Disease relevance of CBR1

• Here, we describe the isolation and characterization of a cDNA clone complementary to human carbonyl reductase mRNA from a human placenta cDNA library constructed in phage lambda gt11 [1].
• Increased brain protein levels of carbonyl reductase and alcohol dehydrogenase in Down syndrome and Alzheimer's disease [2].
• We therefore evaluated the levels of six proteins whose genes are encoded on chromosome 21 (trefoil factor 1, trefoil factor 2, trefoil factor 3, coxsackie virus and adenovirus receptor, carbonyl reductase 1 and interferon- alpha receptor) in fetal cerebral cortex from DS and controls at the early second trimester using Western blot analysis [3].
• Human carbonyl reductase was cloned from a breast cancer cell line (MCF-7) [4].
• CBR activity increased 83-fold in the K562-transfected cells and was associated with a 2-3-fold reduction in DN toxicity [5].

Psychiatry related information on CBR1

• CONCLUSIONS: the WHO CBR programme is highly effective for disabled people in the community being trained at home, for both children and adults, and yields similar results in different types of society; it can be accomplished at very low cost by recruiting volunteers, and mobilizes human resources in the community while promoting self-esteem [6].

High impact information on CBR1

• Several crn genes have human homologs that are important for RNA processing, protein folding, DNA replication, and DNA damage repair, suggesting dual roles for CRN nucleases in cell survival and cell death [7].
• Carbonyl reductase-like 20beta-hydroxysteroid dehydrogenase (CR/20beta-HSD) is an enzyme that converts 17alpha-hydroxyprogesterone to 17alpha, 20beta-dihydroxy-4-pregnen-3-one (the maturation-inducing hormone of salmonid fish) [8].
• The structure reveals that the two calcium-binding regions on C2cPLA2 that display hydrophobic residues, CBR1 and CBR3, are partially inserted into the core of the membrane [9].
• Two different forms of the monomeric NADP(+)-linked prostaglandin dehydrogenase/carbonyl reductase were purified from human placenta and shown to differ by the modification of a lysine residue [10].
• Infusion of PE (ABR and CBR activation) increased mean arterial pressure from 87.2 +/- 2.8 to 94.9 +/- 2.9 mm Hg (+/- SE, p less than .001) [11].

Chemical compound and disease context of CBR1

• Mechanistic roles of Ser-114, Tyr-155, and Lys-159 in 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase from Comamonas testosteroni [12].
• The Comamonas testosteroni 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase gene (hsdA) codes for an adaptive enzyme in the degradation of steroid compounds [13].
• 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) from Comamonas testosteroni, a short chain dehydrogenase/reductase, catalyzes the oxidation of androsterone with NAD+ to form androstanedione and NADH [12].
• However, it exhibited a carbonyl reductase activity with menadione and ubiquinone, and amino acid sequences of its peptides cleaved by Staphylococcus aureus V8 proteinase were consistent with those reported for the enzyme [14].
• In humans, attenuating carotid chemoreceptor activity by hyperoxia does not alter arterial PCO2 (PaCO2) during submaximal exercise, yet a transient hypercapnia occurs in carotid chemoreceptor-resected (CBR) asthmatic subjects during submaximal exercise [15].

Biological context of CBR1

• It is possible that genetic polymorphisms in CBR1 and CBR3 are key for the wide interindividual variability in the disposition of CBR drug substrates [16].
• Mapping of a novel human carbonyl reductase, CBR3, and ribosomal pseudogenes to human chromosome 21q22.2 [17].
• With the PCR method, using primers carrying the conserved nucleotide sequence among mammalian CRs, we isolated three different cDNAs (CHCR1, CHCR2 and CHCR3) which encode a unique carbonyl reductase from the Chinese hamster [18].
• These studies revealed a previously unknown function for CBR1 in serum-withdrawal-induced apoptosis [19].
• Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein [1].

