THE INFLUENCE OF d-GLUCURONOLACTONE ON THE EXCRETION OF l-XYLULOSE BY HUMANS AND GUINEA PIGS

Touster, Oscar; Hutcheson, Ruth M.; Rice, Louise S.

doi:10.1016/s0021-9258(18)65991-5

Cited by 55 publications

(1 citation statement)

References 18 publications

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“…Dicarbonyl/ l -xylulose reductase (DCXR) is a multifunctional homotetrameric enzyme important in carbonyl detoxification and carbohydrate metabolism (see Figure for reactions catalyzed by DCXR). A member of the short-chain dehydrogenase/reductase (SDR) superfamily, it catalyzes the pyridine nucleotide-dependent reduction of various monosaccharides, including pentoses, tetroses, trioses, and ketones, as well as α-dicarbonyl compounds. , DCXR is thought to play a key role in the glucuronic acid/uronate cycle of glucose metabolism, an alternative pathway mediating the oxidation of glucose-6-phosphate. − In this pathway, glucuronic acid is metabolized in a multistep process leading to the formation of the pentose, l -xylulose . Subsequently, DCXR converts l -xylulose to xylitol, and additional reactions shuttle this metabolite into the pentose phosphate pathway, contributing to cellular energy metabolism .…”

Section: Introductionmentioning

confidence: 99%

Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Yang

Jan

Mishin

et al. 2017

Chem. Res. Toxicol.

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Reactive carbonyls such as diacetyl (2,3-butanedione) and 2,3-pentanedione in tobacco and many food and consumer products are known to cause severe respiratory diseases. Many of these chemicals are detoxified by carbonyl reductases in the lung, in particular, dicarbonyl/L-xylulose reductase (DCXR), a multifunctional enzyme important in glucose metabolism. DCXR is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Using recombinant human enzyme, we discovered that DCXR mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity preferentially utilized NADH as a cosubstrate and was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione). Using 9,10-phenanthrenequinone as the substrate, quinone redox cycling was found to inhibit DCXR reduction of L-xylulose and diacetyl. Competitive inhibition of enzyme activity by the quinone was observed with respect to diacetyl (Ki = 190 μM) and L-xylulose (Ki = 940 μM). Abundant DCXR activity was identified in A549 lung epithelial cells when diacetyl was used as a substrate. Quinones inhibited reduction of this dicarbonyl, causing an accumulation of diacetyl in the cells and culture medium and a decrease in acetoin, the reduced product of diacetyl. The identification of DCXR as an enzyme activity mediating chemical redox cycling suggests that it may be important in generating cytotoxic reactive oxygen species in the lung. These activities, together with the inhibition of dicarbonyl/L-xylulose metabolism by redox-active chemicals, as well as consequent deficiencies in pentose metabolism, are likely to contribute to lung injury following exposure to dicarbonyls and quinones.

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Section: Introductionmentioning

confidence: 99%

Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Yang

Jan

Mishin

et al. 2017

Chem. Res. Toxicol.

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Some Problems in the Choice of Oxidative Pathways of Carbohydrate Metabolism

Dickens

Glock

McLean

1959

Ciba Foundation Symposium — Regulation of Cell Metabolism

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Structure of the tetrameric form of human L‐Xylulose reductase: Probing the inhibitor‐binding site with molecular modeling and site‐directed mutagenesis

et al. 2005

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L-Xylulose reductase (XR) is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. In this study we report the structure of the biological tetramer of human XR in complex with NADP(+) and a competitive inhibitor solved at 2.3 A resolution. A single subunit of human XR is formed by a centrally positioned, seven-stranded, parallel beta-sheet surrounded on either side by two arrays of three alpha-helices. Two helices located away from the main body of the protein form the variable substrate-binding cleft, while the dinucleotide coenzyme-binding motif is formed by a classical Rossmann fold. The tetrameric structure of XR, which is held together via salt bridges formed by the guanidino group of Arg203 from one monomer and the carboxylate group of the C-terminal residue Cys244 from the neighboring monomer, explains the ability of human XR to prevent the cold inactivation seen in the rodent forms of the enzyme. The orientations of Arg203 and Cys244 are maintained by a network of hydrogen bonds and main-chain interactions of Gln137, Glu238, Phe241, and Trp242. These interactions are similar to those defining the quaternary structure of the closely related carbonyl reductase from mouse lung. Molecular modeling and site-directed mutagenesis identified the active site residues His146 and Trp191 as forming essential contacts with inhibitors of XR. These results could provide a structural basis in the design of potent and specific inhibitors for human XR.

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THE INFLUENCE OF d-GLUCURONOLACTONE ON THE EXCRETION OF l-XYLULOSE BY HUMANS AND GUINEA PIGS

Cited by 55 publications

References 18 publications

Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells

Some Problems in the Choice of Oxidative Pathways of Carbohydrate Metabolism

Structure of the tetrameric form of human L‐Xylulose reductase: Probing the inhibitor‐binding site with molecular modeling and site‐directed mutagenesis

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