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Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Patients are now being diagnosed earlier because of the initiation of programs in which all hyperphenyalaninemic infants are being investigated for the possibility of defective metabolism of biopterin. However, it has been documented that it is possible to miss a patient with abnormal synthesis of BH4 because early phenylalanine levels may be normal. Therefore, evaluation for a disorder in this pathway should be undertaken in infants with unexplained neurologic disease. Five disorders are considered in this chapter: deficiencies of GTP cyclohydrolase I (GTPCH), recessive as well as dominant forms, 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydropteridine reductase (DHPR), and pterin-4a-carbinolamine dehydratase (PCD) (Figure 16.3). The clinical manifestations of all of them are quite similar, but the carbinolamine hydratase is relatively benign. In addition, variant forms of PTPS and DHPR deficiency exist in which the neurologic signs are either minor or absent. Elevated phenylalanine should initiate investigation in most of these disorders. Sepiapterin reductase, the dominant form of GTPCH I deficiency, and some children with recessively inherited GTPCH deficiency are exceptions in which biopterin is deficient only in the brain [6, 7]. The next step in elucidating a diagnosis is measurement of pterin metabolites in urine or in dry blood spots, and DHPR activity in blood spots. Enzyme activity may be assessed in erythrocytes or cultured fibroblasts. Diagnosis may also be secured by determination of mutations of the relevant gene. Improved prognosis with early therapy makes prompt diagnosis and the timely initiation of therapy important.
The role of biomarkers in stage III non-small cell lung cancer
Published in Expert Review of Respiratory Medicine, 2023
Rafael Rosell, María González-Cao, Masaoki Ito, Mariacarmela Santarpia, Andrés Aguilar, Jordi Codony-Servat
Reactive oxygen species (ROS) production is harmful for polyunsaturated fatty acids (PUFAs) and lipid membranes. Following peroxidation, PUFAs disrupt cellular permeability and membrane function, inducing ferroptosis. In addition to the three previously mentioned resistance mechanisms against ferroptosis (GPX4, FSP1 and DHODH), tetrahydrobiopterin (BH4) has revealed an essential mechanism to compensate from GPX4 inhibition, suggesting that the inhibition of the SLC17A11-GPX4 axis can cause resistance through overexpression of BPH4. Loss of long-chain ACSL4 (Figure 2), which catalyzes the integration of PUFA into membrane phospholipids, improved cell survival when GPX4 is inhibited [59]. It was discovered that under GPX4 inhibition there is an upregulation of enzymes involved in the BH4 pathway, such as GTP cyclohydroxylase−1 (GCH1), 6-pyruvoyltetrahydropterin synthase (PTS) and sepiapterin reductase (SPR). Furthermore, it was identified that dihydrofolate reductase (DHFR) catalyzes the regeneration of BH4 and its inhibition by methotrexate is synergistic with GPX4 blockade [59]. Of utmost relevance, is the fact that sulfasalazine has demonstrated to inhibit sepiapterin reductase (SPR) [60]. Therefore, since sulfasalazine inhibits SLC17A11 (Figures 3, 2), it can presumably be inferred that the use of sulfasalazine could neutralize the counterbalanced rebound effect of BH4 upregulation. Notwithstanding, the action of methotrexate as a potential complementary drug should be kept in mind.
The interplay between aryl hydrocarbon receptor, H. pylori, tryptophan, and arginine in the pathogenesis of gastric cancer
Published in International Reviews of Immunology, 2022
Marzieh Pirzadeh, Nastaran Khalili, Nima Rezaei
Kynurenine, a metabolite of the amino acid tryptophan, is a natural ligand for AHR [13]. Tryptophan dioxygenase, a liver enzyme that drives tryptophan consumption, is upregulated by many cancers, indicating that increased tryptophan consumption might be a possible mechanism of tumors to defeat immune barriers and continue progression [14]. Xanthurenic acid, which is a metabolite of the kynurenine pathway, acts as a potent inhibitor of a terminal enzyme in the synthetic pathway of tetrahydrobiopterin (BH4) named sepiapterin reductase (SPR) [15]. BH4 is a cofactor that is involved in the conversion of amino acids such as phenylalanine, tyrosine, and tryptophan to monoamine neurotransmitters such as dopamine and serotonin [16]. It has been shown that BH4 ameliorates immune response and prevents tumor progression [17]. Thus, the decreased production of BH4 impairs antitumor immune responses and T cell proliferation, resulting in immune suppression. Moreover, BH4 is a cofactor for NO synthesis from arginine [18]. Different studies have implicated that arginine can induce apoptosis in gastric epithelial cells and also mediate NO-induced H. pylori killing[19]. However, being a precursor for NO, a substance which contributes to tumor progression through angiogenesis, suggests a controversial role for BH4 in tumor progression.
Effects Of Endothelin-1 On Intracellular Tetrahydrobiopterin Levels In Vascular Tissue
Published in Scandinavian Cardiovascular Journal, 2018
Ruha Cerrato, Mark Crabtree, Charalambos Antoniades, Karolina Kublickiene, Ernesto L. Schiffrin, Keith M. Channon, Felix Böhm
Finally we wanted to investigate whether ET-1 induced endothelial dysfunction could be inhibited by exogenous BH4. We performed a set of experiments on resistance arteries from subcutaneous fat harvested from women undergoing caesarian section. However, BH4 was not able to inhibit the marked ET-mediated endothelial dysfunction in these resistance arteries (Figure 2(c)). This observation goes in line with Romero et al, who report ET-induced endothelial dysfunction in rat aorta following 2 h incubation with ET-1 which could not be restored with the BH4 precursor sepiapterin [20]. In conflict with our present results, the same study showed that L-NAME inhibitable superoxide production was evident following 2 h ET-1 incubation in the presence of the calcium ionophore A23187. The use of this calcium ionophore and that the incubation time with ET-1 was 75 min longer are two factors that may explain the differences in our studies. Also Loomis et al reported that ET-mediated superoxide production could be inhibited by not only L-NAME, but also by BH4, in the rat aorta [16]. Differences to our study are that pre incubation was 60 min with L-NAME or BH4, and ET-1 incubation followed thereafter for 240 min. Importantly, there may also be species differences and we have in the present study shown that 45 or 240 min ET-1 exposure does not affect biopterins and that there is no L-NAME inhibitable superoxide production in ET-exposed vessels from patients with coronary artery disease.