Disease relevance of biopterin

• Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of phenylketonuria [1].
• Serum biopterin is lower in patients with Parkinson's disease than in normal controls [2].
• DCoH, the dimerization cofactor of hepatocyte nuclear factor-1, stimulates gene expression by associating with specific DNA binding proteins and also catalyzes the dehydration of the biopterin cofactor of phenylalanine hydroxylase [3].
• Furthermore, patients with Alzheimer disease who have extrapyramidal dysfunction or myoclonus are a distinct subgroup, with specific abnormalities of central monoamine markers of dopamine metabolism, serotonin metabolism, and the hydroxylation cofactor, biopterin [4].
• PTR1 purified from engineered Escherichia coli exhibited a MTX-sensitive, NADPH-dependent biopterin reductase activity [5].

Psychiatry related information on biopterin

• Biopterin derivatives in senile dementia [6].
• Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome [7].
• We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Alzheimer type (DAT), with or without extrapyramidal signs, and in 14 age-matched healthy controls [8].
• As a raised N:B ratio implies failure to convert neopterin to biopterin it is possible that reduced availability of tetrahydrobiopterin, the essential cofactor for the formation of noradrenaline, serotonin and dopamine, may exert rate limiting control over the synthesis of monoamines implicated in the pathogenesis of depressive disorders [9].
• To extend our previous finding in schizophrenia, we analyzed plasma biopterin levels from patients with schizoaffective and bipolar disorders [10].

High impact information on biopterin

• We measured erythrocyte DHPR activity and concentrations of the biopterin derivatives of its substrate and of aluminum in 38 patients on hemodialysis who had no clinical evidence of encephalopathy [11].
• After administration of tyrosine, total concentration of biopterin, the cofactor for tyrosine hydroxylase, was increased in the striatum, adrenal glands, and serum of rats, and in the serum of humans [2].
• After oral administration of tyrosine, the increase in serum biopterin concentration was smaller in patients with Parkinson's disease (less than twofold) than in healthy controls (three-to sevenfold) [2].
• Biopterin cofactor biosynthesis: independent regulation of GTP cyclohydrolase in adrenal medulla and cortex [12].
• Pineal glands in organ culture synthesize and release biopterin and are able to maintain concentrations of biopterin occurring in vivo for up to 54 hours in vitro [13].

Chemical compound and disease context of biopterin

• Neopterin and biopterin CSF levels in tardive dyskinesia after clozapine treatment [14].
• We report a child with a systemic biopterin synthesis defect due to an absence of 6-pyruvoyl-tetrahydropterin synthase who had an unusual presentation, with three episodes of coarse "rubral-like" tremor in arms and legs orofacial dyskinesia between the ages of 3 and 6 months [15].
• Tetrahydrobiopterin and total biopterin content of neuroblastoma (N1E-115, N2A) and pheochromocytoma (PC-12) clones and the dependence of catecholamine synthesis on tetrahydrobiopterin concentration in PC-12 cells [16].
• To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia [17].
• They inhibited the enzyme activity prepared from mastocytoma cells in terms of the biopterin cofactor and the substrate L-tryptophan [18].

Biological context of biopterin

• In WT mice, induction of diabetes with streptozotocin (STZ) increased vascular oxidative stress, resulting in oxidative loss of BH4, forming BH2 and biopterin [19].
• Biopterin accumulation had been demonstrated as the result of normal and, especially, of malignant hemopoietic cell proliferation (Ziegler, I. et al. Blut, 44: 231-240, and 261-270, 1982) [20].
• Induced fitting structural changes by the biopterin binding expand large conformational changes in GTPCHI peptide segments forming the active site, resulting in inhibition of the activity [21].
• We have used serial pancreatic biopsy, and measurement of serum biopterin at 30, 60, 90 and 120 days in the BB/S rat to relate histological change to macrophage activation during the course of pre-diabetes [22].
• These changes were followed by an increase in eNOS activity, demonstrating that high biopterin levels offset inhibition of eNOS phosphorylation and diminished interaction with hsp90 [23].

Anatomical context of biopterin

• Biopterin, an obligate cofactor of iNOS enzymatic activity, is undetectable in freshly isolated or cultured human monocytes and peritoneal macrophages [24].
• Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages [24].
• Accordingly, total cerebrospinal fluid biopterin was measured and found to be elevated in patients compared with controls (p less than 0.002) [7].
• Biopterin determinations by means of Crithidia assay in the blood of 136 cases of solid tumors showed that, due to its high rate of renal clearance, blood biopterin is not a reliable and persistent marker for proliferative activity, unless it is contained in the immature blood cells themselves, as is the case during leukemias [25].
• In the autopsied putamen of an asymptomatic GCH1 mutation carrier, we found that brain biopterin loss (-82%) paralleled that reported in dopa-responsive dystonia patients (-84%) [26].

Associations of biopterin with other chemical compounds

• Comparison of the rabbit tryptophan hydroxylase sequence with the sequences of phenylalanine hydroxylase and tyrosine hydroxylase demonstrates that these three biopterin-dependent aromatic amino acid hydroxylases are highly homologous, reflecting a common evolutionary origin from a single primordial genetic locus [27].
• It is assumed that brain biopterin and dopamine loss should not be as severe in asymptomatic dopa-responsive dystonia caused by GCH1 mutations as it is in symptomatic dopa-responsive dystonia [26].
• The results indicate that the anabolic-reduced biopterin derivatives are not simply lymphocytic products, but, in combination with the catabolites xanthopterin and isoxanthopterin, they also participate in the regulation of lymphocyte activation [20].
• Furthermore, the increase of tetrahydrobiopterin levels in intact endothelial cells coincubated with cytokines and ascorbate was associated with a decrease of more oxidized biopterin derivatives (7,8-dihydrobiopterin and biopterin) in cells and cell supernatants [28].
• In animals, the GTPCHI feedback regulatory protein (GFRP) binds GTPCHI to mediate feed-forward activation of GTPCHI activity in the presence of phenylalanine, whereas it induces feedback inhibition of enzyme activity in the presence of biopterin [21].

Gene context of biopterin

• These two enzymes, together with phenylalanine hydroxylase (PAH), constitute the group of biopterin-dependent hydroxylases, which all are involved in the biosynthesis of neurotransmitters [29].
• Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia [30].
• PTPS- and DHPR-deficient cells showed no enzyme activities; in PTPS deficiency the pattern of pterin production was typical (neopterin, 334-734 pmol/mg; controls, 18-98 pmol/mg; biopterin, 0 pmol/mg; controls, 154-303 pmol/mg) [31].
• Both GCH activity and total biopterin content were highly increased in the V-1 clones; whereas the activity of sepiapterin reductase, enzyme in the final step of the BH(4) biosynthesis, was not altered [32].
• This eNOS-dependent O(2)(-) synthesis was associated with reduced intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (-80%) and increased release of 7,8-dihydrobiopterin and biopterin in the extracellular medium (+40%) [33].

Analytical, diagnostic and therapeutic context of biopterin

• Biopterin and organ transplantation [34].
• Gas chromatography isolated a species in this peak with the mass spectrum of biopterin [35].
• Western blot analysis demonstrated that induction of biopterin synthesis in HAECs and ARCM by LPS does not entail augmentation of constitutive GTPCH-I protein levels [36].
• We report an improved "high-performance" liquid-chromatographic (HPLC) method for measuring biopterin and neopterin in serum and urine [37].
• Reduced infectivity of a Leishmania donovani biopterin transporter genetic mutant and its use as an attenuated strain for vaccination [38].

References