Pteridine Metabolism Research Articles

Age determination of Chrysomya megacephala (Diptera: Calliphoridae) using lifespan patterns, gene expression, and pteridine concentration under constant and variable temperatures

Chrysomya megacephala (Fabricius, 1794) (Diptera: Calliphoridae), is a blowfly species widely studied in medical, veterinary, and entomological research. Our study examined the impact of constant (15, 20, 25, 30, and 35 °C) and variable (ranging from 21.0 to 25.4 °C, with an average of 23.31 °C) temperatures on the development and larval body length of C. megacephala. Additionally, we analyzed the age of the adult C. megacephala through pteridine content and related metabolic genes analysis. Our findings revealed three distinct growth patterns: isomorphen diagram, isomegalen diagram, and thermal accumulated models. At constant temperatures of 15, 20, 25, 30, and 35 °C, egg-hatching times were 44.5 ± 8.9, 26.7 ± 4.6, 12.6 ± 1.1, 11.0 ± 1.0, and 9.9 ± 1.9 h, respectively, while it was 15.3 ± 5.9 h at variable temperatures. The total development times from oviposition to adult eclosion in C. megacephala required 858.1 ± 69.2, 362.3 ± 5.9, 289.6 ± 17.8, 207.3 ± 9.3, and 184.7 ± 12.1 h at constant temperatures of 15, 20, 25, 30, and 35 °C, respectively. This duration was extended to 282.0 ± 64.1 h under variable temperatures. However, no significant differences were found in hatching times and the total developmental durations between 25 °C and variable temperatures. A developmental threshold temperature (D0) of 9.90 ± 0.77 °C and a thermal summation constant (K) of 4244.0 ± 347.0° hours were ascertained. Pteridine content patterns varied significantly across constant temperatures, but not between 25 °C and variable temperatures. Sex and temperature were identified as the primary factors influencing pteridine levels in the head of C. megacephala. Gene expression associated with pteridine metabolism decreased following adult eclosion, matching with increased pteridine concentration. Further investigations are needed to explore the use of pteridine cofactors for age-grading adult necrophagous flies. These findings provide valuable insights into the lifespan of C. megacephala, thereby offering valuable groundwork for forthcoming investigations and PMImin determination.

In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase.

The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses' health threats. The parasites' frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the Tb enzymes (0.2 μM < IC50 < 85.1 μM) and ten against the respective Lm enzymes (0.6 μM < IC50 < 84.5 μM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target.

Modulating leishmanial pteridine metabolism machinery via some new coumarin-1,2,3-triazoles: Design, synthesis and computational studies

In accordance with WHO statistics, leishmaniasis is one of the top neglected tropical diseases, affecting around 700 000 to one million people per year. To that end, a new series of coumarin-1,2,3-triazole hybrid compounds was designed and synthesized. All new compounds exerted higher activity than miltefosine against L. major promastigotes and amastigotes. Seven compounds showed single digit micromolar IC50 values whereas three compounds (13c, 14b and 14c) displayed submicromolar potencies. A mechanistic study to elucidate the antifolate-dependent activity of these compounds revealed that folic and folinic acids abrogated their antileishmanial effects. These compounds exhibited high safety margins in normal VERO cells, expressed as high selectivity indices. Docking simulation studies on the folate pathway enzymes pteridine reductase and DHFR-TS imparted strong theoretical support to the observed biological activities. Besides, docking experiments on human DHFR revealed minimal binding interactions thereby highlighting the selectivity of these compounds. Predicted in silico physicochemical and pharmacokinetic parameters were adequate. In view of this, the structural characteristics of these compounds demonstrated their suitability as antileishmanial lead compounds.

Establishing pteridine metabolism in a progressive isogenic breast cancer cell model - part II.

