Fig 5 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Comparison of the cofactor-binding site between the AKR1B15 model (A) and the AKR1B10 crystal structure (B). Interactions of Met265 and His269 with NADP+ in AKR1B15 are similar to those of Val265 and Arg269 in AKR1B10 (black dotted lines). His269 forms a π-stacking interaction with the adenine ring of the cofactor. The substitution of Lys22 by Arg in AKR1B15 prevents its interaction with the pyrophosphate bridge of NADP+. The salt bridge between Asp217 and Lys263 (red dotted line), acting as a safety belt in the coenzyme binding, and the π-stacking interaction of Tyr210 with the cofactor nicotinamide ring are conserved between the two AKRs. Carbon atoms of the cofactor are shown in green, whereas those of the enzyme are colored grey. Figures have been drawn using PyMOL.
Source publication
Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and physiological role of AKR1B15 are still poorly know...
Citations
... High expression of AKR1B10, also known as aldose reductase-like-1 (ARL-1), is seen in the adrenal glands, small intestine, and colon [11,15]. The expression of AKR1B15, a novel enzyme that shares 92% amino acid sequence homology with AKR1B10, is generally low in most tissues and limited to the adipose tissue, testis, and placenta [16]. AKR1B1 (AR), the most extensively studied AKR, catalyzes the nicotinamide adenine dinucleotide phosphate reduced (NADPH)-dependent reduction of aldehydes and ketones to their corresponding alcohols. ...
... There are very few reports on the involvement of AKR1B15 in cancer [16,81]. Yuan et al. [82] developed a novel metabolism-related gene signature with AKR1B15 as one of the six genes with the potential to predict overall survival, prognosis, and treatment efficiency for HCC. ...
... However, there is currently no research on the role of AKR1B15, MTATP8P1, and SP6 in cancer. AKR1B15 is a type of aldo-keto reductase that is similar www.nature.com/scientificreports/ to AKR1B10 in terms of amino acid sequence, with a 92% identity 37 . AKR1B10 is an extensively studied enzyme with high retinaldehyde reductase activity linked to the development of various cancers. ...
Bladder cancer, a prevalent and heterogeneous malignancy, necessitates the discovery of pertinent biomarkers to enable personalized treatment. The mammalian target of rapamycin complex 1 (mTORC1), a pivotal regulator of cellular growth, metabolism, and immune response, exhibits activation in a subset of bladder cancer tumors. In this study, we explore the prognostic significance of mTORC1 signaling in bladder cancer through the utilization of bioinformatics analysis. Our investigation incorporates transcriptomic, somatic mutation, and clinical data, examining the mTORC1 score of each sample, as well as the enrichment of differentially expressed genes (DEGs), differentiation characteristics, immunological infiltration, and metabolic activity. Our findings reveal that elevated mTORC1 levels serve as an adverse prognostic indicator for bladder cancer patients, exhibiting a significant association with Basal-type bladder cancer. Patients with heightened mTORC1 activation display heightened levels of pro-carcinogenic metabolism. Additionally, these individuals demonstrate enhanced response to immunotherapy. Finally, we develop an mTORC1-related signature capable of predicting the prognosis of bladder cancer patients.The signature offers novel mTORC1-related biomarkers and provides fresh insights into the involvement of mTORC1 in the pathogenesis of bladder cancer.
... Inhibition of AKR1B could prevent > Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols > Displays enzymatic activity toward endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosaccharides, bile acids, and xenobiotics substrates > Reduces steroids and their derivatives and prostaglandins. > Displays low enzymatic activity toward alltrans-retinal, 9-cis-retinal, and 13-cis-retinal [21][22][23] > Catalyzes the reduction of diverse phospholipid aldehydes [24] > Plays a role in detoxifying dietary and lipidderived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal (4-HNE), trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GScarbonyls) > Key enzyme in the polyol pathway catalyzes glucose reduction to sorbitol during hyperglycemia [25] > Evolutionarily conserved for sensing glucose uptake [26] > Plays a role in glycosylation [27] > Contributes to progression from cirrhosis to hepatocarcinogenesis [28] > Acts as a selective derepressor of PPARgamma and the retinoic acid receptor [29] > Catalyzes the NADPH-dependent reduction of a wide variety of carbonylcontaining compounds to their corresponding alcohols > Displays strong enzymatic activity toward all-trans-retinal, 9- [31] (Continued on next page) inflammatory diseases such as gastrointestinal diseases, psoriasis, and congenital disorders of glycosylation in vitro and in vivo, further emphasizing the necessity for and importance of developing these enzyme-targeting agents in clinical therapy. Despite being studied for a long time, the significance of AKR1B remains unclear. ...
