title: Human carbonyl reductase 1 as efficient catalyst for the reduction of glutathionylated aldehydes derived from lipid peroxidation.
abstract: Human recombinant carbonyl reductase 1 (E.C. 1.1.1.184, hCBR1) is shown to efficiently act as aldehyde reductase on glutathionylated alkanals, namely 3-glutathionyl-4-hydroxynonanal (GSHNE), 3-glutathionyl-nonanal, 3-glutathionyl-hexanal and 3-glutathionyl-propanal. The presence of the glutathionyl moiety appears as a necessary requirement for the susceptibility of these compounds to the NADPH-dependent reduction by hCBR1. In fact the corresponding alkanals and alkenals, and the cysteinyl and γ-glutamyl-cysteinyl alkanals adducts were either ineffective or very poorly active as CBR1 substrates. Mass spectrometry analysis reveals the ability of hCBR1 to reduce GSHNE to the corresponding GS-dihydroxynonane (GSDHN) and at the same time to catalyze the oxidation of the hemiacetal form of GSHNE, generating the 3-glutathionylnonanoic-δ-lactone. These data are indicative of the ability of the enzyme to catalyze a disproportion reaction of the substrate through the redox recycle of the pyridine cofactor. A rationale for the observed preferential activity of hCBR1 on different GSHNE diastereoisomers is given by molecular modelling. These results evidence the potential of hCBR1 acting on GSHNE to accomplish a dual role, both in terms of HNE detoxification and, through the production of GSDHN, in terms of involvement into the signalling cascade of the cellular inflammatory response.
authors: University of Pisa, Department of Biology, Biochemistry Unit, via S. Zeno, 51, Pisa, Italy.
authors: Rossella
authors: R
authors: Rotondo
authors: University of Pisa, Department of Biology, Biochemistry Unit, via S. Zeno, 51, Pisa, Italy.
authors: Roberta
authors: R
authors: Moschini
authors: Proteomics & Mass Spectrometry Laboratory, ISPAAM-CNR, via Argine, 1085, Napoli, Italy.
authors: Giovanni
authors: G
authors: Renzone
authors: University of Pisa, Department of Pharmacy, via Bonanno, 6, Pisa, Italy.
authors: Tiziano
authors: T
authors: Tuccinardi
authors: University of Pisa, Department of Biology, Biochemistry Unit, via S. Zeno, 51, Pisa, Italy.
authors: Francesco
authors: F
authors: Balestri
authors: University of Pisa, Department of Biology, Biochemistry Unit, via S. Zeno, 51, Pisa, Italy.
authors: Mario
authors: M
authors: Cappiello
authors: Proteomics & Mass Spectrometry Laboratory, ISPAAM-CNR, via Argine, 1085, Napoli, Italy.
authors: Andrea
authors: A
authors: Scaloni
authors: University of Pisa, Department of Biology, Biochemistry Unit, via S. Zeno, 51, Pisa, Italy.
authors: Umberto
authors: U
authors: Mura
authors: University of Pisa, Department of Biology, Biochemistry Unit, via S. Zeno, 51, Pisa, Italy. Electronic address: antonella.delcorso@unipi.it.
authors: Antonella
authors: A
authors: Del-Corso
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000447:Aldehydes / Q000737:chemistry* / Q000378:metabolism; D001253:Astrocytes / Q000737:chemistry* / Q000201:enzymology; D055162:Biocatalysis; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation; D062105:Molecular Docking Simulation; D009249:NADP / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: C000605761:3-glutathionyl-4-hydroxynonanal; D000447:Aldehydes; D007783:Lactones; D011994:Recombinant Proteins; D009249:NADP; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; D005978:Glutathione; C027576:4-hydroxy-2-nonenal
keywords: 3-glutathionyl-4-hydroxynonanal; 4-hydroxy-2-nonenal; Carbonyl reductase 1; Hydroxynonenal detoxification