Determining the biological significance of pteridines in cancer development and progression remains an important step in understanding the altered levels of urinary pteridines seen in certain cancers. Our companion study revealed that several folate-derived pteridines and lumazines correlated with tumorigenicity in an isogenic, progressive breast cancer cell model, providing direct evidence for the tumorigenic origin of pteridines. This study sought to elucidate the pteridine biosynthetic pathway in a progressive breast cancer model via direct pteridine dosing to determine how pteridine metabolism changes with tumorigenicity. First, MCF10AT breast cancer cells were dosed individually with 15 pteridines to determine which pteridines were being metabolized and what metabolic products were being produced. Second, pteridines that were significantly metabolized were dosed individually across the progressive breast cancer cell model (MCF10A, MCF10AT, and MCF10ACA1a) to determine the relationship between each metabolic reaction and breast cancer tumorigenicity. Several pteridines were found to have altered metabolism in breast cancer cell lines, including pterin, isoxanthopterin, xanthopterin, sepiapterin, 6-biopterin, lumazine, and 7-hydroxylumazine (p < 0.05). In particular, isoxanthopterin and 6-biopterin concentrations were differentially expressed (p < 0.05) with respect to tumorigenicity following dosing with pterin and sepiapterin, respectively. Finally, the pteridine biosynthetic pathway in breast cancer cells was proposed based on these findings. This study, along with its companion study, demonstrates that pteridine metabolism becomes disrupted in breast cancer tumor cells. This work highlights several key metabolic reactions within the pteridine biosynthetic pathway that may be targeted for further investigation and clinical applications.

Sesquiterpene Lactones with Dual Inhibitory Activity against the Trypanosoma brucei Pteridine Reductase 1 and Dihydrofolate Reductase.

The parasite Trypanosoma brucei (T. brucei) is responsible for human African trypanosomiasis (HAT) and the cattle disease “Nagana” which to this day cause severe medical and socio-economic issues for the affected areas in Africa. So far, most of the available treatment options are accompanied by harmful side effects and are constantly challenged by newly emerging drug resistances. Since trypanosomatids are auxotrophic for folate, their pteridine metabolism provides a promising target for an innovative chemotherapeutic treatment. They are equipped with a unique corresponding enzyme system consisting of the bifunctional dihydrofolate reductase-thymidylate synthase (TbDHFR-TS) and the pteridine reductase 1 (TbPTR1). Previously, gene knockout experiments with PTR1 null mutants have underlined the importance of these enzymes for parasite survival. In a search for new chemical entities with a dual inhibitory activity against the TbPTR1 and TbDHFR, a multi-step in silico procedure was employed to pre-select promising candidates against the targeted enzymes from a natural product database. Among others, the sesquiterpene lactones (STLs) cynaropicrin and cnicin were identified as in silico hits. Consequently, an in-house database of 118 STLs was submitted to an in silico screening yielding 29 further virtual hits. Ten STLs were subsequently tested against the target enzymes in vitro in a spectrophotometric inhibition assay. Five compounds displayed an inhibition over 50% against TbPTR1 as well as three compounds against TbDHFR. Cynaropicrin turned out to be the most interesting hit since it inhibited both TbPTR1 and TbDHFR, reaching IC50 values of 12.4 µM and 7.1 µM, respectively.

Establishing pteridine metabolism in a progressive isogenic breast cancer cell model.

Pteridines include folate-derived metabolites that have been putatively associated with certain cancers in clinical studies. However, their biological significance in cancer metabolism and role in cancer development and progression remains poorly understood. The purpose of this study was to examine the effects of tumorigenicity on pteridine metabolism by studying a panel of 15 pteridine derivatives using a progressive breast cancer cell line model with and without folic acid dosing. The MCF10A progressive breast cancer model, including sequentially derived MCF10A (benign), MCF10AT (premalignant), and MCF10CA1a (malignant) cell lines were dosed with 0, 100, and 250 mg/L folic acid. Pteridines were analyzed in both intracellular and extracellular contexts using an improved high-performance liquid chromatography-tandem mass spectrometry method. Pteridines were located predominately in the extracellular media. Folic acid dosing increased extracellular levels of pterin, 6-hydroxylumazine, xanthopterin, 6-hydroxymethylpterin, and 6-carboxypterin in a dose-dependent manner. In particular, pterin and 6-hydroxylumazine levels were positively correlated with tumorigenicity upon folate dosing. Folic acid is a primary driver for pteridine metabolism in human breast cell. Higher folate levels contribute to increased formation and excretion of pteridine derivatives to the extracellular media. In breast cancer, this metabolic pathway becomes dysregulated, resulting in the excretion of certain pteridine derivatives and providing in vitro evidence for the observation of elevated pteridines in the urine of breast cancer patients. Finally, this study reports a novel use of the MCF10A progressive breast cancer model for metabolomics applications that may readily be applied to other metabolites of interest.

