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PubMed1992

Characterisation of genes encoding two novel members of the aldo-keto reductase superfamily.

The predicted amino acid sequence of the protein encoded by a cDNA clone isolated from the protozoan haemoparasite Babesia bovis has approximately 22% amino acid identity with the Pichia stipitis xylose reductase. There are similar levels of amino acid identity with other members of the aldo-keto reductase superfamily. The identities include many residues highly conserved in the superfamily. However, the amino acid sequence of the B. bovis protein (AKR1) clearly lies outside the cluster of the previously characterized members of the superfamily. A putative protein encoded by a previously undescribed partially characterized open reading frame at the igrA (increased glyphosate resistance) locus of Pseudomonas sp. strain PG2982 also exhibits similarity to AKR1 and the aldo-keto reductases.

Alcohol Oxidoreductases↗

PubMed1976

Cytoplasmic aldo-keto reductases: a class of drug metabolizing enzymes.

Aldehyde and ketone xenobiotic substances are preferentially reduced to alcohols by cytoplasmic enzymes in mammals. These enzymes are widely distributed in the tissues, have broad substrate specificities, have similar physical-chemical characteristics, and require reduced nicotinamide adenine dinucleotide as cofactor for the reductions. These reductases define a system of detoxification for aldehyde and ketone groups.

Aldehyde Oxidoreductases↗

PubMed1992

Reduction of trioses by NADPH-dependent aldo-keto reductases. Aldose reductase, methylglyoxal, and diabetic complications.

The substrate specificities of human aldose reductase and aldehyde reductase toward trioses, triose phosphates, and related three-carbon aldehydes and ketones were evaluated. Both enzymes are able to catalyze the NADPH-dependent reduction of all of the substrates used. Aldose reductase shows more discrimination among substrates than does aldehyde reductase and is generally the more efficient catalyst. The best substrate for aldose reductase is methylglyoxal (kcat = 142 min-1, kcat/Km = 1.8 x 10(7) M-1 min-1), a toxic 2-oxo-aldehyde that is produced nonenzymatically from triose phosphates and enzymatically from acetone/acetol metabolism. D- and L-glyceraldehyde and D- and L-lactaldehyde are also good substrates for aldose reductase. The aldose reductase-catalyzed reduction of methylglyoxal produces 95% acetol, 5% D-lactaldehyde. Further reduction of acetol produces only L-1,2-propanediol. Acetol and propanediol are two products that accumulate in uncontrolled diabetes. Both acetol and methylglyoxal were compared with glucose for their abilities to produce covalent modification of albumin. All three of these carbonyl compounds reacted with albumin to produce modified proteins with new absorption and emission bands that are spectrally similar. Both methylglyoxal and acetol are much more reactive than glucose. A new integrative model of diabetic complications is proposed that combines the aldose reductase/polyol pathway theory and the nonenzymatic glycation theory except that emphasis is placed both on methylglyoxal/acetol metabolism and on glucose metabolism.

Acetone↗

PubMed1992

Distribution and immunological characterization of microbial aldehyde reductases.

The distribution of microbial aldo-keto reductases was examined and their immunochemical characterization was performed. p-Nitrobenzaldehyde, pyridine-3-aldehyde and ethyl 4-chloro-3-oxobutanoate reductase activities were found to be widely distributed in a variety of microorganisms. In immunodiffusion studies, most yeasts belonging to the genera Sporobolomyces, Sporidiobolus and Rhodotorula formed precipitin bands with anti-Sporobolomyces salmonicolor aldehyde reductase serum. Furthermore, the results of immunotitration experiments suggested that Sporobolomyces salmonicolor AKU 4429 contains other enzyme(s) which can reduce p-nitrobenzaldehyde, pyridine-3-aldehyde and/or ethyl 4-chloro-3-oxobutanoate, and which are inactivated by anti-Sporobolomyces salmonicolor aldehyde reductase serum.

Aldehyde Reductase↗

PubMed1992

Catalytic effectiveness of human aldose reductase. Critical role of C-terminal domain.

