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Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
The conditions result in a deficiency of the cerebral neurotransmitters dopamine and/or serotonin. These rare conditions are generally autosomal recessively inherited. However the condition GTP cyclohydrolase deficiency (also called L-dopa-responsive dystonia) is not that uncommon and inherited in a dominant manner. Thus a number of family members can be affected and they can be surprisingly variable in their symptoms, with one member having perhaps simple intermittent cramping whereas another may have more severe generalised neurological dysfunction.
Enzymes
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Abou-Donia, Wilson, Zimmerman et al. (1986) pointed out that the intracellular level of tetrahydrobiopterin normally may limit the rate of tyrosine hydroxylation. They presented further evidence that tetrahydrobiopterin is a regulatory factor for this reaction, that under certain conditions tetrahydrobiopterin content is regulated by GTP cyclohydrolase activity, and that the synthesis of tetrahydrobiopterin appears to be mediated by cAMP-dependent and -independent processes in a manner analogous to the regulation of TH synthesis.
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.
Dysregulated metabolism: A friend-to-foe skewer of macrophages
Published in International Reviews of Immunology, 2023
Keywan Mortezaee, Jamal Majidpoor
Hypoxia is one the key events in tumorigenesis, so targeting this critical promoter of immunosuppressive TME is important therapeutically [77]. Hypoxia upregulates GTP cyclohydrolase expression in ECs and tumor cells, which is the key enzyme in the production of tetrahydrobiopterin. GTP cyclohydrolase blockade resulted in a shift from M2 to M1 phenotype and reduced tumor growth partly via suppression of angiogenesis [97]. Another strategy is to dampen macrophage recruitment toward avascular areas of tumor. Blockade of Semaphorin 3 A (Sema3A)/Neuropilin-1 (Nrp1) signaling confines TAMs within normoxic areas of tumor, thereby abating angiogenesis and restoring anti-tumor immunity [98]. mTOR/HIF-1α is an inducer of metabolic activation toward aerobic glycolysis [99]. mTOR activation is suppressed by regulated in development and DNA damage response 1 (REDD1). Due to predilection in the acquisition of glycolysis for meeting metabolic demands of both cancer cells and M1 macrophages, preferential activation of mTOR in TAMs or suppression of its inhibitor REDD1 in such cells can offer therapeutics against cancer metastasis [63].
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
It was also inspected that the inactivation of GCH1 and SPR impairs T-cell proliferation in humans and mice, introducing BH4 as a substance that reinforces immune response and its reduction leads to weakening of autoimmune responses. In an in vivo experiment, blockage of BH4 synthesis attenuated allergic inflammations and T cell-mediated immunity. Also, increase of BH4 level through GCH overexpression led to the reinforcement of anti-tumoral activity of CD4 and CD8 T cells [17]. Similarly, treatment of mice with BH4 decreased tumor growth and its influence on effector T cells was observed by their expansion. Nevertheless, it seems that BH4 plays a controversial role in cancer. It has been reported that NO has an important function in tumor angiogenesis. BH4 is an absolute requirement for endothelial NO synthase, thus promoting tumor angiogenesis [107]. Thus, in vitro expression of GTP cyclohydrolase I enhances tumorigenesis, tumor cell proliferation, and angiogenesis. [108] In 2016, a study proclaimed that downregulation of GTP cyclohydrolase with 2,4-diamino-6-hydroxypyrimidine (DAHP) in mice with hepatocellular carcinoma reduces BH4 production, NO level, and subsequently NO-mediated angiogenesis by inhibiting Ras-PI3K/Akt pathway [109]. Pickert et al. similarly reported that inhibition of GCH1 decreases tumor growth by employing three ways; killing the tumor cells directly, ameliorating anti-tumoral immune response, and blockage of angiogenesis [110].
Nutrition-based interventions for mood disorders
Published in Expert Review of Neurotherapeutics, 2021
Lais B Martins, Jenneffer Rayane Braga Tibães, Marsal Sanches, Felice Jacka, Michael Berk, Antônio L Teixeira
Inflammation can influence the production of neurotransmitters traditionally implicated in the regulation of emotion, mainly serotonin and dopamine. Pro-inflammatory cytokines can decrease serotonin availability through the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) which catabolizes tryptophan, an essential amino acid necessary for the synthesis of serotonin, into kynurenine [28,29]. For example, treatment with interferon-α (IFN-α) induces depressive symptoms in association with changes in peripheral and central kynurenine levels [30]. Immune activation also increases the activity of the enzyme GTP-cyclohydrolase 1 (GTP-CH1) which catalyzes the conversion of guanosine-triphosphate (GTP) into dihydrobiopterin (BH2). BH2 is in turn converted into neopterin at the expense of tetrahydrobiopterin (BH4) production. An increase in neopterin levels means a reduction in the bioavailability of BH4, which participates in serotonin and dopamine synthesis [28]. The increase in neopterin levels in MDD has been positively associated with the number of depressive episodes [31].