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PubMed2003

Purification and partial characterisation of camel milk xanthine oxidoreductase.

Xanthine oxidoreductase (XOR) was purified in the presence of dithiothrietol from camel milk with yields of up to 22.2mg/l that were comparable to those obtained from bovine and human milk sources. On SDS-PAGE, the freshly purified camel milk XOR had a protein flavin (A280/A450) ratio of 5.3 +/- 0.4 and appeared homogenous with a single major band of approximately Mr 145.3 KDa. Surprisingly, in all the batches (n = 8) purified camel milk XOR showed no detectable activity towards xanthine or NADH. The molybdenum content of camel XOR was comparable to human and goat milk enzymes. After resulphuration, camel milk XOR gave a specific activity of 1.1 nmol/min/mg and 13.0 nmol/min/mg enzyme towards pterin (fluorimetric assay) and xanthine (spectrophotometric assay) respectively. This activity was markedly lower than that of human, bovine and goat enzymes obtained under the same conditions. These findings suggest that the molybdo-form of camel enzyme is totally under desulpho inactive form. It is possible that camel neonates are equipped with an enzymic system that reactivates XOR in their gut and consequently generates antibacterial reactive oxygen species.

Animals↗
PubMed1989

Regulation of GTP cyclohydrolase I and dihydropteridine reductase in rat pheochromocytoma PC 12 cells.

The addition of 8-bromo cyclic AMP, forskolin, theophylline, and 3-isobutyl-1-methylxanthine to the medium of PC 12 cells resulted in an increase in GTP cyclohydrolase I activity, but had no effect on dihydropteridine reductase activity, except theophylline which caused a decrease in dihydropteridine reductase activity at 96 h. GTP cyclohydrolase I activity peaked at 24 h and returned to normal 96 h after drug treatment. Cycloheximide decreased GTP cyclohydrolase I activity at 48 and 96 h, but had little effect on dihydropteridine reductase activity. The addition of reserpine selectively increased only GTP cyclohydrolase I activity. The addition of tetrahydrobiopterin and sepiapterin, however, coordinately inhibited both GTP cyclohydrolase I and dihydropteridine reductase activities. It appears that GTP cyclohydrolase I activity in PC 12 cells is regulated by cyclic AMP stimulation and by end-product inhibition, whereas dihydropteridine reductase activity is only subject to pterin inhibition.

1-Methyl-3-isobutylxanthine↗
PubMed1976

Enzymatic synthesis of biopterin from D-erythrodihydroneopterin triphosphate by extracts of kidneys from Syrian golden hamsters.

An enzyme system was found in either crude homogenates of dialyzed extracts of liver, kidney, lung, and brain from Syrian golden hamsters that catalyzed the synthesis of radioactive 6(L-erythro-1',2'-dihydroxypropyl)pterin (biopterin) from [U-14C]6(D-erythro-1',2',3'-trihydroxypropyl)-7,8-dihydropterin triphosphate (D-erythrolH2neopterin-PPP) preparation. The specific radioactivity of biopterin was found to be comparable to that of D-erythroH2neopterin-PPP. The enzyme system from hamster kidney was purified severalfold by fractionation with ammonium sulfate and with an Ultrogel AcA-34 column. It was demonstrated that (a) NADPH or NADAH was essential and that (b) Mg2+ was stimulatory for the enzymatic synthesis of biopterin from D-erythroH2-NEOPTERIN-PPP. Also GTP and nonphosphorylated neopterins were not converted to biopterin. Although 6-lactyl-7,8-dihydropterin (sepiapterin) was converted to biopterin in the presence of NADPH, sepiapterin was not detected from D-erythroH2neopterin-PPP in the absence of NADPH. A preliminary experiment was performed to identify dihydrobiopterin.

Animals↗
PubMed1992

New inhibitors of sepiapterin reductase. Lack of an effect of intracellular tetrahydrobiopterin depletion upon in vitro proliferation of two human cell lines.

