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Biomedical subjects

H C Curtius

Publications and source records attributed to H C Curtius.

At least 37 records · Page 2Linked to original sources
PubMed1988

Primapterin, anapterin, and 6-oxo-primapterin, three new 7-substituted pterins identified in a patient with hyperphenylalaninemia.

Three unknown compounds present in the urine of a patient with mild hyperphenylalaninemia were identified to be L-erythro-7-iso-biopterin, D-erythro-7-iso-neopterin, and L-erythro-6-oxo-7-iso-biopterin. The newly identified pterins were named primapterin, anapterin, and 6-oxo-primapterin, respectively. Primapterin and anapterin are present in very low concentrations in every human urine, as well as in the liver of man and mouse, whereas 6-oxo-primapterin was detected in the patient's urine only. Substantial amounts of primapterin were excreted in the patient described. The metabolic origin of primapterin and anapterin is still obscure.

Animals↗
PubMed1988

Tetrahydrobiopterin deficiency: assay for 6-pyruvoyl-tetrahydropterin synthase activity in erythrocytes, and detection of patients and heterozygous carriers.

6-Pyruvoyl-tetrahydropterin synthase (PTS), a key enzyme in the synthesis of tetrahydrobiopterin in man, is defective in the most frequent variant of tetrahydrobiopterin-deficient hyperphenylalaninaemia (atypical phenylketonuria). An assay for PTS activity in erythrocytes was developed. It is based on the PTS-catalysed formation of tetrahydrobiopterin from dihydroneopterin triphosphate in the presence of magnesium, sepiapterin reductase, NADPH, dihydropteridine reductase, and NADH, and fluorimetric measurement of the product as biopterin by high performance liquid chromatography (HPLC) after oxidation with iodine. The PTS activity was higher in younger erythrocytes, including reticulocytes, than in older ones. Fetal erythrocytes showed approx. four times higher activities than those of adults. Using a more purified human liver sepiapterin reductase fraction which gave a lower yield than a crude preparation, adult controls (n = 8) showed a mean erythrocyte PTS activity of 17.6 (range 11.0-29.5) microU/g Hb. Nine of 11 patients with typical PTS deficiency showed activities between 0% and 8% of the mean of controls, and two of 11 showed 14% and 20%, respectively. The obligate heterozygotes (n = 16) had activities of 19% (range 8%-31%) of the mean of controls, i.e., significantly less than the expected 50%. Four patients with the "peripheral" type of the disease showed 7%-10% of the mean of controls. Thus, the assay did not distinguish between patients and heterozygotes in every family. The assay is well suited to the identification of heterozygotes of PTS deficiency in family studies.

Adult↗
PubMed1988

Neopterin and AIDS.

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Acquired Immunodeficiency Syndrome↗
PubMed1987

Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse.

The cellular origin and the control of neopterin release associated with immune stimulation was studied in cell cultures. Using purified human mononuclear cells, the intracellular change in concentrations of GTP and pterins was measured under various kinds of stimulation. Three enzymes involved in tetrahydrobiopterin biosynthesis, i.e. GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, were also determined. Human macrophages stimulated with culture supernatant from activated T-lymphocytes were the main producers of neopterin. In these cells, GTP cyclohydrolase I activity was elevated due to high GTP levels and therefore neopterin accumulated. Human macrophages lack 6-pyruvoyl tetrahydropterin synthase activity. Exogenous tetrahydrobiopterin added to the culture medium of stimulated T cells and macrophages suppressed the elevation of GTP cyclohydrolase I activity and neopterin concentration, but not the elevation of intracellular GTP. Stimulation of macrophages with recombinant human interferon-gamma and neutralization of the effect of T cell supernatants by addition of a monoclonal antibody specific for human interferon-gamma showed that immune interferon induced the alterations in GTP cyclohydrolase I activity and neopterin concentration. In the human macrophage line U-937 and in the leukemia line HL-60, no GTP cyclohydrolase I activity or intracellular pterins were detected, but high levels of GTP. In mouse mononuclear cells, no neopterin was detected, but biopterin and pterin. After stimulation, biopterin was elevated in the same way as neopterin in human mononuclear cells. This is explained by the different regulation of the rate-limiting steps of tetrahydrobiopterin biosynthesis in man and in mouse. These results suggest that neopterin is an unspecific marker for the activation of the cellular immune system.

