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PubMedDate not supplied

Inhibition of tetrahydrobiopterin synthesis reduces nitric oxide production by isolated glomeruli in immune complex glomerulonephritis.

We studied the effect of modulators of tetrahydrobiopterin (BH4) synthesis on the production of nitrite by glomeruli from rats with immune complex-mediated glomerular inflammation. Glomeruli were isolated 24 h after induction of accelerated nephrotoxic nephritis and cultured at 2,000/ml for 48 h. Lipopolysaccharide dose dependently increased ex vivo nitrite production. 2,4-Diamino-6-hydroxypyrimidine (DAHP), an inhibitor of the de novo synthetic pathway of BH4, inhibited nitrite production by up to 50% and this effect was reversed by sepiapterin, a substrate for the salvage pathway of BH4 synthesis. Sepiapterin alone increased nitrite generation indicating that BH4 is rate limiting. Inhibition of both pathways with DAHP and methotrexate led to 80% inhibition of nitrite. Pharmacological inhibition of BH4 synthesis may be a useful mechanism to reduce nitric oxide synthesis in immune complex inflammation.

Animals↗
PubMedDate not supplied

The pathway from GTP to tetrahydrobiopterin: three-dimensional structures of GTP cyclohydrolase I and 6-pyruvoyl tetrahydropterin synthase.

The complex organic chemistry involved in the transformation of GTP to tetrahydrobiopterin is catalysed by only three enzymes: GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. The committing reaction step from GTP to dihydroneopterin triphosphate is catalysed by GTP cyclohydrolase I and requires no cofactor. 6-Pyruvoyl tetrahydropterin synthase, a Zn-dependent metalloprotein, transforms dihydroneopterin triphosphate into 6-pyruvoyltetrahydropterin in the presence of Mg(II). Sepiapterin reductase is a NADPH-dependent short-chain dehydrogenase which reduces 6-pyruvoyltetrahydropterin to BH4. Here we review the structural and mechanistic information on the biosynthetic pathway from GTP to BH4 on the basis of the recently determined crystal structures of CYH and PTPS.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Reconstitution of a metabolic pathway with triple-cistronic IRES-containing retroviral vectors for correction of tetrahydrobiopterin deficiency.

BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor for catecholamine and serotonin neurotransmitter biosynthesis. BH4 biosynthesis is carried out in a three-enzyme pathway involving GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS) and sepiapterin reductase (SR). Treatment of genetic defects leading to BH4 deficiency requires neurotransmitter replacement since synthetic cofactor does not efficiently penetrate the blood-brain barrier. Autologous fibroblasts transplanted into the brain as depository cells for drug delivery might offer an alternative. However, normal fibroblasts do not express GTPCH, and fibroblasts from PTPS patients lack two biosynthetic enzymes for BH4 production. METHODS: We engineered primary fibroblasts by the use of triple-cistronic, retroviral vectors for cofactor production. RESULTS: Constitutive SR activity in these cells enabled BH4 biosynthesis by transducing GTPCH and PTPS cDNAs together with a selective marker coupled in a single transcript with two IRES-elements in tandem. Upon reaching a critical concentration (> 400 pmol/mg protein) of intracellular BH4, the fibroblasts efficiently released cofactor even under non-dividing conditions. CONCLUSION: The use of triple-cistronic vectors for single transduction to reconstitute metabolic pathways or to treat multi-genetic diseases may be useful for engineering, for instance, depository cells for various organs, including the nervous system.

Biopterins↗
PubMed2001

Isolation and expression of a Bacillus cereus gene encoding benzil reductase.

Benzil was reduced stereospecifically to (S)-benzoin by Bacillus cereus strain Tim-r01. To isolate the gene responsible for asymmetric reduction, we constructed a library consisting of Escherichia coli clones that harbored plasmids expressing Bacillus cereus genes. The library was screened using the halo formation assay, and one clone showed benzil reduction to (S)-benzoin. Thus, this clone seemed to carry a plasmid encoding a Bacillus cereus benzil reductase. The deduced amino acid sequence had marked homologies to the Bacillus subtilis yueD protein (41% identity), the yeast open reading frame YIR036C protein (31%), and the mammalian sepiapterin reductases (28% to 30%), suggesting that benzil reductase is a novel short-chain de-hydrogenases/ reductase.

