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Molybdenum cofactor deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The MOCS2 gene was found by homology search and localized to chromosome 19. It also codes for two molybdopterin synthase proteins; they sequentially convert precursor Z to molybdopterin. Mutations have been found in both MOCS2A and 2B [20, 21].
Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development
Published in Drug Metabolism Reviews, 2022
Siva Nageswara Rao Gajula, Tanaaz Navin Nathani, Rashmi Madhukar Patil, Sasikala Talari, Rajesh Sonti
Human AO is a homodimer of 150 kDa, with each monomeric subunit having 1336 amino acids. Each subunit is subdivided into three distinct domains: a 20 kDa N-terminal domain that consists of two iron-sulfur redox clusters, a 40 kDa domain harboring a flavin adenine dinucleotide (FAD) binding site, a 90 kDa C terminal molybdopterin (MPT) domain containing a dithiolene group coordinated to the catalytic center (Moco) (Leimkühler; Coelho et al. 2015; Lepri et al. 2017). Figure 2 illustrates the crystal structure of AOX1 and the molecular mechanism of AO mediated drug metabolism. The crystallographic structure of human AOX1 reveals that 2Fe/2S clusters are distant from each other. The FeS-I is located near the Moco site, and FeS-II is proximal to the FAD site. The two iron centers and Moco act as active sites for substrate binding and facilitate electron transfer. The binding of substrate to the active site leads to the oxidation of the substrate to the corresponding product by an oxygen atom derived from H2O instead of molecular oxygen with a simultaneous reduction of Moco (Coelho et al. 2015; Lepri et al. 2017).
Aldehyde oxidase at the crossroad of metabolism and preclinical screening
Published in Drug Metabolism Reviews, 2019
Narges Cheshmazar, Siavoush Dastmalchi, Mineko Terao, Enrico Garattini, Maryam Hamzeh-Mivehroud
Mammalian aldehyde oxidases (AOX; EC 1.2.3.1) are cytosolic enzymes and they are detectable in many tissues of different animal species (Pryde et al. 2010). The first scientific article on AOXs dates back to 1930s, although most of the literature available has been published in the last decade (Pryde et al. 2010). AOXs are members of the molybdo-flavoenzyme (MFE) family (Garattini et al. 2008) along with the structurally related xanthine oxidoreductase (XOR) protein, a key enzyme in purine catabolism. In fact, the catalytically active form of these enzymes requires FAD and the molybdopterin cofactor known as Moco (Mendel 2009). Unlike XOR, which catalyzes the biotransformation of hypoxanthine into xanthine and xanthine into uric acid, AOXs are characterized by broad substrate specificity. Indeed, AOXs catalyze the oxidation of numerous substrates which do not necessarily contain aldehyde groups (Garattini and Terao 2011). This broad substrate specificity is at the basis of the involvement of human AOX1 and other mammalian AOXs in phase I drug metabolism (Sanoh et al. 2015).
Anti-hyperuricemic property of 6-shogaol via self-micro emulsifying drug delivery system in model rats: formulation design, in vitro and in vivo evaluation
Published in Drug Development and Industrial Pharmacy, 2019
Qiuxuan Yang, Qilong Wang, Yingshu Feng, Qiuyu Wei, Congyong Sun, Caleb Kesse Firempong, Michael Adu-Frimpong, Ran Li, Rui Bao, Elmurat Toreniyazov, Hao Ji, Jiangnan Yu, Ximing Xu
As a homo-dimer, each monomer of xanthine oxidase (XO) comprised of one molybdenum-molybdopterin (Mo-pt), and one flavin-adenine dinucleotide (FAD) alongside two clear-cut (2Fe–2S) centers. XO is essential purine catabolism enzyme, which broadly distributes in mammalian tissues’ proteins, especially abundant in liver. Specifically, XO catalyzes the conversion of hypoxanthine to xanthine and subsequently to UA, which is coupled with the generation reactive oxygen species (ROS), superoxide and hydrogen peroxide [45]. The overproduction and/or under-elimination of the UA will lead hyperuricemia incidence. Thus, a particular XO inhibitor could serve as important hyperuricemic therapy for gout as well as treatment for other free radical-induced diseases [46]. Further, the 6-shogaol possesses superior antioxidant activities, which could scavenge stable free radicals (DPPH), superoxide (O2•−), hydroxyl radicals (OH•) and reactive oxygen species (ROS). In summary, 6-shogaol could effectively curb XO together with reduction of levels of UA.