Correlation of Lead Exposure on Calcium Metabolism, Vitamin D3 in Battery Manufacturing Workers

Background: Chronic lead exposure from the lead-acid–battery manufacturing process has been linked to a variety of health effects, including dental health, cardiovascular disease risk, Matrix–gamma– carboxy glutamic acid protein (MGP) polymorphism, oxidative stress, immunological, genotoxicity, reproductive, neuropsychological, and pteridine metabolism with neurotransmitters synthesized.&#x0D; Aim of the Work: effects of lead exposure on calcium metabolism in battery workers.&#x0D; Subjects and Methods: The present study will be conducted in Department of Biochemistry, Index Medical College and research center, Indore. A total of 100 lead exposed battery workers and 100 aged (20-60 yr) matched non lead exposed controls. Blood sample was withdrawn from the anticubital vein and centrifuged to obtain serum after that serum was quantitatively analyzed for lead level, calcium, phosphorous and vitamin D3. &#x0D; Result and Conclusion: In lead-exposed battery workers, correlation analysis revealed a strong negative connection between blood lead levels and serum vitamin D levels. Similarly, serum calcium levels were found to be inversely linked with blood lead levels.&#x0D; Keywords: Battery workers, Lead

Nile Tilapia: A Model for Studying Teleost Color Patterns.

The diverse color patterns of cichlid fishes play an important role in mate choice and speciation. Here we develop the Nile tilapia (Oreochromis niloticus) as a model system for studying the developmental genetics of cichlid color patterns. We identified 4 types of pigment cells: melanophores, xanthophores, iridophores and erythrophores, and characterized their first appearance in wild-type fish. We mutated 25 genes involved in melanogenesis, pteridine metabolism, and the carotenoid absorption and cleavage pathways. Among the 25 mutated genes, 13 genes had a phenotype in both the F0 and F2 generations. None of F1 heterozygotes had phenotype. By comparing the color pattern of our mutants with that of red tilapia (Oreochromis spp), a natural mutant produced during hybridization of tilapia species, we found that the pigmentation of the body and eye is controlled by different genes. Previously studied genes like mitf, kita/kitlga, pmel, tyrb, hps4, gch2, csf1ra, pax7b, and bco2b were proved to be of great significance for color patterning in tilapia. Our results suggested that tilapia, a fish with 4 types of pigment cells and a vertically barred wild-type color pattern, together with various natural and artificially induced color gene mutants, can serve as an excellent model system for study color patterning in vertebrates.

Comparative transcriptome analysis of molecular mechanism underlying gray-to-red body color formation in red crucian carp (Carassius auratus, red var.).

Red crucian carp (Carassius auratus red var.) is an ornamental fish with vivid red/orange color. It has been found that the adult body color of this strain forms a gray-to-red change. In this study, skin transcriptomes of red crucian carp are first obtained for three different stages of body color development, named by gray-color (GC), color-variation (CV), and red-color (RC) stages, respectively. From the skins of GC, CV, and RC, 103,229; 108,208; and 120,184 transcripts have been identified, respectively. Bioinformatics analysis reveals that 2483, 2967, and 4473 unigenes are differentially expressed between CV and GC, RC and CV, and RC and GC, respectively. A part of the differentially expressed genes (DEGs) are involved in the signaling pathway of pigment synthesis, such as the melanogenesis genes (Mitfa, Pax3a, Foxd3, Mc1r, Asip); tyrosine metabolism genes (Tyr, Dct, Tyrp1, Silva, Tat, Hpda); and pteridine metabolism genes (Gch, Xdh, Ptps, Tc). According to the data of transcriptome and quantitative PCR, the expression of Mitfa and its regulated genes which include the genes of Tyr, Tyrp1, Dct, Tfe3a, and Baxα, decreases with gray-to-red change. It is suggested that Mitfa and some genes, being related to melanin synthesis or melanophore development, are closely related to the gray-to-red body color transformation in the red crucian carp. Furthermore, the DEGs of cell apoptosis and autophagy pathway, such as Tfe3a, Baxα, Hsp70, Beclin1, Lc3, Atg9a, and Atg4a, might be involved in the melanocytes fade away of juvenile fish. These results shed light on the regulation mechanism of gray-to-red body color transformation in red crucian carp, and are helpful to the selective breeding of ornamental fish strains.