Alcohol Oxidoreductases↗
PubMed2002

Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes.

Free radical nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS) in astrocytes and macrophages, has been implicated in CNS inflammatory disorders such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibited interferon-gamma (IFN-gamma) + lipopolysaccharide (LPS)-induced NO production dose-dependently in astrocytes, but not in macrophages. The effect of MPA was not mediated through interference with IMPDH-dependent synthesis of iNOS cofactor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. However, MPA markedly inhibited IFN-gamma + LPS-triggered astrocyte expression of mRNA for iNOS and its transcription factor IRF-1, while the expression of tumor necrosis factor-alpha (TNF-alpha) gene was not altered. The observed MPA suppression of NO release and iNOS and IRF-1 induction in astrocytes were efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH-dependent synthesis of guanosine nucleotides. This IRF-1-dependent inhibition of iNOS activation might be partly responsible for the protective effect of MPA in EAE, prompting investigation of its potential use in multiple sclerosis.

Animals↗
PubMed1990

Analysis of the tetrahydrobiopterin synthesizing system during maturation of murine reticulocytes.

The enzymes of tetrahydrobiopterin synthesis have been studied in murine bone marrow, in spleen, in erythrocytes, and in reticulocytes. Mice with chemically induced and with genetically conditioned reticulocytosis as found in the lactate dehydrogenase deficient strain (Ldh-1c/Ldh-1c) were used for analysis of reticulocytic enzyme activities. The activity of the biopterin synthesizing system is highest in bone marrow even though it amounts to only about 10% as compared with liver. The first enzyme of the biosynthetic pathway, GTP-cyclohydrolase, virtually disappears during the final maturation step of reticulocytes. In contrast, the activities of 6-pyruvoyltetrahydropterin synthase and of sepiapterin reductase of erythrocytes are only reduced to about one half of the reticulocyte level. The absence of biopterin in erythrocytes is therefore caused by the loss of the enzyme that initiates the pterin biosynthetic pathway.

Alcohol Oxidoreductases↗
PubMed1987

Female heterogamety in the swordtail, Xiphophorus alvarezi Rosen (Pisces, Poeciliidae), with comments on a natural polymorphism affecting sword coloration.

The sex-determining mechanism of swordtails (Xiphophorus, Poeciliidae, Pisces) is poorly understood, because many laboratory strains of these species are characterized by biased sex ratios in either the male or female direction. Because of these ratios sex determination is said to be controlled by numerous male and female factors scattered over many chromosomes. However, direct experimental evidence for the polygenic theory is absent. Three strains of X. alvarezi were derived from natural populations in Guatemala, two of which (Dolores, Candelaria) always exhibit a ratio of 1:1, whereas the third one (San Ramón) shows a preponderance of males. Males of X. alvarezi, like those of other species of swordtails, develop a caudal appendage or sword at maturity. Chromatophores with carotenoid pigment (orange) are present in the sword of Dolores males and pigment cells containing sepiapterin (green) are present in the swords of males and the other two stocks. F1 and backcross hybrids were produced between the Dolores and Candelaria stocks. The sex ratios of all hybrid pedigrees was always in statistical agreement with unity. The pattern of inheritance of the two pigmentary traits demonstrated sex-linkage with female heterogamety (WY female female-YY male male).

Animals↗
PubMed2000

The enzyme that synthesizes tetrahydrobiopterin from 6-pyruvoyl-tetrahydropterin in the lemon mutant silkworm consists of two carbonyl reductases.

