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Biocatalytic Reduction of Organic Compounds by Marine-Derived Fungi
Published in Se-Kwon Kim, Marine Biochemistry, 2023
Gabriel S. Baia, David E. Q. Jimenez, André Luiz Meleiro Porto
The aldo-keto reductase (AKR) enzymes can catalyze asymmetric reductions of carbonyl compounds. The difference between ERs and AKRs is that the latter needs coenzymes, for example, nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADPH) and flavin [14]. The carbonyl group reduction proceeds in two steps: (1) the hydroxyl group of the substrate is reduced, and the coenzyme is oxidized to NAD(P)+, and (2) the NAD(P)+ and alcohol product system are dissociated from the enzyme. Sheng et al. (2019) described the use of AKRs by perakine reductase in the reduction of (E)-4-phenylbut-3-en-2-one to (S,E)-4-phenylbut-3-en-2-ol. The reduction reaction conditions were 30°C and 150 rpm in Kpi buffer for 10 h. AKR affords the alcohol product in 60% yield and >99% ee of the S-enantiomer as shown in Figure 15.6 [15].
Drug Analysis of Protein Microspheres: From Pharmaceutical Preparation to In Vivo Fate
Published in Neville Willmott, John Daly, Microspheres and Regional Cancer Therapy, 2020
Jeffrey Cummings, David Watson, John F. Smyth
The major metabolite of doxorubicin is the C13 carbonyl-reduced alcohol referred to as doxorubicinol. This metabolite is formed by a ubiquitously distributed group of cytoplasmic aldo-ketoreductases. It is important to note that aldo-keto-reductase activity resides in blood elements and possibly plasma and that doxorubicinol can be produced in situ. Conjugates of doxorubicin (a 4-0-sulfate and 4-0-glucuronide) have been identified in patient urine by TLC,15 but their presence in urine or plasma awaits confirmation using more sensitive HPLC methods. Removal of the daunosamine sugar group can occur at two points by different mechanisms to produce a series of aglycone metabolites. 7-Hydroxyaglycones, as mentioned, are formed by hydrolytic cleavage, which can occur in vitro at acid pH or, less probably, in vivo by microsomal hydrolases. 7-Deoxyaglycones are formed after doxorubicin quinone reduction by a process originally termed “reductive deglycosylation”19 and are not in vitro degradation products but genuine drug metabolites. A full separation of doxorubicin, doxorubicinol, and their respective 7-hydroxyaglycones and 7-deoxyaglycones can be achieved by reversed phase HPLC with isocratic elution.20
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
dehydrogenases) and the aldo-keto reductase (AKR) family (reviewed in Penning et al.92). Mammalian 3a HSDs are members of the AKR1 family of the AKR superfamily. A systematic nomenclature for the AKR superfamily originally was adopted in 1996 and was updated in September 2000.93 This nomenclature is recognized by the Human Genome Project (HUGO), and genomic information, including chromosomal localization, gene boundaries, human ESTs and SNPs, etc., can also be found on the website: http://www.med.upenn.edu/akr.
Deoxynivalenol and its modified forms: key enzymes, inter-individual and interspecies differences in metabolism
Published in Drug Metabolism Reviews, 2022
Yating Wang, Jiefeng Li, Xu Wang, Wenda Wu, Eugenie Nepovimova, Qinghua Wu, Kamil Kuca
An aldo-keto reductase family member, AKR18A1, oxidizes DON to form 3-epi-DON, with the help of the cofactor NADP+. Nevertheless, in the presence of the coenzyme NADH, AKR18A1 catalyzes the reverse conversion of 3-epi-DON to DON (He et al. 2017). Degradation of DON to 3-keto-DON in Devosia mutans 17-2-E-8 is mediated by DepA, a dehydrogenase able to selectively oxidize DON at the C3 position in the presence of the coenzyme pyrroloquinoline quinone (PQQ) (Carere et al. 2018a). A quinone-dependent dehydrogenase gene, QDDH, from the DON-converting bacterium Devosia sp. D6-9, mediates the conversion of DON to 3-keto-DON (He et al. 2020). Furthermore, Pelagibacterium halotolerans ANSP101 shares some similarity with Devosia sp. and produces a dehydrogenase and aldo-keto reductase to catalyze DON to 3-keto-DON. The enzymes or proteins in this strain have a high degradation efficiency for DON within certain temperature (30–40 °C) and pH (8.0–10.0) ranges; however, further studies are needed for the identification of these DON-degrading genes or enzymes in the strain remains (Zhang et al. 2020a).
Intra-site differential inhibition of multi-specific enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mario Cappiello, Francesco Balestri, Roberta Moschini, Umberto Mura, Antonella Del-Corso
The multi-specific enzyme on which differential inhibition was first proposed as a potentially useful inhibition approach is AKR1B1 (EC 1.1.1.21). This enzyme is an aldo-keto reductase able to catalyse the NADPH-dependent reduction of numerous aldehydic compounds. AKR1B1 is usually presented as the first enzyme of the so-called polyol pathway, in which glucose is reduced by the enzyme to sorbitol, which is in turn transformed into fructose through a NAD+-dependent oxidation catalysed by sorbitol dehydrogenase21. Due to the relatively poor affinity the enzyme shows towards glucose22–26, it is debateable whether glucose can be considered as the native substrate for AKR1B1. However, although the polyol pathway is not a highly efficient metabolic route for glucose metabolism, it has been linked to the cellular osmotic control mediated by intracellular sorbitol levels27,28. The situation changes in hyperglycaemic conditions, where the flux of the pathway dramatically increases, thus making it a co-causative factor in the aetiology of secondary diabetic complications. The accumulation of sorbitol and the consequent osmotic unbalance, together with an alteration of the proper redox status of both NAD and NADP cofactors and the accumulation of the potent glycating agent fructose, lead to cell damage29–32. Thus, AKR1B1 has been extensively studied in terms of its inhibition33–38.
Future directions in endometriosis treatment: discovery and development of novel inhibitors of estrogen biosynthesis
Published in Expert Opinion on Investigational Drugs, 2019
Fabio Barra, Andrea Romano, Giovanni Grandi, Fabio Facchinetti, Simone Ferrero
The aldo/keto reductase (AKR) superfamily includes the enzyme AKR1C3 (also known as 17β-HSD-5): this enzyme can catalyze the reduction of estrone to estradiol, of androstenedione to testosterone and can act as prostaglandin F2α (PGF2α) synthase as well, and it has a broad substrate specificity [22]. Because of the possibility to inhibit multiple signalings relevant to endometriosis, 17β-HSD-5 attracted considerable attention as a novel drug target, although the expression and function of AKR1C3 mRNA within the different endometriotic phenotypes or the eutopic endometrium of women affected by endometriosis are not completely clear [20,23]. Inhibitors of AKR1C3 have been developed for clinical indications such as breast cancer and prostate cancer [24], and, in particular, an AKR1C3 inhibitor (BAY 1,128,688) has been developed and tested for the treatment of patients with endometriosis. After the end of a promising randomized, placebo-controlled, double-blind, dose–response study on different oral doses of BAY 1,128,688 (NCT03373422, definitive results not yet available), a recent phase II clinical trial preliminary ended due to the development of drug-related hepatotoxicity (NCT03373422).