Human aldose reductase and aldehyde reductase are members of the aldo-keto reductase superfamily that share three domains of homology and a nonhomologous COOH-terminal region. The two enzymes catalyze the NADPH-dependent reduction of a wide variety of carbonyl compounds. To probe the function of the domains and investigate the basis for substrate specificity, we interchanged cDNA fragments encoding the NH2-terminal domains of aldose and aldehyde reductase. A chimeric enzyme (CH1, 317 residues) was constructed in which the first 71 residues of aldose reductase were replaced with first 73 residues of aldehyde reductase. Catalytic effectiveness (kcat/Km) of CH1 for the reduction of various substrates remained virtually identical to wild-type aldose reductase, changing a maximal 4-fold. Deletion of the 13-residue COOH-terminal end of aldose reductase, yielded a mutant enzyme (AR delta 303-315) with markedly decreased catalytic effectiveness for uncharged substrates ranging from 80- to more than 600-fold (average 300-fold). The KmNADPH of CH1 and AR delta 303-315 were nearly identical to that of the wild-type enzyme indicating that cofactor binding is unaffected. The truncated AR delta 303-315 displayed a NADPH/D isotope effect in kcat and an increased D(kcat/Km) value for DL-glyceraldehyde, suggesting that hydride transfer has become partially rate-limiting for the overall reaction. We conclude that the COOH-terminal domain of aldose reductase is crucial to the proper orientation of substrates in the active site.

Aldehyde Reductase↗

PubMed2026

AKR7A3 rs1738023 association with susceptibility to female hepatocellular carcinoma and its role in AFB1 metabolism and tumor.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. In this study, we performed a two-stage exome-chip association analysis and found that the aldo-keto reductase family7 member A3 (AKR7A3) rs1738023 may be a potential susceptibility locus for HCC in females. We aimed to explore its role and mechanism. METHODS: The association between genotype and phenotype was analyzed through GWAS method. The expression of AKR7A3 in cancer tissue and blood analysis by qRT-PCR. The relationship of AKR7A3 and aflatoxin B1 (AFB1) was also analyzed. The effect of AKR7A3 on the biological behavior of HCC cell line was investigated on proliferation and invasion. The potential mechanism was analyzed by transcriptome analysis and western blot. RESULTS: Through genome-wide association analysis (GWAS), AKR7A3 (rs1738023), KIF2C (rs4342887), and CYP3A5 (rs6977165 and rs4646450) were found to be associated with susceptibility to hepatocellular carcinoma (HCC) in women. Further expression quantitative trait loci (eQTL) analysis showed that only AKR7A3 (rs1738023) was significantly associated with gene expression. The expression of AKR7A3 was significantly lower in HCC than adjacent non-tumorous tissues (P < 0.001). The genotype of rs1738023 was significantly associated with AKR7A3 expression (P = 0.0085). Rs1738023[C] genotype had a low AKR7A3 expression level and limited detoxification ability of AFB1. Literature data showed that AKR7A3 is involved in the metabolism of aflatoxin B1 (AFB1). Functional experimental results showed that overexpression of AKR7A3 in the normal liver cell line HL-7702 could significantly reduce AFB1-induced ROS levels and DNA adduct formation, suggesting that it plays a protective role in AFB1 metabolic detoxification. Cell function test showed that overexpression of AKR7A3 inhibit the proliferation, migration and invasion of HCC cells, and block the cell cycle. Transcriptome sequencing and KEGG pathway enrichment analysis revealed that overexpression of AKR7A3 affected the PI3K signaling pathway and led to downregulation of HIF1A and its downstream VEGFA protein expression. The validation results were confirmed in HCC cell lines Huh-7 and SUN-387. CONCLUSION: Overexpression of AKR7A3 contributes to inhibition of HCC progression and reduction of aflatoxin toxicity. AKR7A3 may serve as a potential prognostic and therapeutic target for HCC patients, although further validation is needed.

AKR7A3↗

PubMed1992

A novel NADPH-dependent carbonyl reductase of Candida macedoniensis: purification and characterization.

A novel NADPH-dependent carbonyl reductase was purified to homogeneity from the soluble fraction of a cell extract of Candida macedoniensis AKU 4588. The enzyme catalyzes not only the reduction of quinones, but also the reduction of aromatic aldehydes, conjugated polyketones, 2'-ketopantothenate esters, and 4-chloro-3-oxobutanoate esters. The enzyme shows absolute specificity for NADPH as a coenzyme and also shows quite high affinity toward NADPH (Km less than 5 microM). The apparent Km values for menadione and p-toluquinone are 167 and 180 microM, respectively. The enzyme is not a flavoprotein and is a monomer protein with a relative molecular mass of 45,000. Dicoumarol, quercetin, and some sulfhydryl reagents inhibit the enzyme activity.

