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T1 - Biopterin synthesis defects

Recent research has focused on the effects of excess glucocorticoids on biosynthesis because reduced cofactor levels can alter the production of serotonin, and catecholamines by NO synthase and the aromatic amino acid hydroxylases. This review will focus on the mechanisms and consequences of excess glucocorticoids on the biosynthesis pathway and the enzymes that utilize as a cofactor.

The balance between the use of methylene-H4 folate for synthesis rather than for methionine synthesis might depend on the presence of the 677T variant of methylenetetrahydrofolate reductase (MTHFR) and the nutritional folate status. Given adequate dietary folate, the 677T variant of functions as a 'valve', preferentially routing one-carbon units to at the expense of methionine. If folate nutritional status is poor, the 677T variant might promote the misincorporation of uracil into leading to chromosome breakage. This mechanism might therefore select embryos that are best suited to reproductive success for a given environmental abundance of dietary folate by augmenting dTMP (deoxythymidine monophosphate) synthesis. Therefore, given the current practice of increasing dietary folate before conception, in utero selection of the 677T variant might lead to a negative, long-term effect on the prevalence of cancer and vascular disease for which this mutation is a potential risk factor.

MethylTHF is essential for all  including  synthesis

Methionine is an intermediate in the biosynthesis of cysteine,

Biosynthesis of tetrahydrobiopterin starts from guanosine triphosphate by the action of guanosine triphosphate cyclohydrolase I, which yields the first intermediate, 7,8-dihydroneopterin triphosphate. This compound is then converted by subsequent enzymes, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, to tetrahydrobiopterin, the biologically active metabolite. Cytokines such as gamma-interferon or tumor necrosis factor-alpha strongly stimulate the activity of guanosine triphosphate cyclohydrolase I in murine and human cells, yielding a potentiation of intracellular tetrahydrobiopterin concentrations. In human cells, particularly in human monocytes and macrophages, the low activity of 6-pyruvoyl tetrahydropterin synthase leads to the additional accumulation of neopterin derivatives, which leak from the cells after dephosphorylation and are found increased in body fluids of humans with diseases challenging cell-mediated immunity. A functional role for the stimulation of tetrahydrobiopterin biosynthesis by cytokines is the formation of a limiting cofactor required for the enzymatic conversion of L-arginine to citrulline and nitric oxide. ()

The effects of 6R-5,6,7,8-tetrahydro-L-biopterin (6A-BH4), the in vivo cofactor for tryptophan hydroxylase, on the synthesis, release, and metabolism of serotonin were studied in superfused slices from rat hippocampus. 6A-BH4 did not alter the spontaneous release of [3H]serotonin but it did significantly increase release when slices were depolarized with 30 mM KCl. Under the same incubation conditions, 6A-BH4 altered neither the synthesis (basal or tryptophanstimulated) nor the metabolism of serotonin in hippocampal slices. The synthetic pteridine 6-methyl-5,6,7,8-tetrahydropterin also augmented release under depolarizing conditions whereas biopterin, the oxidized form of 6R-BH4, did not. The 6S isomer of BH4, which is relatively inactive as a cofactor for tryptophan hydroxylase, was equipotent with 6R-BH4 in stimulating serotonin release. 6R-BH4 did not inhibit serotonin uptake nor did it function as a serotonin autoreceptor antagonist to increase release. A direct serotonin releasing effect of 6R-BH4, like that produced by p-chloroamphetamine, could also be ruled out. At suboptimal concentrations of extracellular calcium, the KCl-induced release of 3H was significantly reduced, yet the increase in release caused by BH4 remained the same in magnitude. It is concluded that 6R-BH4 increases the depolarization-induced release of serotonin through an interaction with the release mechanism itself, possibly by enhancing calcium influx or by increasing the sensitivity of the release mechanism to calcium. The effects of 6R-BH4 on serotonin release are independent from its function as the cofactor for tryptophan hydroxylase.

5-MTHF regulates biosynthesis of BH4.

N2 - The effects of (6R)-5,6,7,8-tetrahydro-l-biopterin (BH4) on the uptake of tryptophan, its conversion to serotonin (5-HT) and 5-hydroxyindoleacetic acid and on the basal release of 5-HT was studied in rat brain synaptosomes. When BH4, the essential cofactor for tryptophan hydroxylase, was incubated with synaptosomes in concentrations varying from 10 to 200 μM, there was no effect on 5-HT formation, metabolism or release. Concentrations of 1-2 mM BH4 had strong inhibitory effects on 5-HT synthesis. The incubation of synaptosomes with tryptophan increased the synthesis of 5-HT, but BH4 did not further increase this effect. BH4 was taken up into synaptosomes in a concentration-dependent manner under all incubation conditions and was stable in the chemically reduced (tetrahydro-) form. These results indicate that increases in the synaptosomal concentration of BH4 do not increase the synthesis and release of 5-HT. It is concluded from the present results that tryptophan hydroxylase is saturated with BH4 in synaptosomes.

