may have the potential to code for separate translation products with different catalytic and regulatory capabilities.…”

Section: Laboratory Observationsmentioning

confidence: 99%