Evaluation of pteridine metabolism in battery workers chronically exposed to lead

Occupationally-exposed lead affects the neuromuscular junction and might cause disturbances in the locomotor activity. This study was undertaken to evaluate pteridine metabolism, in which neurotransmitters are synthesized in battery workers. Urinary neopterin, biopterin and creatinine were measured using high performance liquid chromatography. Serum neopterin concentrations were detected by enzyme-linked immunoassay. Blood dihydropteridine reductase (DHPR) activities and deltaaminolevulinic acid (delta-ALA) were measured spectrophotometrically. Blood and urinary lead were detected by atomic absorption spectroscopy. Significantly increased blood and urinary lead levels, urinary neopterin, biopterin and delta-ALA were found in workers, while DHPR activities were indifferent compared to control group. Urinary creatinine decreased. This is the first study to demonstrate that increased activity of the pteridine pathway results in the accumulation of the neurotransmitters that may be responsible for the neurological disorders.

Effect of Aluminum Exposure on Pteridine Metabolism

Occupational and environmental aluminum (Al) exposure cause serious health problems by interaction with biological systems. Al is one of the most documented metals because its cellular targets are unclear biochemical processes and membranes of organisms. The major aim of the present study was to investigate the alteration of serum and urine aluminum in occupational exposure and to observe whether the metal exposure could cause any changes in pteridine-pathway-related critical compounds such as urinary neopterin and biopterin and blood dihydropteridine reductase (DHPR). In this study, determination of the metal concentrations was carried out in Al-exposed workers (n=23) and healthy volunteers (n=18) by using atomic absorption spectrometer. DHPR enzyme activity and levels of neopterin and biopterin were detected by spectrophotometric and high-performance liquid chromatographic methods, respectively. It was found that occupational exposure to the metal led to a statistically significant increase in serum Al levels compared to the controls (p<0.05). At the same time, urinary neopterin and biopterin concentrations of the exposed group were higher than nonexposed subjects (both p<0.05). The correlations among Al levels and DHPR activity, magnesium concentration in serum and urine, working years, smoking status, and age were evaluated.

Linkage of Pteridine Metabolism to Iron Homeostasis

Abstract Iron is an essential growth factor for the proliferation and differentiation of all living cells in being centrally involved in oxygen transport by hemoglobin and myoglobin, in electron transport during mitochondrial respiration as being a part of complex I and II enzymes or in the regulation of transcription via its role as central component of ribonucelotid reductase (1,2). Moroever, iron plays a critical role in macrophage mediated cytotoxicity by contributing to the production of highly toxic hydroxy radical species needed for host defense (3). In addition, radicals formed by the catalytic action of by iron can modulate the binding affinities of several transcription factors to their target promoter region, such as hypoxia inducible factor -1 or nuclear factor-kB, thus affecting transcription of stress inducible genes (4-6).

Molecular mechanisms of impaired endothelial function associated with insulin resistance.

Dysfunction of the endothelium in large- and medium-sized arteries plays a central role in atherogenesis. The insulin resistance syndrome encompasses more than a subnormal response to insulin-mediated glucose disposal. Patients with this syndrome also frequently display elevated blood pressure, hyperlipidemia, and dysfibinolysis, even without any clinically manifested alteration in plasma glucose concentrations. Of note endothelial dysfunction and atherosclerosis also have been demonstrated in patients with hypertension, which is one of the features of the syndrome of insulin resistance. Insulin-induced vasodilation, which is mediated by the release of nitric oxide (NO) release, is impaired in obese individuals who display insulin resistance. Although it is tempting to speculate that loss of endothelium-dependent vasodilation and increased vasoconstriction might be etiological factors of elevated blood pressure, the factors contributing to NO-mediated endothelial dysfunction in the insulin-resistant state are not fully defined. Experimental evidences suggest that (6R)-5,6,7,8-tetrahydrobiopterin (BH(4)), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O(2)(-)) in the endothelial cells. Under insulin-resistant conditions where BH(4) levels are suboptimal, in addition to a reduced synthesis of NO, an accelerated inactivation of NO by O(2)(-) within the vascular wall was observed. Furthermore, oral supplementation of BH(4) restored endothelial function and relieved oxidative tissue damage, through activation of eNOS in the aorta of insulin-resistant rats. These results indicate that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin-resistant state.

Localization of sepiapterin reductase in pigment cells of Oryzias latipes.

