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Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
FAD, a redox cofactor important for catalysis in many enzymes, is derived from the vitamin riboflavin. As in most FAD-containing enzymes, the adenine part of the molecule binds to a Rossman fold in the protein. The isoalloxazine ring part of FAD is held in position by a covalently bond to a cysteine residue in MAO (Fig. 10.3). In all crystal structures of MAO B, the isoalloxazine ring is bent by about 30° (Binda et al., 2003) with about 0.3° difference between the oxidized and reduced forms. However, molecular dynamics has now enabled a more realistic picture of the shape of the flavin in the flexible protein active site. Two different studies have shown that it is almost planar in the oxidized form (FAD) (Vianello et al., 2012; Zapata-Torres et al., 2015), but when it is reduced either by a hydride ion from the substrate transferred to N5 in the first step of the catalytic mechanism or after the propargylamine adduct has formed at N5, the FADH2 is bent by almost 30 degrees (Borstnar et al., 2011) in agreement with the crystal structure.
Cancer
Published in Stephen P. Coburn, The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Shapiro et al.448 combined deoxypyridoxine (40 mg/kg twice daily, 4 hr apart) with azaguanine, testosterone, and 6,7-dimethyl-9-hydroxyethyl-isoalloxazine. Again, the combination was more effective than individual agents and more effective than the triple combination without the isoalloxazine compound.
Riboflavin
Published in Judy A. Driskell, Ira Wolinsky, Sports Nutrition, 2005
The majority of riboflavin found in food is in the form of FAD. Smaller amounts are present in the form of FMN and free riboflavin, which is an isoalloxazine ring bound to a ribitol side chain, with the absorption half-life of about 1.1 h.7 Flavins that are covalently bound do not appear to be available for absorption. However, FAD and FMN are predominantly in a non-covalently-bound form attached to an enzyme. FAD and FMN must be hydrolyzed to riboflavin before absorption can occur. Nonspecific phosphatases in the brush border membranes of enterocytes are responsible for this catalysis.8 Once in the enterocytes, free riboflavin undergoes ATP-dependent phosphorylation, which is catalyzed by cytosolic flavokinase to form FMN; it can now enter the plasma and small intestine. However, most of this is further converted to FAD by the FAD-dependent FAD synthetase.9 In the rare instance when riboflavin may be in excess, it is excreted in the urine as riboflavin, 7-hydroxymethylriboflavin (7-α-hydroxyriboflavin), or luminflavin.10
The Effect of Irradiated Riboflavin in Human Tenon’s Fibroblast – A Study on Cellular Viability
Published in Current Eye Research, 2022
Wendy Yen Nee See, Fazliana Ismail, Siti Hamimah Sheikh Abdul Kadir, Visvaraja Subrayan
The antiproliferative effect of IR is sustained up to 48 hours (Table 2). However, the change in effect with time of IR on human tenon fibroblasts is not significant in this study. We postulate that this could be due to two reasons. Firstly, the reactive oxygen species that are formed during the photodegradation process are unstable.3,16 The short lifetimes of these reactive oxygen species are not able to exert their effects onto the cells once the irradiation process is stopped or when in lower concentrations.16 Secondly, it has also been suggested that IR produces stable photoproducts, such as 7,8-dimethyl-10-(formylmethyl) isoalloxazine, lumichrome and lumiflavin16 that do not disintegrate with time. Consequently, duration of treatment is not the causative factor for the effect in our study.
Discovery of antimicrobial compounds targeting bacterial type FAD synthetases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
María Sebastián, Ernesto Anoz-Carbonell, Begoña Gracia, Pilar Cossio, José Antonio Aínsa, Isaías Lans, Milagros Medina
An activity-based HTS was performed on the 1240 compounds of the Prestwick Chemical Library®. The assays consisted in recording the time dependent decrease in the fluorescence of the isoalloxazine ring, produced upon transformation of RF and FMN into FAD, as a consequence of the fluorescence quenching in this later flavin27. When either the RFK or the FMNAT activities were inhibited, less FAD was produced and, consequently, the fluorescence decrease registered in a specific time interval was less pronounced. Measurements were carried out using a multimode microplate reader, Synergy™ HT Biotek, with BRAND 96-well plates pure Grade™. To optimise the assay conditions, a previous study was performed using constant concentrations of RF, ATP and CaFADS (∼5, ∼50 and ∼0.4 µM, respectively) and variable concentrations of MgCl2 (0.2–10 mM) and DMSO (0–12.5% v/v). Optimum conditions were 2.5% DMSO, 10 mM MgCl2 and sensitivity 70.
Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies
Published in Expert Opinion on Drug Discovery, 2018
Bence Szilágyi, György G. Ferenczy, György M. Keserű
The third-generation inhibitors (Table 3) are based on cyclic carboxylic acid bioisosters connected to bulky nonpolar moieties with a flexible linker. This type of inhibitors keeps the essential interactions of former inhibitors, namely those with Arg283, Tyr228 and the isoalloxazine ring of FAD and they extend in the direction perpendicular to the plane of the isoalloxazine ring. This extension is possible owing to the flexibility of the Tyr224 residue first observed in the X-ray structure of pig DAAO complexed with imino tryptophan [69]. Flexibility of Tyr224 was detected in complexes of human DAAO with imino-DOPA (15) [70] and also with inhibitors containing phenethyl substituents [68].