... As a multifunctional NADPH-dependent reductase, AKR1B can reduce a variety of endogenous carbonyl compounds [83]. The intricate network of signaling pathways, which includes oxidative stress and inflammation, is also anchored by AKR1B [31,84,85]. AKR1B1 has been proven to play an essential role in glycosylation by tracing metabolomics [27]. ...
... However, their clinical efficacy is hampered by tumor resistance. Three isoforms of AKR1B have been linked to developing therapeutic resistance to these specific anticancer medications and 3rd-generation EGFR-TKI [31,33,48,163,179]. In an early report, AKR1B10 was first discovered to metabolize the side-chain C13-ketonic group of daunorubicin and idarubi-cin, resulting in acquired resistance to these compounds [180]. ...
... Although there is no report on porcine ONE and HNE reductases, several human enzymes reduce the two aldehydes. The K m values for ONE and HNE of pAKR1C1 and pAKR1C4 are lower than or comparable to those of the human enzymes: aldose reductase (AKR1B1) [34], aldose reductase-like proteins (AKR1B10 and AKR1B15), hAKR1C1 and hAKR1C3 [21,[48][49][50][51]. pAKR1C1 and pAKR1C4 also showed low K m values for other lipid peroxidation-derived aldehydes, except pAKR1C4 for acrolein. ...
... [52] and AKR1B15 [50]. Recently, two Nrf2 binding sites (i.e., AREs) have been identified in the pAKR1C1 promotor region, indicating that the enzyme expression is regulated through the Nrf2/ARE signaling pathway [19]. ...
... pAKR1C1 is unique in its ability to reduce aliphatic ketones, in which 2,5-hexanedione and 2,4-pentanedione are neurotoxic [63,64]. Although human AKR1B15 [50] and rat AKR1C15 [65] were reported to reduce 2,4-pentanedione and/or 2,5-hexanedione, pAKR1C1 represents the first enzyme detoxifying the neurotoxic diketones in pigs. ...
Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs). Similarly to humans, four genes for AKR1C proteins (AKR1C1-AKR1C4) have been identified in the pig, which is a suitable species for biomedical research model of human diseases and optimal organ donor for xenotransplantation. Previous study suggested that, among the porcine AKR1Cs, AKR1C1 and AKR1C4 play important roles in steroid hormone metabolism in the reproductive tissues; however, their biological functions are still unknown. Herein, we report the biochemical properties of the two recombinant enzymes. Kinetic and product analyses of steroid specificity indicated that AKR1C1 is a multi-specific reductase, which acts as 3α-HSD for 3-keto-5β-dihydro-C19/C21-steroids, 3β-HSD for 3-keto-5α-dihydro-C19-steroids including androstenone, 17β-HSD for 17-keto-C19-steroids including estrone, and 20α-HSD for progesterone, showing Km values of 0.5-11 µM. By contrast, AKR1C4 exhibited only 3α-HSD activity for 3-keto groups of 5α/β-dihydro-C19-steroids, 5β-dihydro-C21-steroids and bile acids (Km: 1.0-1.9 µM). AKR1C1 and AKR1C4 also showed broad substrate specificity for nonsteroidal carbonyl compounds including endogenous 4-oxo-2-nonenal, 4-hydroxy-nonenal, acrolein, isocaproaldehyde, farnesal, isatin and methylglyoxal, of which 4-oxo-2-nonenal was reduced with the lowest Km value of 0.9 µM. Moreover, AKR1C1 had the characteristic of reducing aliphatic ketones and all-trans-retinal. The enzymes were inhibited by flavonoids, synthetic estrogens, nonsteroidal anti-inflammatory drugs, triterpenoids and phenolphthalein, whereas only AKR1C4 was activated by bromosulfophthalein. These results suggest that AKR1C1 and AKR1C4 function as 3α/3β/17β/20α-HSD and 3α-HSD, respectively, in metabolism of steroid hormones and a sex pheromone androstenone, both of which also play roles in metabolism of nonsteroidal carbonyl compounds.
... Since the 1980s, AR has been deeply studied as a drug target [8,9] because it transforms cytosolic glucose into sorbitol (a reaction that AKR1B10 and AKR1B15 cannot perform [7,10]), though only under hyperglycemia. Despite many positive pre-clinical studies on ARIs, most clinical trial outcomes have been disappointing. ...