Alcohol Oxidoreductases↗
PubMed1987

[Neopterin today].

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Acquired Immunodeficiency Syndrome↗
PubMed1987

Identification of new steroids in patients with 17 alpha-hydroxylase deficiency by capillary gas chromatography/mass spectrometry.

Urines of two children with 17 alpha-hydroxylase deficiency contained a number of 5-pregnane- and pregnenediols, -triols and -tetrols with a hydroxy or oxo group in position 11 of the steroid ring. They are formed mainly from progesterone via 11-hydroxyprogesterone, pregnanolone and corticosterone, respectively, or from pregnenolone. Three metabolites not previously described, 16-hydroxypregnenolone, 6,21-dihydroxypregnanediol and 6-hydroxytetrahydrocorticosterone, were identified.

Adrenal Hyperplasia, Congenital↗
PubMed1987

"Peripheral" tetrahydrobiopterin deficiency with hyperphenylalaninaemia due to incomplete 6-pyruvoyl tetrahydropterin synthase deficiency or heterozygosity.

Four patients in three families with "peripheral" tetrahydrobiopterin deficiency were investigated. They were characterized biochemically by a tetrahydrobiopterin-responsive hyperphenylalaninaemia, a high neopterin/biopterin ratio in urine and plasma, and normal or elevated concentrations of biopterin, homovanillic acid, and 5-hydroxyindole acetic acid in cerebrospinal fluid. From measurements of the activity of erythrocyte 6-pyruvoyl tetrahydropterin synthase (PTS, formerly called phosphate-eliminating enzyme) and phenylalanine loading tests in the patients and their parents, one patient was demonstrated to be heterozygous for PTS deficiency. The others were obviously genetic compounds (allelism) with incomplete PTS deficiency. Three of the children developed normally, two of them under treatment with tetrahydrobiopterin. In the latter two patients, significantly lower concentrations of biopterin, homovanillic acid, and 5-hydroxyindole acetic acid in cerebrospinal fluid were noted at age 7 months (when treatment was interrupted) than those observed at 3 and 5 weeks, respectively. The infant who is heterozygous for PTS deficiency was born small for gestational age and showed a moderately delayed psychomotor development. It is concluded that "peripheral" tetrahydrobiopterin deficiency is caused by a partial PTS deficiency with sufficient activity to cover the tetrahydrobiopterin requirement of tyrosine 3-hydroxylase and trytophan 5-hydroxylase in brain but not enough for phenylalanine 4-hydroxylase in liver. For therapy, tetrahydrobiopterin, 2-5 mg/kg in a single oral dose per day, is recommended to keep plasma phenylalanine normal. A careful observation of the mental development is indicated.

Alcohol Oxidoreductases↗
PubMed1987

Tetrahydrobiopterin biosynthetic pathway and deficiency.

It has been proven that the most common defect in the tetrahydrobiopterin biosynthesis is caused by 6-pyruvoyl tetrahydropterin synthase deficiency. The enzyme 6-pyruvoyl tetrahydropterin synthase consists of four identical subunits which convert dihydroneopterin triphosphate to 6-pyruvoyl tetrahydropterin in the presence of magnesium. UV, NMR, and MS data prove that the enzyme catalyzes the elimination of triphosphate as well as the intramolecular rearrangement. The 6-pyruvoyl tetrahydropterin synthase activity was measured in fetal erythrocytes and together with the neopterin and biopterin measurements in amniotic fluid this enabled performing prenatal diagnosis of 6-pyruvoyl tetrahydropterin synthase deficiency. Peripheral tetrahydrobiopterin deficiency was shown to be due to an incomplete 6-pyruvoyl tetrahydropterin synthase deficiency or heterozygosity.

Alcohol Oxidoreductases↗
PubMed1987

Entrance of tetrahydropterin derivatives in brain after peripheral administration: effect on biogenic amine metabolism.