Body colors of poikilothermal vertebrates are derived from three distinct types of pigment cells, melanophores, erythro/xanthophores and irido/leucophores. It is well known that melanin in melanophores is synthesized by tyrosinase within a specific organelle termed the melanosome. Although sepiapterin reductase (SPR) is an important enzyme involved in metabolizing biopterin and sepiapterin (a conspicuous pteridine as a coloring pigment in xanthophores) the distribution of SPR has not been shown in pigment cells. An antibody raised in rabbits against rat SPR was used to demonstrate the presence of SPR in pigment cells of Oryzias latipes. This study, which used immunohistochemistry with fluorescence or peroxidase/diaminobenzidine as markers, revealed that SPR could be detected readily in xanthophores, but only faintly in melanophores. These results suggest that sepiapterin is metabolized within xanthophores. Moreover, these experiments show that a protein sharing immunological cross-reactivity with rat SPR is located in teleost O. latipes xanthophores, which is significant considering the relationship of pteridine metabolism between poikilothermal vertebrates and mammals. Further progress in investigations of the roles of pteridines in vertebrates will be promoted by using these fish which can be bred in mass rather easily in the laboratory.

Trypanosoma cruzi genome encodes a pteridine reductase 2 protein.

Pteridine metabolism in Trypanosoma cruzi is poorly understood. The term ‘pteridine’ is used collectively for two classes of structurally-related compounds, folates and biopterins, which differ only in the nature of the side chain attached to the C6 atom of the pterin ring. Both folate and biopterin, in their reduced (tetrahydro) forms, serve as essential cofactors in a number of critical metabolic steps in many organisms [1]. While some microorganisms and parasites such as Plasmodium can synthesize folate, mammals and trypanosomatid parasites lack this ability. On the other hand, mammalian cells can synthesize tetrahydrobiopterin de novo from GTP, while these parasites cannot synthesize biopterin either [2–4]. In order to meet the need for these essential nutrients, folate and biopterin are transported from the host into the parasite, and are subsequently reduced to their respective dihydro and tetrahydro forms by parasitic dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) enzymes [1,2]. DHFR is one of the best characterized enzymes. Structure function relationships in DHFR from a variety of sources have been studied in detail and a number of inhibitors targeting DHFR has been successfully used in cancer chemotherapy and against some infectious pathogens including malaria parasite [1,5,6]. On the other hand, much of our current knowledge about pteridine reductase 1 (PTR1) is derived from research in Leishmania [7–12]. The Leishmania gene encoding PTR1 enzyme was found to be responsible for resistance to the classical antifolate drug methotrexate (MTX). The enzyme belongs to the family of short-chain dehydrogenases/reductases (SDR). Biochemical studies showed that it had broad substrate specificity and was able to reduce both folates and biopterins using NADPH as cofactor. PTR1 is considerably less sensitive (at

Molecular Mechanisms of Endothelial Dysfunction in the Insulin-Resistant State: the Roles of Abnormal Pteridine Metabolism

Abstract Although abnormalities in endothelial function are described in various insulin-resistant conditions, including obesity, diabetes, and hypertension in both humans and animal models, the underlying mechanisms are poorly understood. Experimental evidence suggests that (6R)-5,6,7,8-tetrahydrobiopterin (BH4), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS bat also in Controlling the formation of superoxide anion (O2 ) in endothelial cells. Under insulin-resistant conditions where BH4 levels are suboptimal, the production of O2 by NO synthase leads to endothelial dysfunction. Furthermore, oral supplementation of BH4 (10 mg/kg/day) for 8 weeks restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of eNOS in the aorta of insulin-resistant rats. These results suggest that abnormal pteridine metabolism contributes to causing endothelial dysfunction and the enhancement of vascular oxidative stress in the insulin-resistant State.

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease).

Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dopa-responsive dystonia caused by mutation of the GCH-I gene located on 14q22.1-q22.2. Neurohistochemical examination revealed a decrease of the tyrosine hydroxylase protein as well as its activity in the striatum and decrease of dopamine content, particularly in its ventral portion rich in D1 receptors (striatal direct pathways). Neuroimaging, clinical neurophysiological, and biochemical studies showed preservation of the structure and function of the terminal of the nigrostriatal DA neuron. Clinical neurophysiological studies showed no progressive decrement of DA activities. As the enzymatic activity of pteridine metabolism is highest in the early developmental course, it may modulate dopamine receptors maturing early in the developmental course. Its product, tetrahydrobiopterin, has higher affinity to tyrosine hydroxylase among hydroxylases. Thus, partial deficiency of tetrahydrobiopterin caused by heterozygous mutation of the GCH-I gene decreases dopamine activity rather selectively. This affects the DA receptors that mature early and demonstrates characteristic symptoms age-dependently along with the developmental decrement of the tyrosine hydroxylase activities at the terminals and the maturational processes of the projecting neurons of the basal ganglia. A difference in the ratio of mutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype.

Stress and vascular responses: oxidative stress and endothelial dysfunction in the insulin-resistant state.