Alcohol Oxidoreductases↗

PubMed1992

A novel membrane associated carbonyl reducing enzyme is present in smooth endoplasmic reticulum of mouse liver.

Evidence supporting the existence of two distinct carbonyl (metyrapone) reducing enzymes which differ in subcellular localization and immunological homology has been provided. A soluble enzyme, designated as carbonyl reductase (EC 1.1.1.184) is located in the cytosol. The distribution of the second, membrane associated, MPON-reductase shows an excellent linear correlation to NADPH-cytochrome c reductase and, on the other hand, is reciprocal to the RNA/protein ratio of submicrosomal preparations. This indicates that the membrane associated MPON-reductase is exclusively located in the smooth endoplasmic reticulum. Using antibodies against the purified membrane associated enzyme the extent of immunological crossreaction corresponds well to the specific activities of MPON-reductase in the granular fractions, thus further confirming the localization of this enzyme within this organelle. The absence of antigenic crossreaction to cytosolic MPON-reductase indicates differences also in terms of the immunological relationship between the two enzymes.

Alcohol Oxidoreductases↗

PubMed1992

High carbonyl reductase activity in adrenal gland and ovary emphasizes its role in carbonyl compound detoxication.

Carbonyl reduction has been studied in liver, kidney, adrenal gland and ovary of female Wistar and Sprague-Dawley rats as well as of female NMRI mice by using metyrapone as a substrate and by means of direct HPLC analysis of the reduced alcohol metabolite metyrapol. Carbonyl reducing activities were found in all tissues examined so far, with that in rat ovary and adrenal gland cytosol exceeding the liver cytosolic specific activity severalfold: 15-fold and 12-fold in the Wistar strain; 12-fold and 7-fold in the Sprague-Dawley strain, respectively. In general, Wistar rat enzyme activities were about four times higher than those of Sprague-Dawley rats in all fractions, which indicates an interesting genetic difference between the two rat strains. Due to the sensitivity towards the diagnostic inhibitor quercitrin, carbonyl reductase (EC 1.1.1.184) seems to be mainly responsible for metyrapone reduction in rat and mouse adrenal gland and ovary cytosol. However, sensitivity towards dicoumarol in microsomal fractions of mouse tissues points to the involvement of further carbonyl reducing enzymes. Western blot experiments revealed immunological differences between metyrapone reductase from liver microsomes and respective enzymes of all other tissues. In conclusion, the difference in tissue and intracellular distribution suggests that several enzymes are involved in carbonyl reduction of metyrapone and the intracellular multiplicity of the enzymes may have some relation to their significance in carbonyl compound detoxification. These results support the hypothesis that carbonyl reductases, besides their participation in the metabolism of physiologically occurring substances, provide the enzymatic basis for the detoxification of xenobiotic carbonyl compounds in adrenal gland and ovary which have escaped their metabolic conversion by the liver.

Adrenal Glands↗

PubMed1992

Carbonyl reductase from human testis: purification and comparison with carbonyl reductase from human brain and rat testis.

Carbonyl reductase (EC 1.1.1.184) is a cytosolic, monomeric, NADPH-dependent oxidoreductase with broad specificity for carbonyl compounds and a general distribution in human tissues. A carbonyl reductase closely resembling the human enzyme is exclusively expressed in rat reproductive tissues and adrenals (Iwata, N., Inazu, N. and Satoh, T. (1989) J. Biochem. 105, 556-564). In order to investigate the relationship between the human and rat enzyme, carbonyl reductase from human testis was purified to homogeneity. The enzyme was indistinguishable from carbonyl reductase from other human tissues on the basis of physicochemical properties, substrate specificity, inhibitor sensitivity and immunological reactivity. Likewise, the human and rat testis enzymes exhibited greatly overlapping substrate specificities for prostaglandins, steroids as well as many xenobiotic carbonyl compounds, and showed the same susceptibility to inhibition by flavonoids and sulfhydryl-blocking agents. Structural homology between the two enzymes was indicated by the mutual cross-reactivity of antibodies against carbonyl reductase from one species and the enzyme protein from the other species. Unlike the rat enzyme, which is confined to Leydig cells, the human enzyme was detectable in Leydig cells as well as Sertoli and spermatogenic cells.