N-Acetylserotonin (compound 1) and N-acetyldopamine (compound 7) inhibit bovine adrenal medullary sepiapterin reductase in a manner competitive with the pterin substrate and have Ki values of 0.12 and 0.4 microM, respectively. Molecular modeling suggests that the phenyl rings of the two compounds bind in the pyrimidine pocket of the enzyme with the 3-hydroxyl of dopamine or the 5-hydroxyl of serotonin aligned at the pyrimidine 4-position. Further, the acetyl moieties of the two inhibitors appear to mimic the substrate side chain. Consistent with this analysis, N-acetyl-m-tyramine (compound 13) is also an excellent competitive inhibitor (Ki = 0.13 microM), whereas N-acetyltryptamine (compound 2), N-acetyl-p-tyramine (compound 14) and N-acetylphenylethylamine (compound 15) all bind poorly. Interestingly, restricted-rotation analogs of N-acetyldopamine and N-acetyl-m-tyramine are noncompetitive inhibitors of the enzyme. Modification of N-acetyldopamine to N-chloroacetyldopamine (compound 10) or of N-acetylserotonin to the N-chloroacetyl (5) or N-methoxyacetyl (compound 6) analogs results in greatly increased competitive affinity, with Ki = 0.014 microM for the dopamine analog and 0.006 and 0.008 microM, respectively, for the serotonin analogs. In MOLT-4 T-cell leukemia and MCF-7 breast adenocarcinoma in culture, 0.1 mM N-methoxyacetylserotonin depleted tetrahydrobiopterin by greater than or equal to 97 and greater than 50%, respectively, with no effect upon cell growth. In both cell lines, the GTP cyclohydrolase inhibitor, 2,4-diamino-6-hydroxypyrimidine at 1-5 mM also depleted tetrahydrobiopterin greater than or equal to 97%. In this case, however, modest growth inhibition did occur. Since the growth inhibition could not be reversed upon tetrahydrobiopterin repletion, inhibition was due to other effects of the inhibitor rather than to tetrahydrobiopterin depletion. The results show that there is no effect on cell growth when at least 97% of the tetrahydrobiopterin in these cell lines is depleted. Since the sepiapterin reductase inhibitor depleted tetrahydrobiopterin with fewer nonspecific effects than the cyclohydrolase inhibitor, it will be useful for determining metabolic effects of tetrahydrobiopterin depletion.

Alcohol Oxidoreductases↗
PubMed1992

31P-NMR of free and protein-bound molybdopterin guanine dinucleotide.

Molybdopterin guanine dinucleotide was studied by 31P-NMR in the free, iodoacetamide derivatized form [di(carboxamidomethyl)molybdopterin] and in the native state in the dimethyl sulfoxide reductase from Rhodobacter sphaeroides. The spectra confirm the presence of a pyrophosphate moiety in the cofactor molecule. Comparison of the spectrum of the free pterin with that of the protein-bound cofactor reveals a substantial upfield shift of the 31P resonances in the enzyme-bound form with respect to the free form. This shift is attributed to differences in the bond and torsional angles of the phosphates. The spectrum of the protein suggests significant coupling between the two phosphorus nuclei with coupling constants of approximately 200 Hz. Comparison of the 31P-NMR spectra of molybdopterin guanine dinucleotide and flavin adenine dinucleotide suggests that the two cofactors have similar conformations in both their free and protein-bound forms.

Animals↗
PubMedDate not supplied

[Method for the direct spectrophotometric determination of the rate of the tyrosine hydroxylase reaction].

A rate of the tyrosine hydroxylase reaction was estimated by an increase in absorption at 335 nm, which was caused by oxidation of pterin cofactor 6,7-dimethyl-5, 6, 7, 8-tetrahydroxypterin (DMPH) coupled with the convertion of the substrate 1-tyrosine into dihydroxyphenylalanine. At pH 6.2 the ratios of molar extinction were as follows: in trisacetate ADMPH4-1370, ADMPH2-5350; in tris-malate tadmph4-1250, admph25300. the enzyme, associated with membranes, had the Km value for Tyr-0.045 mM, the Km for DMPH4 was 0.18 mM; the soluble enzyme had Km for Tyr-0,050 mM, the Km for DMPH4 was 0.74 mM. The stoichiometry of the reaction was 1:1 (I mole DOPA per I mole of DMPH2 formed).

Absorption↗
PubMed1991

Molybdenum cofactor biosynthesis in Escherichia coli. Requirement of the chlB gene product for the formation of molybdopterin guanine dinucleotide.

The chlorate-resistant mutants of Escherichia coli are affected in the biosynthesis of the molybdenum cofactor and show pleiotropic loss of the activities of those enzymes which require the cofactor. The molybdenum cofactor in all molybdoenzymes other than nitrogenase is a complex of the metal with a unique pterin termed molybdopterin. The molybdenum cofactor in a number of E. coli enzymes has been shown to contain GMP in addition to the metal-molybdopterin complex, with the GMP appended in pyrophosphate linkage to the terminal phosphate ester on the molybdopterin side chain. In this paper, we have examined the biochemistry of the chlB mutant and show that the gene product of the chlB locus is essential for the addition of the GMP moiety to form molybdopterin guanine dinucleotide, a step which occurs late in the cofactor biosynthetic pathway in E. coli. Sensitive techniques were developed for the identification of fluorescent derivatives of molybdopterin and of molybdopterin guanine dinucleotide in extracts of E. coli cells. Wild type cells were shown to contain both molybdopterin and molybdopterin guanine dinucleotide, while cells of chlB mutants were found to contain elevated levels of molybdopterin but no detectable molybdopterin guanine dinucleotide.