Although insulin-resistant states have been associated with endothelial dysfunction due to increased vascular oxidative stress, the underlying mechanisms are pooly understood. Recent experimental evidence suggests that tetrahydrobiopterin (BH(4)), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O(2)(-)) in endothelial cells. Because insulin resistance has been suggested to be a significant contributing factor in the development of abnormal pteridine metabolism and endothelial dysfunction, we investigated pteridine content and NO/O(2)(-) production with the use of isolated thoracic aortas obtained from fructose-induced insulin-resistant rats. Under insulin-resistant conditions where BH(4) levels are suboptimal, the production of O(2)(-) by NOS leads to endothelial dysfunction. Furthermore, oral supplementation of BH(4) restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of endothelial NOS (eNOS) in the aorta of insulin-resistant rats. These results indicate that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O(2)(-), which are caused by relative deficiency of BH(4) in vascular endothelial cells.

Plasma pteridine concentrations in patients with chronic renal failure.

Pteridine metabolism is impaired in the uraemic state. This may affect cardiovascular function and contribute to malnutrition. We wished to clarify further the impact of impaired pteridine metabolism. Using the HPLC method, the plasma concentrations of endogenous pteridines were determined in 64 patients with chronic renal failure (33 on intermittent haemodialysis (HD) treatment vs 31 not yet on renal replacement therapy), and in 18 healthy controls. The patients were classified into three groups on the basis of creatinine clearance (Ccr): group (a), Ccr >60 ml/min; group (b), Ccr=10-60 ml/min; group (c), all patients receiving HD. Total neopterin (NP) and biopterin (BP) levels and the NP/BP ratio (a biomarker for macrophage activity) were significantly higher, whereas tetrahydrobiopterin (BH(4))/dihydrobiopterin (BH(2)) ratio (a biomarker for nitric oxide synthase and phenylalanine hydroxylase activities) was significantly lower in group (c) (118.9+/-11.7 ng/ml, 18.8+/-1.2 ng/ml, 6.79+/-0.53, and 0.26+/-0.06) than in healthy subjects (5.17+/-0.29 ng/ml, 2.83+/-0.19 ng/ml, 1.92+/-0.13, and 1.15+/-0.11; P<0.01). These significant differences were also observed between control and group (b) (12.4+/-2.20 ng/ml, 4.48+/-0.36 ng/ml, 2.81+/-0.48, and 0.74+/-0.08; P<0.01). In groups (a) and (b), significant negative correlations were found between Ccr and the total NP level (r=-0.663, P<0.01), the total BP level (r=-0.492, P<0.01), the BH(2) level (r=-0.677, P<0.01), and the NP/BP ratio (r=-0.493, P<0.01). Conversely, significant positive correlations were found between Ccr and the BH(4)/BH(2) ratio (r=0.602, P<0.01). The reduction of quinoid-type BH(2) to BH(4) is modified in patients with advanced chronic renal failure, before and after the initiation of regular HD treatment. These metabolic alterations may play a role in the impaired macrophage, endothelial constitutive nitric oxide synthase, or phenylalanine hydroxylase (PH) activities observed in such patients.

Pteridines and affective disorders.

The pteridine tetrahydrobiopterin (BH4) is an essential cofactor in the biosynthesis of dopamine, (nor)epinephrine, serotonin and nitric oxide (NO). Furthermore, BH4 has a direct influence on release mechanisms of these neurotransmitters and on serotonin receptor binding activity immunology. The synthesis of BH4 is stimulated by interferon-gamma and hence there is a close relationship with the immune system HPA-axis. In animal experiments it was also found that the hypothalamus-pituitary-adrenal axis influences the pteridine metabolism. In clinical studies, so far, no evidence has been found for this relationship diseases. A congenital biopterin deficiency results in atypical phenylketonuria with severe neuropsychiatric symptoms. In several neurological diseases, such as Parkinson's disease, decreased levels of BH4 are found depression. Since 1984 there have been reports on decreased biopterin and increased neopterin levels in urine and plasma of depressed patients. Conflicting results have also been found, however, due probably to methodological problems therapy. Until now, oral administration of BH4 to depressed patients has been performed by two investigators, which resulted in mainly temporal clinical improvement discussion. Understanding of biochemical mechanisms in which pteridines are involved may contribute to our knowledge of the pathogenesis and treatment of affective disorders. This paper aims to provide an overview of the relevant literature and warrant for further research on this intriguing compound.