N2 - Hyperphenylalaninemia due to a biopterin synthesis defect was detected in an infant with decreased biopterin and increased neopterin levels in plasma and urine. Tetrahydrobiopterin (BH4) administration normalized plasma phenylalanine levels. CSF biopterin and neurotransmitter metabolite levels were normal and with the infant's normal growth and development suggest that the defect in biopterin synthesis did not not affect CNS biopterin metabolism. Comparison of plasma and urine pterin levels from this patient with levels reported in patients who have neurologic complications fails to reveal differences that would distinguish patients at risk for neurologic problems. CSF pterin and neurotransmitter levels may correlate with neurologic function in these patients. CSF pterin and neurotransmitter determinations should be performed prior to initiation of neurotransmitter precursor and BH4 replacement therapies in patients who were determined to have diopterin synthesis defect(s).

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Synthesis and Structural Investigation of Zr(BH4)4 - …


Every cell is able to synthesize BH4 (tetrahydrobiopterin) from GTP

Hyperphenylalaninemia due to a biopterin synthesis defect was detected in an infant with decreased biopterin and increased neopterin levels in plasma and urine. Tetrahydrobiopterin (BH4) administration normalized plasma phenylalanine levels. CSF biopterin and neurotransmitter metabolite levels were normal and with the infant's normal growth and development suggest that the defect in biopterin synthesis did not not affect CNS biopterin metabolism. Comparison of plasma and urine pterin levels from this patient with levels reported in patients who have neurologic complications fails to reveal differences that would distinguish patients at risk for neurologic problems. CSF pterin and neurotransmitter levels may correlate with neurologic function in these patients. CSF pterin and neurotransmitter determinations should be performed prior to initiation of neurotransmitter precursor and BH4 replacement therapies in patients who were determined to have diopterin synthesis defect(s).

The synthesis, recycling and effects of BH4 are shown here.

AB - The effects of (6R)-5,6,7,8-tetrahydro-l-biopterin (BH4) on the uptake of tryptophan, its conversion to serotonin (5-HT) and 5-hydroxyindoleacetic acid and on the basal release of 5-HT was studied in rat brain synaptosomes. When BH4, the essential cofactor for tryptophan hydroxylase, was incubated with synaptosomes in concentrations varying from 10 to 200 μM, there was no effect on 5-HT formation, metabolism or release. Concentrations of 1-2 mM BH4 had strong inhibitory effects on 5-HT synthesis. The incubation of synaptosomes with tryptophan increased the synthesis of 5-HT, but BH4 did not further increase this effect. BH4 was taken up into synaptosomes in a concentration-dependent manner under all incubation conditions and was stable in the chemically reduced (tetrahydro-) form. These results indicate that increases in the synaptosomal concentration of BH4 do not increase the synthesis and release of 5-HT. It is concluded from the present results that tryptophan hydroxylase is saturated with BH4 in synaptosomes.

Tetrahydrobiopterin synthesis. An absolute requirement …

N2 - The effects of 6R-5,6,7,8-tetrahydro-L-biopterin (6A-BH4), the in vivo cofactor for tryptophan hydroxylase, on the synthesis, release, and metabolism of serotonin were studied in superfused slices from rat hippocampus. 6A-BH4 did not alter the spontaneous release of [3H]serotonin but it did significantly increase release when slices were depolarized with 30 mM KCl. Under the same incubation conditions, 6A-BH4 altered neither the synthesis (basal or tryptophanstimulated) nor the metabolism of serotonin in hippocampal slices. The synthetic pteridine 6-methyl-5,6,7,8-tetrahydropterin also augmented release under depolarizing conditions whereas biopterin, the oxidized form of 6R-BH4, did not. The 6S isomer of BH4, which is relatively inactive as a cofactor for tryptophan hydroxylase, was equipotent with 6R-BH4 in stimulating serotonin release. 6R-BH4 did not inhibit serotonin uptake nor did it function as a serotonin autoreceptor antagonist to increase release. A direct serotonin releasing effect of 6R-BH4, like that produced by p-chloroamphetamine, could also be ruled out. At suboptimal concentrations of extracellular calcium, the KCl-induced release of 3H was significantly reduced, yet the increase in release caused by BH4 remained the same in magnitude. It is concluded that 6R-BH4 increases the depolarization-induced release of serotonin through an interaction with the release mechanism itself, possibly by enhancing calcium influx or by increasing the sensitivity of the release mechanism to calcium. The effects of 6R-BH4 on serotonin release are independent from its function as the cofactor for tryptophan hydroxylase.

Synthesis of alcohols using Grignard reagents I

T1 - Synthesis, characterization, and X-ray crystal structures of the divalent titanium complex Ti(η2-BH4)2(dmpe)2 and the unidentate tetrahydroborate complex V(η1-BH4)2(dmpe)2

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