Chromatography, High Pressure Liquid↗
PubMed1990

[Monapterin and biopterin in degenerated retinas].

We measured the concentrations of biopterin, neopterin and monapterin in the neuroretina of humans and different rat strains and found a relatively high amount of oxidized monapterin in these tissues. The dystrophic retinae of RCS rats revealed an inverse ratio of biopterin-to-monapterin compared to LE rats. This ratio was altered in LE rats after exposure to strong light. These results suggest that changes in pterin metabolism may correlate with retinal dystrophy.

Animals↗
PubMed1988

Methanopterin and methanogenic bacteria.

Methanogenic bacteria comprise a selected group of microorganisms that derive their energy for growth from the hydrogen-dependent reduction of CO2 to methane or the disproportionation of reduced one-carbon compounds and acetate to CO2 and methane. In the reduction and oxidation steps at the formyl, hydroxymethyl and methyl level the one-carbon unit remains bound to the reduced form of methanopterin, a pterin derivative typical of methanogenic bacteria. In addition, the reduced methanopterin, 5,6,7,8-tetrahydromethanopterin, is involved in a number of anabolic reactions. Methanopterin is structurally and functionally the counterpart of folic acid found in other organisms. In this review the occurrence and properties of methanopterin and its derivatives, as well as the biosynthesis and the role in the different catabolic and anabolic reactions are discussed against the background of folic acid biochemistry.

Euryarchaeota↗
PubMed1988

The tyrosine-dependent oxidation of tetrahydropterins by lysolecithin-activated rat liver phenylalanine hydroxylase.

In the presence of tyrosine, phenylalanine hydroxylase, which has been activated with lysolecithin, catalyzes the oxidation of tetrahydrobiopterin at a rate 10-20% that of the parallel reaction with phenylalanine. Unlike the reaction with phenylalanine, there is no net concomitant hydroxylation of tyrosine, although the amino acid is still a necessary component. Tyrosine appears to form an abortive complex with the activated enzyme, the pterin cofactor and molecular oxygen. The Km for tetrahydrobiopterin is identical for the reactions with phenylalanine and tyrosine, whereas the Km for tyrosine is approximately 3 1/2 times greater than the Km for phenylalanine. The tyrosine-dependent oxidation of tetrahydrobiopterin proceeds at both pH 6.8 and 8.2 and shows a similar dependence on the pH as that of the physiological reaction. Tetrahydrobiopterin can be replaced by the artificial cofactor, 6-methyltetrahydropterin, in the tyrosine-dependent oxidation at both pH 6.8 and 8.2. As in the parallel reaction with phenylalanine, both the Km for the cofactor and the Km for the aromatic amino acid increase with this substitution.

Animals↗
PubMed1987

The structure of the molybdenum cofactor. Characterization of di-(carboxamidomethyl)molybdopterin from sulfite oxidase and xanthine oxidase.

A di-(carboxamidomethyl) derivative of molybdopterin, the organic component of the molybdenum cofactor, has been prepared under conditions favoring retention of all of the structural features of the molecule. The specific radioactivity of [1-14C]iodoacetamide incorporated relative to the amount of phosphate indicated two alkylation sites per pterin. Energy-dispersive x-ray analysis of the derivative showed the presence of 2 sulfurs in the derivative. An exact mass corresponding to the molecular formula C14H18N7O5S2 was obtained for the MH+ ion of the alkylated, dephosphorylated compound by fast atom bombardment mass spectroscopy. 1H NMR spectra of the phosphorylated and dephosphorylated forms of alkylated molybdopterin, in conjunction with the other data, have provided strong corroboration of the validity of the proposed structure of molybdopterin (Johnson, J. L., and Rajagopalan, K. V. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 6856-6860) as a 6-alkylpterin with a 4-carbon side chain containing an enedithiol on C-1' and C-2', a secondary alcohol on C-3', and a phosphorylated primary alcohol on C-4'. As isolated, the di-(carboxamido-methyl)molybdopterin was found to be a 5,6,7,8-tetrahydropterin.

