Importance of the substrate-binding loop region of human monomeric carbonyl reductases in catalysis and coenzyme binding

Miura, Takeshi; Nishinaka, Toru; Terada, Tomoyuki

doi:10.1016/j.lfs.2009.06.005

Cited by 6 publications

(9 citation statements)

References 36 publications

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“…The region-swapping study clearly showed that the C-terminal low-identity region is the major n.a. no activity detected * very little activity detected source of the differences between human CBR1 and CBR3 in both catalytic and coenzyme-binding properties [10]. In line with this finding, El-Hawari et al demonstrated that substitutions in the CBR3 primary structure at residues 230 and 236-244 by amino acids corresponding to those of the CBR1 primary structure significantly induced catalytic efficiencies toward both isatin and 9,10-phenanthrenequinone [14].…”

Section: Origin Of Enzymatic Differences Between Cbr1 and Cbr3mentioning

confidence: 93%

“…The reducing activity of CBR1 was demonstrated to decrease rapidly with the increasing side chain length of certain quinones [41]. Thus, CoQ 1 is readily reduced by CBR1, whereas much lower or no enzymatic activity was observed for CoQ 10 [5,17,41]. CoQ 10 that contains 10 isoprenoid units is the predominant form of CoQ in humans [68].…”

Section: Quinonesmentioning

confidence: 99%

“…Miura et al found two low-identity regions between CBR1 and CBR3 [10]. One was the region near the catalytic Ser140 (at amino acid positions 140-159; the N-terminal low identity region).…”

Section: Origin Of Enzymatic Differences Between Cbr1 and Cbr3mentioning

confidence: 99%

“…In contrast, CBR3, despite sharing high similarity with CBR1 in amino acid sequence, exhibits limited carbonyl reductase activity [5,10,[12][13][14]. CBR4 differs in its substrate spectrum from other CBRs.…”

mentioning

confidence: 98%

“…A homologous enzyme is not present in human tissues and, to date, its gene has not been found in the human genome [2,10]. Animal CBR2s exhibit low sequence identity with CBR1 [2].…”

mentioning

confidence: 99%

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Human Carbonyl Reductases

Malátková¹,

Maser²,

Wsól

2010

CDM

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Enzymatic carbonyl reduction means the formation of a hydroxy function out of a ketone or aldehyde moiety and applies for the metabolism of physiological (endogenous) or xenobiotic (exogenous) molecules. As for endogenous substrates, carbonyl reduction is often part of a reversible oxidoreductase process and involves the activation or inactivation of important signal molecules like steroids, prostaglandins, retinoids and biogenic amines. These reactions are carried out by NAD(P)(H)-dependent dehydrogenases belonging to two protein superfamilies, the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). With regard to exogenous substrates, carbonyl reduction of xenobiotics is generally a "one-way" detoxification reaction, since the resulting alcohol is easier to conjugate and to eliminate. Interestingly, the participating enzymes do also belong to the AKR and SDR superfamilies. Moreover, some enzymes from the two protein superfamilies exhibit pluripotency in that they are able to catalyze the oxidoreduction of endobiotics but do also function in the reductive metabolism of carbonyl group bearing xenobiotics. A special case are carbonyl reductases per se which belong to the SDR superfamily and whose substrates or physiological roles are not quite clear. Usually, carbonyl reductases have a broad and diverse substrate spectrum for xenobiotics, however, for some of them a specific physiological function has been speculated. In the human genome, three SDR genes have been identified to code for the carbonyl reductases CBR1 (SDR21C1), CBR3 (SDR21C2) and CBR4 (SDR45C1). The present review summarizes the current knowledge on these enzymes with special emphasis on their role as a defence system against toxicants, as well as their possible physiological function and medical application. In detail, we have screened the recent literature on these three enzymes with regard to endogenous and exogenous substrates, their three-dimensional structure, tissues specific expression, polymorphisms, transcriptional regulation, occurrence in pathological states, and their possible association with cancer. Combined, this review contributes to understanding the complex nature and biological roles(s) of the human carbonyl reductases CBR1, CBR3 and CBR4.

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Section: Origin Of Enzymatic Differences Between Cbr1 and Cbr3mentioning

confidence: 93%

Section: Quinonesmentioning

confidence: 99%

“…Miura et al found two low-identity regions between CBR1 and CBR3 [10]. One was the region near the catalytic Ser140 (at amino acid positions 140-159; the N-terminal low identity region).…”

Section: Origin Of Enzymatic Differences Between Cbr1 and Cbr3mentioning

confidence: 99%

mentioning

confidence: 98%

“…A homologous enzyme is not present in human tissues and, to date, its gene has not been found in the human genome [2,10]. Animal CBR2s exhibit low sequence identity with CBR1 [2].…”

mentioning

confidence: 99%

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Human Carbonyl Reductases

Malátková¹,

Maser²,

Wsól

2010

CDM

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Identification of a functional antioxidant responsive element in the promoter of the Chinese hamster carbonyl reductase 3 (Chcr3) gene

Miura

Taketomi

Nakabayashi

et al. 2015

Cell Biology International

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CHCR3, a member of the short-chain dehydrogenase/reductase superfamily, is a carbonyl reductase 3 enzyme in Chinese hamsters. Carbonyl reductase 3 in humans has been believed to involve the metabolism and/or pharmacokinetics of anthracycline drugs, and the mechanism underlying the gene regulation has been investigated. In this study, the nucleotide sequence of the Chcr3 promoter was originally determined, and its promoter activity was characterised. The proximal promoter region is TATA-less and GC-rich, similar to the promoter region of human carbonyl reductase 3. Cobalt stimulated the transcriptional activity of the Chcr3 gene. The results of a luciferase gene reporter assay demonstrated that cobalt-induced stimulation required an antioxidant responsive element. Forced expression of Nrf2, the transcription factor that binds to antioxidant responsive elements, enhanced the transcriptional activity of the Chcr3 gene. These results suggest that cobalt induces the expression of the Chcr3 gene via the Nrf2-antioxidant responsive element pathway.

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New computational method for prediction of interacting protein loop regions

Danielson¹,

Lill²

2010

Proteins

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Flexible loop regions of proteins play a crucial role in many biological functions such as protein-ligand recognition, enzymatic catalysis, and protein-protein association. To date, most computational methods that predict the conformational states of loops only focus on individual loop regions. However, loop regions are often spatially in close proximity to one another and their mutual interactions stabilize their conformations. We have developed a new method, titled CorLps, capable of simultaneously predicting such interacting loop regions. First, an ensemble of individual loop conformations is generated for each loop region. The members of the individual ensembles are combined and are accepted or rejected based on a steric clash filter. After a subsequent side-chain optimization step, the resulting conformations of the interacting loops are ranked by the statistical scoring function DFIRE that originated from protein structure prediction. Our results show that predicting interacting loops with CorLps is superior to sequential prediction of the two interacting loop regions, and our method is comparable in accuracy to single loop predictions. Furthermore, improved predictive accuracy of the top-ranked solution is achieved for 12-residue length loop regions by diversifying the initial pool of individual loop conformations using a quality threshold clustering algorithm.

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Importance of the substrate-binding loop region of human monomeric carbonyl reductases in catalysis and coenzyme binding

Cited by 6 publications

References 36 publications

Human Carbonyl Reductases

Human Carbonyl Reductases

Identification of a functional antioxidant responsive element in the promoter of the Chinese hamster carbonyl reductase 3 (Chcr3) gene

New computational method for prediction of interacting protein loop regions

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