Alcohol Oxidoreductases↗

PubMed1992

A lung type prostaglandin F synthase is expressed in bovine liver: cDNA sequence and expression in E. coli.

Using the cDNA of bovine lung prostaglandin F synthase (EC 1.1.1.2) as a probe, we isolated a clone from a bovine liver cDNA library which differed in only eleven nucleotides from the probe. The corresponding protein contained three amino acid substitutions, including a leucine residue which is conserved throughout all aldo-keto reductases. We inserted the liver cDNA into expression vector pUC19 and expressed the recombinant liver enzyme in E.coli. The purified liver enzyme reduced prostaglandin H2 as well as prostaglandin D2 and various carbonyl compounds. The high relative activity against prostaglandin H2 in combination with a high Km value for prostaglandin D2 identified this liver enzyme as a lung type prostaglandin F synthase. However, the binding constant for NADPH of the liver enzyme was 3.5 fold higher than that of lung prostaglandin F synthase.

Amino Acid Sequence↗

PubMed1978

Cellular uptake and metabolism of daunorubicin as determined by high-performance liquid chromatography. Application to L1210 cells.

The metabolism of daunorubicin (DNR) to daunorubicinol and daunomycinone in murine leukaemia cells has been examined by means of high-performance liquid chromatography. A rapid and efficient extraction method has been developed that permits the recovery of the drug and its metabolites from cell homogenates. By means of high-performance liquid chromatography daunorubicinol and daunomycinone have been separated from DNR and the intracellular concentration of the compounds determined. The method developed is very rapid and sensitive, and amounts as small as 30 pg of DNR can be detected. The results indicate that the aldo-keto reductase is not very active in L1210 cells in culture, the main intracellular product found being DNR.

Animals↗

PubMed2024

The AKR1C1-CYP1B1-cAMP signaling axis controls tumorigenicity and ferroptosis susceptibility of extrahepatic cholangiocarcinoma.

Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1-CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP-PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1-CYP1B1-cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.

Humans↗

PubMed2025

Human xenobiotic metabolism proteins have full-length and split homologs in the gut microbiome.

Xenobiotics, including pharmaceutical drugs, can be metabolized by both host and microbiota, in some cases by homologous enzymes. We conducted a systematic search for all known human proteins with gut microbial homologs. Because gene fusion and fission can obscure homology detection, we built a pipeline to identify not only full-length homologs, but also cases where microbial homologs were split across multiple adjacent genes in the same neighborhood or operon ("split homologs"). We found that human proteins with full-length gut microbial homologs disproportionately participate in xenobiotic metabolism. While this included many different enzyme classes, short-chain and aldo-keto reductases were the most frequently detected, especially in prevalent gut microbes, while cytochrome P450 homologs were largely restricted to lower-prevalence facultative anaerobes. In contrast, human proteins with split homologs tended to play roles in central metabolism, especially of nucleobase-containing compounds. We identify twelve specific drugs that gut microbial split homologs may metabolize; 2 of these, 6-mercaptopurine by xanthine dehydrogenase and 5-fluorouracil by dihydropyrimidine dehydrogenase, have been recently confirmed in mouse models. This work provides a comprehensive map of homology between the human and gut microbial proteomes, indicates which human xenobiotic enzyme classes are most likely to be shared by gut microorganisms, and finally demonstrates that split homology may be an underappreciated explanation for microbial contributions to drug metabolism.

Humans↗

PubMed1992

Immunohistochemical localization of carbonyl reductase in human tissues.

Carbonyl reductase, an NADPH-dependent oxidoreductase of broad specificity, is present in many human tissues. Its precise localization, however, has remained unclear, as well as its physiological and possible pathophysiological significance. The present study reports the immunohistochemical localization of the enzyme in normal human tissues. Immunostaining was detectable in all organs investigated. The highest concentrations were found in the parenchymal cells of the liver, the epithelial cells of the stomach and small intestine, the epidermis, the proximal tubules of the kidney, neuronal and glial cells of the central nervous system, and certain cells of the anterior lobe of the pituitary gland. Consistently pronounced staining was also observed in smooth muscle fibers and the endothelium of blood vessels. The results are in agreement with a housekeeping function of carbonyl reductase in the elimination of reactive carbonyl compounds.

