Identification of Components from Acetobacter pasteurianus and their Xanthine Oxidase Inhibitory Activity
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IDENTIFICATION OF COMPONENTS FROM Acetobacter pasteurianus AND THEIR XANTHINE OXIDASE INHIBITORY ACTIVITY
Ming-Der Wu,* Ming-Jen Cheng,* Yen-Lin Chen, Mei-Huei Chen, Siao-Jhen Chen, Li-Wen Yu, and Hsun-Yin Hsu
Xanthine oxidase (XO) acts at the end of a catabolic sequence of purine nucleotide metabolism in humans and a few other uricotelic species. This enzyme catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid [1]. Overproduction of uric acid, termed hyperuricemia, is the underlying cause of gout. XO inhibitors can be broadly classified as purine or nonpurine analogs based on their structural similarities with natural purines. The best known XO inhibitor is allopurinol, 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one. Allopurinol is a substrate for XO, and its oxidation product, oxypurinol, is also an effective inhibitor. However, allopurinol may induce hypersensitivity in patients with renal insufficiency and concomitant administration of thiazide diuretics. These side effects have led researchers to search for novel XO inhibitors. In a preliminary screening assay, the liquid fermentation of Acetobacter pasteurianus (strain BCRC 12325) was found to be active against XO (> 70% inhibitions). This paper focuses on XO inhibitory activity since this activity is used to characterize natural products. Acetobacter pasteurianus is an acetic acid-producing Gram-negative bacterium found usually on sugary substances like flowers and fruits in the wild. It is widely used in the production of fermented foods, such as kefir and vinegar [2, 3]. So far, 11 prokaryotic triterpenoids of the hopane series, namely, bacteriohopanetetrols, with a new side-chain configuration from the Acetobacter species were investigated [4]. However, investigations on the chemical constituents and biological activities of Acetobacter pasteurianus have seldom been conducted. The 95% ethanolic extract of the title bacterium showed XO inhibitory activity. It is worth investigating its bioactive compounds. In this study, the strain of A. pasteurianus (BCRC 12325) was fermented on media (1% soy peptone, 0.2% yeast extract, 3% glucose, 0.2% malt extract, and 3% fructose) for 7 days. The liquid-state fermentation (20 L) was partitioned with EtOAc and n-BuOH. The EtOAc layer showed strong xanthine oxidase inhibitory activity. Further bioassay-directed fractionation of this fraction led to the isolation of one β-carboline derivative, flazin (1) [5], one furancarboxylic acid, 5-hydroxymethyl-2furancarboxylic acid (2) [6], and three benzenoids, p-hydroxybenzoic acid (3) [7], gallic acid 4-methyl ether (4) [8], and isovanillic acid (5) [7]. The structures of 1–5 were established using spectroscopic data analysis, including 1D and 2D NMR techniques (COSY, NOESY, HSQC, and HMBC). Moreover, all isolates (1–5) were evaluated for their inhibitory effects on xanthine oxidase. The two isolated compounds (1, 2) were evaluated for inhibitory activity against XO. Compounds 1 and 2 (IC50 = 9.9 mg/mL (32.1 mM), 16.2 mg/mL (114.1 mM), respectively) showed
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