The ability of various structural analogs of tetrahydrobiopterin to enter the rat brain and remain in the reduced form after i.p. administration was tested because tetrahydrobiopterin itself enters poorly. The total content of various pterins in different brain areas was measured by high-pressure liquid chromatography-fluorescence detection, whereas high-pressure liquid chromatography-electrochemical detection was used to measure the content of reduced pterins. The effect of injection of certain tetrahydropterins on brain content of biogenic amines and their major metabolites was also monitored. In general, when the position 6 side-chain of tetrahydrobiopterin was made shorter and smaller in size, entrance into the brain from the periphery was markedly enhanced. Increasing the lipophilicity or size of the position 6 side-chain did not allow for better entry into brain and, in some cases, hindered entry. Under the conditions tested, none of the tetrahydropterins influenced the brain content of biogenic amines or their major metabolites; higher brain concentrations of tetrahydropterins are probably necessary to modify central nervous system biogenic amine metabolism. Other types of structural modifications or experimental approaches may be necessary to achieve higher brain concentrations of active cofactors, which may be required for the successful treatment of certain human diseases with tetrahydropterins.

Animals↗
PubMed1986

Biosynthesis of tetrahydrobiopterin. Purification and characterization of 6-pyruvoyl-tetrahydropterin synthase from human liver.

6-Pyruvoyl-tetrahydropterin synthase, which catalyzes the first step in the conversion of 7,8-dihydroneopterin triphosphate to tetrahydrobiopterin, was purified approximately 140,000-fold to apparent homogeneity from human liver. The molecular mass of the enzyme is estimated to be 83 kDa. 7,8-Dihydroneopterin triphosphate was a substrate of the enzyme in the presence of Mg2+, and the pH optimum of the reaction was 7.5 in Tris HCl buffer. The Km value for 7,8-dihydroneopterin triphosphate was 10 microM. The product of this enzymatic reaction was the presumed intermediate 6-pyruvoyl-tetrahydropterin. This latter compound was converted to tetrahydrobiopterin in the presence of NADPH and partially purified sepiapterin reductase from human liver. The conditions and the effect of N-acetylserotonin on this reaction, and on the formation of the intermediates 6-(1'-hydroxy-2'-oxopropyl)-tetrahydropterin and 6-(1' oxo-2'-hydroxypropyl)-tetrahydropterin have been studied.

Alcohol Oxidoreductases↗
PubMed1986

Purification of 6-pyruvoyl-tetrahydropterin synthase from human liver.

The enzyme which catalyzes the first step in the conversion of dihydroneopterin triphosphate to tetrahydrobiopterin has been purified approx. 40,000-fold from human liver to apparent homogeneity. The enzyme has a native molecular weight of approximately 83,000 and consists of four identical subunits, each of which has a molecular weight of approximately 19,000. It contains carbohydrates and is remarkably stable to heat treatment. In the presence of purified sepiapterin reductase, Mg2+, and NADPH, this enzyme catalyzes efficiently the formation of tetrahydrobiopterin from dihydroneopterin triphosphate. This indicates that these two proteins are sufficient for the overall conversion.

Alcohol Oxidoreductases↗
PubMed1986

Prenatal diagnosis of "dihydrobiopterin synthetase" deficiency, a variant form of phenylketonuria.

Amniocentesis was performed at 19 weeks gestation in a mother who had previously delivered a boy with "dihydrobiopterin synthetase" (DHBS) deficiency. The amniotic fluid contained neopterin in high (136 nmol/l) and biopterin in very low concentrations (1.8 nmol/l). The activity of the phosphate-eliminating enzyme (PEE, also called 6-pyruvoyl tetrahydropterin synthase, substrate: 7,8-dihydroneopterin triphosphate) which is present in liver and erythrocytes and defective in DHBS deficiency, was measured in the erythrocytes of the family members. The fetal sample showed only 2% of the activity of healthy adult controls and was comparable with that of the affected sibling. Obligate heterozygotes had activities around 20% of the controls. Two fetal control samples showed even higher activities than adult erythrocytes, Sepiapterin reductase activities wer normal in all cases. At autopsy, PEE deficiency was confirmed in the liver of the fetus. We concluded that DHBS deficiency (and most probably also GTP cyclohydrolase I deficiency) can be diagnosed by metabolite measurements in amniotic fluid. PEE activity is measurable in erythrocytes, although the assay needs to be improved. Since maternal tetrahydrobiopterin does not cross the placenta, treatment of a tetrahydrobiopterin-deficient fetus with tetrahydrobiopterin in utero is not possible.

Alcohol Oxidoreductases↗