Tetrahydrobiopterin plays an important role in the biosynthesis of certain neurotransmitters. Using DEAE-Sepharose FF column chromatography, we separated the enzyme that synthesizes tetrahydrobiopterin from 6-pyruvoyl-tetrahydropterin [which is different from sepiapterin reductase (EC 1.1.1.153)] in the lemon mutant of the silkworm Bombyx mori into two fractions, which were named carbonyl reductase I (CR I) and carbonyl reductase II (CR II). The CR I enzyme converted 6-pyruvoyl-tetrahydropterin to 6-lactoyl-tetrahydropterin, while CR II converted 6-pyruvoyl-tetrahydropterin to 1'-hydroxy-2'-oxopropyl-tetrahydropterin, both reactions occurring only in the presence of NADPH. Neither of the two carbonyl reductases alone was able to catalyze the conversion of 6-pyruvoyl-tetrahydropterin to tetrahydrobiopterin in the presence of NADPH. However, when CR I was mixed with CR II in the reaction mixture, 6-pyruvoyl-tetrahydropterin was reduced to tetrahydrobiopterin in the presence of NADPH. Moreover, CR I catalyzed the formation of tetrahydrobiopterin from 1'-hydroxy-2'-oxopropyl-tetrahydropterin, while CR II converted 6-lactoyl-tetrahydropterin to tetrahydrobiopterin, both reactions occurring only in the presence of NADPH. Our results suggest that there are two potential routes for formation of tetrahydrobiopterin from 6-pyruvoyl-tetrahydropterin in the lemon mutant silkworm. In the first route, 1'-hydroxy-2'-oxopropyl-tetrahydropterin is formed from 6-pyruvoyl-tetrahydropterin by CR II and then reduced to tetrahydrobiopterin by CR I, both reactions occurring only in the presence of NADPH. In the other route, 6-pyruvoyl-tetrahydropterin is reduced to 6-lactoyl-tetrahydropterin by CR I and then converted to tetrahydrobiopterin by CR II, both reactions occurring only in the presence of NADPH.

Alcohol Oxidoreductases↗
PubMed1993

Enzymatic synthesis of 6R-[U-14C]tetrahydrobiopterin from [U-14C]GTP.

An enzymatic method for preparing 6R-[U-14C]-tetrahydrobiopterin from [U-14C]GTP is presented. This method utilizes purified preparations of three biosynthetic enzymes for 6R-tetrahydrobiopterin, i.e., Escherichia coli GTP cyclohydrolase I, rat 6-pyruvoyl-tetrahydropterin synthase, and rat sepiapterin reductase. Based on the catalytic properties of these enzymes, the reaction conditions were optimized to complete the entire conversion reaction from GTP to 6R-tetrahydrobiopterin in a single reaction solution without the need to isolate unstable intermediates after each enzymatic reaction. The reaction conditions thereby established yielded [U-14C]biopterin in an amount equivalent to 75%, on a molar basis, of the initial amount of [U-14C]GTP. The product was subsequently isolated by high-performance liquid chromatography. The method produced labeled 6R-tetrahydrobiopterin with a specific activity of 450 Ci/mol and an overall yield of more than 60%.

Alcohol Oxidoreductases↗
PubMed2001

Electrochemistry of pterin cofactors and inhibitors of nitric oxide synthase.

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), but its function is not fully understood. Specifically, it is unclear whether BH4 participates directly in electron transfer. We investigated the redox properties of BH4 and several other pteridines with cyclic voltammetry and Osteryoung square wave voltammetry. BH4 was oxidized at a potential of +0.27 V vs normal hydrogen electrode (NHE); the corresponding reductive signal after the reversal of the scan direction was very small. Instead, reduction occurred at a potential of -0.16 V vs NHE; there was no corresponding oxidative signal. These two transitions were interdependent, indicating that the reductive wave at -0.16 V represented the regeneration of BH4 from its product of oxidation at +0.27 V. Similar voltammograms were obtained with tetrahydroneopterin and 6,7-dimethyltetrahydropterin, both of which can substitute for BH4 in NOS catalysis. Completely different voltammograms were obtained with 7,8-dihydrobiopterin, sepiapterin, 2'-deoxysepiapterin, and autoxidized BH4. These 7,8-dihydropterins, which do not sustain NOS catalysis, were oxidized at much higher potentials (+0.82-1.04 V vs NHE), and appreciable reduction did not occur between +1.2 and -0.8 V, in line with the concept of a redox role for BH4 in NOS catalysis. However, the electrochemical properties of the potent pterin-site NOS inhibitor 4-amino-BH4 resembled those of BH4, whereas the active pterin cofactor 5-methyl-BH4 was not re-reduced after oxidation. We conclude that the 2-electron redox cycling of the pterin cofactor between BH4 and quinonoid dihydrobiopterin is not essential for NO synthesis. The data are consistent with 1-electron redox cycling between BH4 and the trihydrobiopterin radical BH3(*).