Animals↗
PubMed1981

The enzymatic synthesis of sepiapterin by chicken kidney preparations.

A chicken kidney preparation which catalyzes the conversion of D-erythro-dihydroneopterin triphosphate to dihydrobiopterin in the presences of Mg2+ and NADPH has been fractionated into three fractions, A2, A1, and B. Fraction A2 in the presence of Mg2+ catalyzes the conversion of D-erythro-dihydroneopterin triphosphate to an unknown intermediate designated compound X. Fraction A1 in the presence of NADPH catalyzes the conversion of compound X to sepiapterin. Fraction B, in the presence of NADPH, catalyzes the conversion of sepiapterin to dihydrobiopterin. Fraction B which is sepiapterin reductase was not studied any further. Fraction A1 is heat-labile and its molecular weight is estimated to be 3.0 x 10(4), whereas fraction A2 is heat-stable and its molecular weight, 7.7 x 10(4). Compound X is labile and its degradation products have been identified to be pterin and pyruvic acid. This information suggests that compound X is 6-(1,2-dioxopropyl)-7,8-dihydropterin.

Alcohol Oxidoreductases↗
PubMed1982

Are the redox properties of tetrahydrofolate cofactors utilized in folate-dependent reactions?

Tetrahydrofolate (H4folate) derivatives are chemically analogous to tetrahydropterins and dihydroflavins, and like these compounds can be oxidized readily. The roles of pterin and flavin cofactors in biological oxidoreductions are well documented. However, with the exception of the reaction catalyzed by thymidylate synthase, explicit oxidoreductions of the H4folate cofactor do not occur in enzyme-catalyzed folate-dependent reactions. We have been studying methylenetetrahydrofolate reductase from pig liver. This enzyme catalyzes the reversible conversion of the exocyclic N5,N10-methylene substituent to an N5-methyl group. Our studies suggest that the detailed mechanism of this reduction of an exocyclic group involves the oxidoreduction of the tetrahydropterin ring system in a manner that is not apparent from the overall reaction stoichiometry. We suggest that such latent oxidoreductions of H4folate cofactors may also occur in other H4folate-dependent reactions, such as the reaction catalyzed by methionine synthase.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1993

Characterization of a novel tungsten-containing formaldehyde ferredoxin oxidoreductase from the hyperthermophilic archaeon, Thermococcus litoralis. A role for tungsten in peptide catabolism.

Thermococcus litoralis is a strictly anaerobic archaeon (archaebacterium) that grows at temperatures up to 98 degrees C by fermenting peptides. Its growth is stimulated by tungsten, and a tungsten-containing iron-sulfur protein that has formaldehyde ferredoxin oxidoreductase (FOR) activity has been purified. FOR is a homotetramer with a subunit M(r) of 70,000. It contains approximately four irons, four acid-labile sulfides, and one tungsten atom per subunit. The tungsten appears to be present as a pterin cofactor, and the Fe/S seems to comprise an unusual [4Fe-4S] cluster that in the reduced state exists in a pH-independent S = 3/2 form and a pH-dependent S = 1/2 form. FOR catalyzed the oxidation of C1-C3 aldehydes with a temperature optimum > or = 90 degrees C and used T. litoralis ferredoxin as an electron acceptor. It did not oxidize aldehyde phosphates, utilize CoASH, or reduce NAD(P). The N-terminal sequence of FOR shows homology with the tungsto-iron-sulfur aldehyde ferredoxin oxidoreductase previously purified from the saccharolytic, hyperthermophilic archaeon Pyrococcus furiosus, in which it is proposed to function in a novel pyroglycolytic pathway (Mukund, S., and Adams, M. W. W. (1991) J. Biol. Chem. 266, 14208-14216). We show here that P. furiosus, which will also grow on peptides, albeit poorly, contains a second aldehyde-oxidizing enzyme analogous to FOR. Similarly, T. litoralis, which utilizes saccharides if limited for peptides, contains low concentrations of an enzyme analogous to AOR. It is proposed that formaldehyde (apparent Km, 62 mM) is not the true substrate for FOR; rather, the enzyme has an as yet unknown role in peptide fermentation in hyperthermophilic archaea.

Aldehyde Oxidoreductases↗
PubMed1996

[Photosensitized DNA damage: mechanisms and clinical use].

