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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
The synthesis of the BH4 cofactor is originally from guanosine triphosphate (GTP), and it proceeds through a number of steps in Mg2+-, Zn2+-, and NADPH-dependent reactions in which reduced neopterin triphosphate (7, 8-dihydroneopterin triphosphate) and 6-pyruvoyl-5, 6, 7, 8-tetrahydropterin are the intermediates (Figure 16.3) [5]. The first committing and rate-limiting step is the GTPCH I reaction (EC 3.5.4.16). The next step is the 6-PTPS (EC 4.6.1.10). SR and the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH) are involved in the proper stereospecific conversion of 6-pyruvoyltetrahydropterin to BH4 and likely also in the pterin salvage pathway by catalyzing the conversion of sepiapterin to 7, 8-dihydrobiopterin that is then transformed to BH4 by dihydrofolate reductase [14]. Aldose reductases, the 3β-hydroxysteroid dehydrogenase type 2, carbonyl reductases and dihydrofolate reductase may also serve to the conversion of 6-pyruvoyltetrahydropterin to BH4 [15]. Because of low expression and activity of dihydrofolate reductase and 3β-hydroxysteroid dehydrogenase type 2 in human brain, the biosynthesis from 6-pyruvoyl-tetrahydropterin to BH4 cannot be completed in the absence of SR, leading to central BH4 deficiency with normal phenylalanine metabolism in the liver.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Kandace L. Amend, Ji-Yeob Choi, Christine B. Ambrosone
Carbonyl reductase (CBR) is a monomeric, NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of carbonyl compounds, including doxorubicin and daunorubicin. In humans, two CBRs have been identified, CBR1 and CBR3. An SNP has been identified in CBR3 (CBR3 V244M), where the M244 isoform results in higher Vmax and is 100% more efficient in catalyzing the reduction of substrate (39). To our knowledge, CBRs have not been investigated in relation to breast cancer outcomes following treatment with anthracyclines.
Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
As an alternative to the above-enumerated enzyme systems, carbonyl reductases have been employed to recycle the co-factor NAD(P)H by converting isopropanol into the volatile acetone (Mangan et al., 2012; Tauber et al., 2011). When using this approach, however, it is important to keep in mind that especially α,β -unsaturated aldehydes and, to a lesser extent, ketones may be reduced to the alcohol moiety by the carbonyl reductase leading to the formation of undesired side-products in form of the saturated and unsaturated alcohols.
Maternal, umbilical arterial metabolic levels and placental Nrf2/CBR1 expression in pregnancies with and without 25-hydroxyvitamin D deficiency
Published in Gynecological Endocrinology, 2021
Haiying Chen, Hongping Zhang, Han Xie, Jiayong Zheng, Meimei Lin, Jingjing Chen, Yu Tong, Jiang Jin, Kai Xu, Jie Yang, Congcong Sun, Xiaoming Xu, Jianqiong Zheng
The nuclear factor erythroid 2 related factor 2 (Nrf2) is a redox-sensitive transcription factor that activates many genes encoding antioxidant and detoxifying enzymes [11]. In addition to its antioxidant effect, Nrf2 plays an important role in glucose regulation and lipid metabolism in obesity [12]. Carbonyl reductase 1 (CBR1) is an anti-oxidative factor that protects pancreatic β-cells against oxidative stress [13]. Nrf2 can directly alter the CBR1 transcription level [14], and vitamin D can regulate Nrf2 expression. 1,25-(OH)2D3 attenuates LPS-induced high-mobility group box 1 (HMGB1) secretion in macrophages via the Nrf2/heme oxygenase 1 (HO-1) pathway [15]. Furthermore, pretreatment with 1,25-(OH)2D3 in the presence of a high concentration of leptin benefits human umbilical vein endothelial cells (HUVECs) by regulating Nrf2-mediated antioxidant activity and inflammation [16].
Nucleoside diphosphate kinase 2 confers acquired 5-fluorouracil resistance in colorectal cancer cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Shaojia Wen, Xun Wang, Yamin Wang, Jianfeng Shen, Junyi Pu, Hui Liang, Chao Chen, Linna Liu, Penggao Dai
Among the regulated genes, the methylation of CBR1, UGT2A1 and RFC3 were all downregulated (β difference >0.3), indicating that these genes might involve in 5-FU chemoresistance to in CRC. Carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, catalyses the reduction of the ketone, aldehyde and C=C bond of ONE into 4-hydroxy-2-nonenal (HNE), 4-oxo-2-nonenol and 4-oxononanal, respectively [32]. This gene has been reported to mediate DOX reduction and suggested to develop the chemoresistance in cancer cells [33]. UGT2A1 belongs to UDP-glycosyltransferase family, which catalyse biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase water solubility and enhance excretion. They are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds, UGT2A1 exhibited highest expression in the lung, colon and liver and other tissues [34], hence, it may play an important role in drug resistance. RFC3 mainly functioned in DNA replication, nucleotide excision repair and mismatch repair. It may affect the efficacy of drugs similar to paclitaxel’s and it also reported to over-expressed in many kinds of cancers. When RFC3 gene was silenced, ovarian tumour cells proliferation were greatly suppressed [35].
Valbenazine as the first and only approved treatment for adults with tardive dyskinesia
Published in Expert Review of Clinical Pharmacology, 2018
Harini Sarva, Claire Henchcliffe
TBZ’s metabolism is complex, as it is a racemate consisting of two ketone enantiomers, (+)- and (-)-tetrabenazine. Carbonyl reductase reduces the ketone moiety of both TBZ enantiomers to form active secondary alcohol metabolites, four in total due to the formation of an additional chiral center, which are collectively referred to as dihydrotetrabenazine (HTBZ) and individually referred to as (+)-α-HTBZ, (-)-α-HTBZ, (+)-β-HTBZ, and (-)-β-HTBZ [36,37]. Both (+)-α-HTBZ and (+)-β-HTBZ potently inhibit VMAT2 activity. However, both (-)-α-HTBZ and (-)-β-HTBZ are not potent VMAT2 inhibitors and bind to D2 receptors and other CNS relevant targets which may contribute to unwanted side effects of sedation and parkinsonism with chronic use [37].All four isomers are deactivated to O-demethylated and other metabolites by either CYP2D6 or CYP3A4 [36,37]. The α-enantiomers can be deactivated by either enzyme but the β-enantiomer isoforms are only deactivated by CYP2D6 [36,37]. This enzyme system’s activity varies among individuals and as a result of other medication interactions. In addition, CYP2D6 has genetic polymorphisms, and dihydrotetrabenazine products have a short half-life. As a result, TBZ is commonly prescribed as three times per day dosing [36]. This short half-life, complex metabolism, and side effects therefore resulted in the need for an improved TD treatment.