Antioxidants↗
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↗
PubMed1976

Correlation of guanosine triphosphate cyclohydrolase activity and the synthesis of pterins in Drosophila melanogaster.

The enzyme guanosine triphosphate cyclohydrolase (GTP cyclohydrolase), which in bacteria is known to be the first enzyme in the biosynthetic pathway for the synthesis of pteridines, has been discovered in extracts of Drosophila melanogaster. Most of the enzyme (80%) is located in the head of the adult fly. An analysis of enzyme activity during development in Drosophila has revealed the presence of a relatively small peak of activity at pupariation and a much larger peak that appears at about the time of eclosion. Enzyme activity declines radidly as the fly ages. Analysis for the production of the typical pteridine pigments of Drosophila have indicated that the small peak of GTP cyclohydrolase activity evident at pupariation coincides with the appearance of isoxanthopterin, sepiapterin, and pterin, and the larger peak at eclosion roughly corresponds to the accumulation of drospterin as well as to the appearence in larger amounts of pterin and sepiaterin. These observations strongly suggest that in Drosophila, like bacteria, GTP cyclohydrolase is involved in the biosynthesis of pteridines. Analyses of a variety of zeste mutants of Drosophila melanogaster have shown that these mutants all contain GTP cyclohydrolase equal approximately to the amount found in the wild-type fly. These observations do not support the suggestions made by Rasmusson et al. (1973) that zeste is the strucural locus for GTP cyclohydrolase.

Aminohydrolases↗
PubMed1987

Mechanism of suppression in Drosophila: regulation of tryptophan oxygenase by the su(s)+ allele.

The suppressor gene, su(s)2, in Drosophila melanogaster restores the production of red and brown eye pigments for some purple and vermilion mutant alleles, respectively. We showed previously that the product of the su(s)+ allele caused inhibition of the sepiapterin synthase A produced by the purple mutant but did not affect the wild-type enzyme. Suppression was accomplished by removing su(s)+ from the genome. We now report that the tryptophan oxygenase, produced by suppressible vermilion alleles, is also inhibited by extracts from su(s)+ flies. The inhibition of the vermilion enzyme can be reduced or eliminated, respectively, by prior storage of the extract at 4 or -20 degrees C or by boiling, whereas the wild-type enzyme is not affected by extracts of su(s)+ flies. Also, when the suppressible vermilion strain is raised on certain diets, brown eye pigment production occurs. This epigenetic suppression was reduced by the presence of an extra copy of su(s)+ in the genome. These data support a posttranslational mechanism for regulation of enzyme activity in which the activity of the mutant enzyme is reduced by the product of the su(s)+ allele. How the su(s)+ gene product can distinguish between the normal and the mutant forms of these two enzymes is discussed, along with other mechanisms for suppression that are currently under investigation.

Alleles↗
PubMed1989

Regulation of pteridine biosynthesis and aromatic amino acid hydroxylation in Drosophila melanogaster.

The relationship between high dietary levels of aromatic amino acid and regulation of pteridines in Drosophila eyes was examined by measuring changes in pool levels of six pterins in the wild type and mutants and amino acid pool levels in flies that carry mutations for pteridine biosynthesis. The effect upon relative viability and developmental times was also analyzed; relative viability was affected by L-phenylalanine, L-tryptophan, and L-tyrosine in decreasing order and the D-amino acids had little or no effect. The changes in concentration of biopterin, dihydrobiopterin, pterin, sepiapterin, drosopterins, and isoxanthopterin showed a characteristic pattern of increased and/or decreased amounts in response to each of the three L-amino acids. Pterin was regularly increased, and isoxanthopterin decreased. L-Tyrosine caused a 2.1-fold increase in dihydrobiopterin, the largest increase found in this study; L-tryptophan also caused dihydrobiopterin to increase but L-phenylalanine did not. Of 18 eye-color mutants examined, 2 were found to contain high levels of phenylalanine and/or tyrosine, Pu2 and Hnr3. These two mutants, along with prc4 cn/prm2b cn, were shown to be very sensitive to dietary L-phenylalanine, indicating that having low levels of certain pteridines makes them susceptible to toxic effects of these amino acids. Therefore, high levels of aromatic amino acids can perturb the balance among pteridine pools, and low levels of some pteridines in mutants are correlated with the inability to withstand the toxic effects of phenylalanine. From the patterns of change in the pteridines we suggest that tetrahydropterin may also be a cofactor for hydroxylation of phenylalanine, along with tetrahydrobiopterin.

