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Biochemical Effects in Animals
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Probably the most revealing data on the interaction between tryptophan and deoxypyridoxine comes from Milholland and Rosen.327 Using a B6-deficient diet containing 100 mg deoxypyridoxine hydrochloride per kilogram, they found that compared with the B6-deficient diet alone, deoxypyridoxine markedly increased urinary xanthurenic acid excretion after a tryptophan load even after just 1 day on the diet. Increasing the activity of tryptophan pyrrolase threefold with cortisone produced little change in xanthurenic acid excretion either before or after a tryptophan load. The excretion of xanthurenic acid was correlated with the dose of tryptophan. Using cyclohexamide also failed to reduce xanthurenic acid excretion. Treatment with the deficient diet alone or with deoxypyridoxine was equally effective in reducing liver kynureninase but the deoxypyridoxine group excreted five to ten times more xanthurenic acid than the group receiving only the B6-deficient diet. Therefore, the authors noted that changes in enzyme activity detected in vitro may not have significant effects in vivo. They also agreed with Spiera and Vallarino471 that spontaneous increases in urinary excretion of tryptophan metabolites without tryptophan load may result from altered renal clearance. In deoxypyridoxine-treated rats, intraperitoneal administration of 1 mg pyridoxine HC11 hr after the tryptophan load prevented the excretion of xanthurenic acid.
Vitamins, trace elements and metals
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Pyridoxal phosphate is needed for the conversion of tryptophan to nicotinic acid, and this pathway is impaired in pyridoxine deficiency. Xanthurenic acid is the excretion product of 3-hydroxykynurenic acid, the metabolite before the ‘block’; in pyridoxine deficiency, it is found in abnormally high amounts in the urine after an oral tryptophan load. The urinary metabolite of pyridoxal phosphate, 4-pyridoxic acid, may also be measured. Increase in the activity of erythrocyte aspartate transaminase after the addition of pyridoxal phosphate may be measured. The more severe the pyridoxine deficiency, the greater the increase in enzyme activity after addition of the vitamin. Excess pyridoxine can occur with overdose regularly greater than 10 mg/day and may lead to a peripheral neuropathy.
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.
Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2021
Fanni Annamária Boros, László Vécsei
The first step of the KP is the conversion of Trp into N-formyl-L-kynurenine in a reaction catalyzed by indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO) enzymes. N-formyl-L-kynurenine is then metabolized into L-kynurenine (KYN) by formamidase. KYN is situated at an important branch point of the KP, since it can be converted into i) kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), ii) anthranilic acid (AA) by kynureninase (KYNU), and iii) 3-hydroxykynurenine (3-HK) via a reaction catalyzed by kynurenine 3-monooxygenase (KMO). 3HK can further be metabolized into xanthurenic acid (XA) by KATs or can form 3-hydroxyanthranilate (3-HAA), which is further converted into 2-amino-3-carboxymuconate semialdehyde (ACMS) in a reaction catalyzed by 3-hydroxyanthranilate 3,4-dioxygenase. ACMS can be further processed by aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) for the synthesis of 2-aminomuconate semialdehyde, which is then further metabolized into picolinic acid (PIC). ACMS can also undergo non-enzymatic cyclization and form quinolinic acid (QUIN), which is then ultimately metabolized into nicotinamide adenine dinucleotide (NAD+), a crucial molecule for cellular energy production and metabolism.
Emerging role of metabolomics in protein conformational disorders
Published in Expert Review of Proteomics, 2021
Nimisha Gupta, Sreelakshmi Ramakrishnan, Saima Wajid
A number of reports have shown that the concentration of several other metabolites, such as tyrosine, glycine, arginine, L-glutamyl-glycine, N-acetylcysteine, LPCs, histidinyl-phenylalanine, choline-cytidine, metabolites propionate and acetone and choline, were also altered in AD patients, suggesting that these metabolites can be considered as potential biomarkers for therapeutic purposes [32,35,36,42,49–51,57,58]. A panel of 26 metabolites has been identified from the classes – sphingolipids and glycerophospholipids, that discriminated AD and control samples with high accuracy (83.33%), sensitivity (86.67%), and specificity (80%) [46]. Recently, indole-3-pyruvic acid, a metabolite of tryptophan, was identified as a signature for the prediction and discrimination of AD along with five short-chain fatty acids for progression and pre-onset of AD [59]. A metabolic phenotyping study by Whiley et al. (2021) revealed a reduction in tryptophan pathway metabolites (serotonin, tryptophan, and xanthurenic acid) in both the serum and urine samples of AD patients [60]. Multiple studies are being carried out on AD where therapeutic approaches are being applied to identify still unknown outcomes [61].