On the basis of our recent investigations by a DNA sequencing technique, mechanisms of photoinduced DNA damage in the presence of various endogenous molecules are summarized with special reference to UV carcinogenesis. In particular, riboflavin and pterin derivatives have been shown to induce DNA damage, mainly 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) formation, specifically at the 5' site of 5'-GG-3' sequences through electron transfer reaction. The involvement of 8-oxodG formation in ras mutation is discussed. In addition, recent works concerning the mechanism of photodynamic therapy and the properties of photoactivatable DNA-cleaving molecules are described.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

A 9359 bp fragment from the right arm of Saccharomyces cerevisiae chromosome VII includes the FOL2 and YTA7 genes and three unknown open reading frames.

In the framework of the EU programme for systematic sequencing of the Saccharomyces cervisiae genome we determined the sequence of a 9359 bp fragment of the right arm of chromosome VII. Five open reading frames (ORFs) of at least 300 nucleotides were found in this region. YGR267c encodes a protein with significant similarity to the enzyme GTP-cyclohydrolase I, that controls the first step in the biosynthetic pathway leading to various pterins and shows a high degree of sequence conservation from bacteria to mammals. We have recently demonstrated (Nardese et al., 1996) that YGR267c corresponds to the FOL2 gene, previously localized in the same chromosomal region by genetic mapping. The protein deduced from YGR270w belongs to the superfamily of putative ATPases associated with diverse cellular activities. It corresponds to the YTA7 gene, a member of a set of yeast genes coding for putative ATPases with high similarity to constituents of the 26S protease. The three ORFs YGR266w, YGR268c and YGR269w encode putative products of unknown function, with neither significant similarity to proteins in databases nor recognizable domains. YGR268c and YGR269w are partially overlapping ORFs: YGR268c seems to correspond to a real gene. whereas YGR269w is probably a fortuitous ORF.

Adenosine Triphosphatases↗
PubMed1998

Glyceryl-ether monooxygenase [EC 1.14.16.5]. A microsomal enzyme of ether lipid metabolism.

The history, biological, and medical aspects of glyceryl ethers, as well as their chemical syntheses, biosynthesis, and their chemical and physical properties are briefly reviewed as background information for appreciating the importance of the enzyme glyceryl-ether monooxygenase, and for embarking on new studies of this enzyme. The occurrence, isolation and general properties of the microsomal, membrane-bound, glyceryl-ether monooxygenase from rat liver are described. Radiometric, nonradiometric, and coupled and direct spectrophotometric assays for this enzyme are detailed. The effects of detergents on the kinetics of this enzyme are described together with the stoichiometry and the effects of inhibitors. The structure-activity relationships of pterin cofactors and of ether lipid substrates, including their stereospecificities, have been summarized from enzyme kinetic data which are also tabulated. The mechanism of enzymic hydroxylation of glyceryl ethers and a model for the active site of glyceryl-ether monooxygenase are proposed from these apparent kinetic data. Notes on useful future studies of this monooxygenase have been made.

Animals↗
PubMed2002

Evolution of nitrate reductase: molecular and structural variations on a common function.

The biological transformation of nitrogen oxyanions is widespread in nature and gives rise to a robust biogeochemical cycle. The first step in nitrate reduction is carried out by the enzyme nitrate reductase (NR). Although NR always catalyzes the same chemical reaction (conversion of nitrate into nitrite), its location in the cell, structure, and function are organism-dependent. We use protein sequence data to determine phylogenetic relationships and to examine similarities in structure and function. Three distinct clades of NR are apparent: the eukaryotic assimilatory NR (Euk-NR) clade, the membrane-associated prokaryotic NR (Nar) clade, and a clade that includes both the periplasmic NR (Nap) and prokaryotic assimilatory NR (Nas). The high degree of sequence similarity and a phylogenetic distribution that follows taxonomic classification suggest a monophyletic origin for the Euk-NR early on in the evolution of eukaryotic cells. In contrast, sequence conservation, phylogenetic analysis, and physiology suggest that both Nar and Nap were acquired by horizontal gene transfer. Nap and Nas share a lesser degree of similarity, with Nap a subclade of Nas. Nap from strict anaerobic bacteria such as Desulfovibrio desulfuricans is ancestral to facultative species and may provide an evolutionary link between Nap and Nas. We observed conserved binding sites for molybdenum and pterin cofactors in all four proteins. In pathways involving Euk-NR, Nas, and Nar, for which ammonia is the end product, nitrite is reduced to ammonia by a siroheme nitrite reductase. Nap, however, is coupled to a pentaheme nitrite reductase. In denitrification, whether Nar or Nap is involved, nitrite is reduced to nitric oxide by either a cytochrome cd1 or a copper-containing nitrite reductase. This complexity underscores the importance of nitrate reduction as a key biological process.

Amino Acid Sequence↗