Anatomical context of CBR1

• In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol [20].
• In order to investigate the relationship between the human and rat enzyme, carbonyl reductase from human testis was purified to homogeneity [21].
• Southern analysis of 17 mouse/human somatic cell hybrids showed that carbonyl reductase is located on chromosome 21 [4].
• NP was applied during sustained PE infusion to eliminate the increase in transmural carotid sinus pressure and thus remove CBR activation, thereby causing ABR stimulation alone [11].
• In this report, the effects of CBR expression on DN metabolism and cell toxicity were determined by cloning and expressing a human CBR cDNA in DN reductase-deficient myeloid erythroleukemia K562 cells [5].

Associations of CBR1 with chemical compounds

• Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase [22].
• Comparative three-dimensional analyses based on the structure of the homologous porcine carbonyl reductase suggested that the V244M substitution is positioned in a region critical for interactions with the NADP(H) cofactor [16].
• Bacterial recombinant CHCRs showed typical carbonyl reductase activities towards 4-benzoylpyridine, 4-nitrobenzaldehyde and pyridine 4-carboxyaldehyde [18].
• Carbonyl reductase (CR) is an enzyme which can catalyze the oxidoreduction of various carbonyl compounds in the presence of NAD(P)H [18].
• Genomic sequence and expression of a cloned human carbonyl reductase gene with daunorubicin reductase activity [23].
• We further demonstrate that the structural isostere of HMGSH, S-nitrosoglutathione, is an ideal hCBR1 substrate (Km = 30 microm, kcat = 450 min(-1)) with kinetic constants comparable with the best known hCBR1 substrates [24].

Physical interactions of CBR1

• These findings suggest the presence of an essential arginine residue in the substrate-binding domain of aldehyde reductase and the coenzyme-binding site of carbonyl reductase [25].

Enzymatic interactions of CBR1

• 4. Recombinant human carbonyl reductase catalysed low-affinity reduction of E-10-oxonortriptyline with preferential transfer of the pro-4S-3H of labelled NADPH [26].

Other interactions of CBR1

• A nonspecific NADPH-dependent carbonyl reductase from human brain (formerly designated as aldehyde reductase 1; Ris, M. M., and von Wartburg, J. P. (1973) Eur. J. Biochem. 37, 69-77) has been purified to homogeneity [22].
• The CBR gene was mapped by high-resolution fluorescence in situ hybridization to band 21q22.12, very close to the SOD1 locus at position 21q22.11 [27].
• Carbonyl reductase (EC 1.1.1.184) is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds that are generally referred to as the aldoketoreductases [1].
• Both aldo-keto reductase activity and quinone reductase activity have been shown to be associated with carbonyl reductase [27].
• Carbonyl reductase activity was extensively inhibited by menadione, rutin and quercitrin, whereas medroxyprogesterone acetate, phenolphthalein and flufenamic acid were potent inhibitors of AKR1C1, 1C2 and 1C4 [28].

Analytical, diagnostic and therapeutic context of CBR1

• The predicted amino acid sequence was confirmed by partial sequence analysis of the carbonyl reductase protein [1].
• In order to identify the reactive residue and investigate its possible role in glutathione binding, alanine was substituted for each cysteine residue of human carbonyl reductase by site-directed mutagenesis [29].
• We quantified protein levels of CBR and its agonist/antagonist ADH using 2D gel electrophoresis with subsequent MALDI-identification and specific software in several brain regions of DS as well as AD patients and compared them to levels of CBR and ADH in brains of controls [2].
• We observed varying levels in 11beta-HSD 1 and carbonyl reductase expression in these patients, as revealed by RT-PCR and ELISA [30].
• In eight normal men (group I), we measured MSNA (microneurography) during sustained elevation of arterial pressure produced by intravenous infusion of phenylephrine (PE) alone (combined ABR and CBR activation) versus during PE infusion with superimposed application of sustained external neck pressure (NP) [11].

References