Amino Acids↗
PubMed1989

Inhibition of biopterin synthesis and DOPA production in PC-12 pheochromocytoma cells induced by 6-aminonicotinamide.

Pheochromocytoma cells (clone PC-12) were treated with 6-aminonicotinamide. Tetrahydrobiopterin content and DOPA production of the cells were determined by reverse-phase HPLC and subsequent electrochemical detection. The same chromatographic system was used to determine total biopterin (tetrahydrobiopterin, dihydrobiopterin and quinoide dihydrobiopterin) by fluorescence detection. Tetrahydrobiopterin plays a decisive role as cofactor of tyrosine hydroxylase for the biosynthesis of DOPA and dopamine. Addition of 6-aminonicotinamide to the culture medium resulted in the accumulation of 6-phosphogluconate, suggesting that PC-12 cells synthesize 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP) by a glycohydrolase localized in the endoplasmic reticulum. This substance is known to be a strong inhibitor of 6-phosphogluconate dehydrogenase and leads to a blockade of the pentose phosphate pathway. In our experiments, the synthesis of biopterins was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin by 6-aminonicotinamide at different concentrations was strongly correlated with a reduced cellular DOPA production. The decreased content of biopterin cofactor was compensated by addition of the precursor sepiapterin, indicating that the NADPH2-dependent reductases in biopterin synthesis are not inhibited by the antimetabolite. However, DOPA production remained suppressed at the same time. After application of NADH2, we observed an increased DOPA production though the decreased biopterin levels remained almost unchanged. The results imply that the first step in the synthesis of biopterin from GTP as well as the recycling pathways of the oxidized cofactor might be the site of action of the antimetabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Aminonicotinamide↗
PubMed1999

Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin.

Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.

Amino Acid Sequence↗
PubMed1985

Biosynthesis of tetrahydrobiopterin: conversion of dihydroneopterin triphosphate to tetrahydropterin intermediates.

It is known that the first step in the de novo synthesis of tetrahydrobiopterin from GTP is the conversion of GTP to dihydroneopterin triphosphate. Recent evidence supports the conclusion that beyond this first step, the pterin intermediates in the pathway are all at the tetrahydro level of reduction. We have now shown that partially purified fractions from rat liver, rat brain and bovine adrenal medulla catalyze the conversion of dihydroneopterin triphosphate to tetrahydrobiopterin, as well as to the putative intermediates in the pathway, 6-pyruvoyl-tetrahydropterin and 6-lactoyl-tetrahydropterin. Results of both enzymatic and chemical studies support the assigned structures for the latter two tetrahydropterins. We have also purified extensively from brain an enzyme, distinct from sepiapterin reductase, that catalyzes the TPNH-dependent reduction of 6-pyruvoyl-tetrahydropterin to 6-lactoyl-tetrahydropterin. The role of this reductase in tetrahydrobiopterin synthesis has not yet been established.

Adrenal Medulla↗
PubMed1991

Computer studies on the stereostructure and quantum chemical properties of 6-pyruvoyl tetrahydropterin, the key intermediate of tetrahydrobiopterin biosynthesis.

The optimized geometry of the conformation of atoms constituting the 6-pyruvoyl tetrahydropterin molecule, the labile key intermediate of tetrahydrobiopterin biosynthesis, was obtained by molecular orbital calculations within the MINDO/3 framework. The stereostructure of the molecule showing the preferred mode for binding to sepiapterin reductase or pyruvoyl tetrahydropterin reductase was drawn in perspective. The resulting structure with the equatorial staggered configuration of the 6-1',2'-dioxopropyl (pyruvoyl) side chain indicated that O(1') and H(6) were located in the trans position around the C(6)-C(1') bond and that the two vicinal carbonyls in the side chain were fixed in the incomplete trans form. The calculation of atomic charges and LUMO coefficients of these carbonyls suggests that the C2'-carbonyl may be more reactive toward NADPH than the C1'-carbonyl in the enzymatic reaction.

Alcohol Oxidoreductases↗