Adrenal Glands↗

PubMed1992

Consecutive treatment of disulfiram inhibits ovarian carbonyl reductase activity in rats.

We investigated the effects of disulfiram (DS) on ovarian carbonyl reductase activity in rats to determine the influence of DS on female reproductive function. Three consecutive treatments with DS significantly inhibited ovarian carbonyl reductase activity as well as ovulation, dose-dependently. Single treatment with DS had no effect on ovarian carbonyl reductase activity. Our observations indicate that consecutive treatment with DS has an inhibitory action on female reproductive function, although DS is well-known to inhibit aldehyde dehydrogenase and dopamine beta-hydroxylase.

Alcohol Oxidoreductases↗

PubMed2026

Integrative single-cell and genomic analysis reveals NMB as a driver of metastatic adaptation in esophageal squamous cell carcinoma via metabolic rewiring and immune evasion.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has high mortality, and metastasis is the leading cause of patient death. Neuromedin B (NMB) promotes tumor development in various cancers, yet its role in ESCC metastasis remains unclear. METHODS: We integrated single-cell transcriptomic data from matched primary and metastatic ESCC lesions (GSE309392) with bulk transcriptomic cohorts from TCGA and GSE53624. In silico gene perturbation, ligand-receptor communication analysis, and single-cell prognostic model construction were performed, followed by functional validation through siRNA-mediated NMB knockdown in TE-1 and KYSE30 cell lines. RESULTS: NMB was identified as a key gene enriched in metastatic ESCC lesions, and its high expression was associated with coordinated upregulation of oxidative phosphorylation pathway genes and aldo-keto reductase family antioxidant enzymes (AKR1C1, AKR1C2, AKR1B10). Genomic analysis revealed that NMB-high tumors carried a higher clonal mutation burden and a markedly increased frequency of NFE2L2 activating mutations (23% vs. 8%, P = 0.04). In silico knockout and correlation analysis identified AKR1C1 as a downstream effector of NMB. NMB expression was negatively correlated with CD8+ T cell and activated NK cell infiltration. CellChat analysis revealed communication between NMB-positive cells and monocytes via the TGM2-ADGRG1 axis, and specifically detected IFNG signaling. In the single-cell prognostic model, NMB-positive cells accounted for 50% of the high-risk group but only 20% of the low-risk group. TCGA-based survival analysis demonstrated that high NMB expression was associated with shorter overall survival (HR = 2.98, P = 0.03). In vitro NMB-targeted RNA interference markedly inhibited proliferation, colony formation, and migration in TE-1 and KYSE30 cells. CMap screening identified the endothelin-PDE5-cGMP axis as a potential therapeutic target. CONCLUSION: NMB serves as a key driver of metastatic adaptation in ESCC, conferring a survival advantage to tumor cells during metastatic colonization through genomic evolution and immune remodeling, with metabolic adaptation as a downstream consequence of genomic alterations.

NMB↗

PubMed1992

Pig testicular 20 beta-hydroxysteroid dehydrogenase exhibits carbonyl reductase-like structure and activity. cDNA cloning of pig testicular 20 beta-hydroxysteroid dehydrogenase.

cDNA inserts encoding 20 beta-hydroxysteroid dehydrogenase (EC 1.1.1.53) were, for the first time, isolated and cloned from a pig testis cDNA library using synthetic oligonucleotides deduced from the partially determined amino acid sequences. The cDNA contains an open reading frame predicted to encode 289 amino acid residues. Surprisingly, it has 85% amino acid homology to human carbonyl reductase. The purified enzyme exhibited carbonyl reductase activity. Adenine-rich sequence was located in the 3'-untranslated nine-rich sequence was located in the 3'-untranslated region, which may mean that the gene originates by retroposition. RNA transcripts of 1.3, 3, and 6 kilobases were detected in poly(A)+ RNA extracted from pig testis by Northern blot hybridization. The steady-state level of the RNA species increased to a maximum in testes from 10-day-old pigs, but rapidly declined thereafter to the same levels found in testes of mature animals.

Alcohol Oxidoreductases↗