... This was surprising because most AKR1B and AKR1C enzymes are inhibited by bile acids [44,45]. However, His269 in AKR1B14 (a lysine in AKR1B10 and in most AKR1Bs apart from AKR1B15, [7]) was identified as a key residue for activation. Since the molecular basis for activation in AKR1B14 is well defined, and the differences with AKR1B10 are minimal, it is possible to envisage that a focused library of bile acid derivatives could help find the specific AKR1B10 activators. ...
... Regarding NCAIs solved in complex to AKR1B10 holoenzyme (Table A1), fidarestat and sorbinil (Figure 1), both cyclic imide ARIs, display an almost identical binding to the two enzymes ( Figure 3A), not opening the SP but with a flipped Trp112. Next, we screened a library of synthetic polyhalogenated compounds lacking the usual CA or cyclic imide moieties (in collaboration with Biomar Microbial Technologies) and discovered JF0064, a pan-inhibitor against human AKR1B (in order of potency, inhibiting AKR1B15 > AR > AKR1B10 [7,11]) with a new anchoring moiety. We determined K i values and complexes with AR and AKR1B10 holoenzymes, identifying it as a non-competitive inhibitor where the acidic hydroxyl group is binding the ABP, again not opening the SP but with a flipped Trp112. ...
Human aldo-keto reductase 1B10 (AKR1B10) is overexpressed in many cancer types and is involved in chemoresistance. This makes AKR1B10 to be an interesting drug target and thus many enzyme inhibitors have been investigated. High-resolution crystallographic structures of AKR1B10 with various reversible inhibitors were deeply analyzed and compared to those of analogous complexes with aldose reductase (AR). In both enzymes, the active site included an anion-binding pocket and, in some cases, inhibitor binding caused the opening of a transient specificity pocket. Different structural conformers were revealed upon inhibitor binding, emphasizing the importance of the highly variable loops, which participate in the transient opening of additional binding subpockets. Two key differences between AKR1B10 and AR were observed regarding the role of external loops in inhibitor binding. The first corresponded to the alternative conformation of Trp112 (Trp111 in AR). The second difference dealt with loop A mobility, which defined a larger and more loosely packed subpocket in AKR1B10. From this analysis, the general features that a selective AKR1B10 inhibitor should comply with are the following: an anchoring moiety to the anion-binding pocket, keeping Trp112 in its native conformation (AKR1B10-like), and not opening the specificity pocket in AR.
... AKR1B1, AKR1B10, and an enzymatically active isoform of AKR1B15 are 36-kDa soluble monomeric proteins consisting of 316 amino acids and sharing >68% amino acid sequence identity, of which 91.5% are shared between AKR1B10 and AKR1B15 [2,3]. The three AKRs are NADPH-dependent reductases and display overlapping substrate specificities for aromatic and aliphatic aldehydes but differ in their catalytic efficiencies [2][3][4][5][6], which is notably higher for retinal (all-trans-retinaldehyde) in AKR1B10 [5]. In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 [2,4,5], and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 [7]. ...
... AKR1B1, AKR1B10, and an enzymatically active isoform of AKR1B15 are 36-kDa soluble monomeric proteins consisting of 316 amino acids and sharing >68% amino acid sequence identity, of which 91.5% are shared between AKR1B10 and AKR1B15 [2,3]. The three AKRs are NADPH-dependent reductases and display overlapping substrate specificities for aromatic and aliphatic aldehydes but differ in their catalytic efficiencies [2][3][4][5][6], which is notably higher for retinal (all-trans-retinaldehyde) in AKR1B10 [5]. In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 [2,4,5], and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 [7]. ...
... The three AKRs are NADPH-dependent reductases and display overlapping substrate specificities for aromatic and aliphatic aldehydes but differ in their catalytic efficiencies [2][3][4][5][6], which is notably higher for retinal (all-trans-retinaldehyde) in AKR1B10 [5]. In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 [2,4,5], and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 [7]. ...
AKR1B10 is a human nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase belonging to the aldo-keto reductase (AKR) 1B subfamily. It catalyzes the reduction of aldehydes, some ketones and quinones, and interacts with acetyl-CoA carboxylase and heat shock protein 90α. The enzyme is highly expressed in epithelial cells of the stomach and intestine, but down-regulated in gastrointestinal cancers and inflammatory bowel diseases. In contrast, AKR1B10 expression is low in other tissues, where the enzyme is upregulated in cancers, as well as in non-alcoholic fatty liver disease and several skin diseases. In addition, the enzyme’s expression is elevated in cancer cells resistant to clinical anti-cancer drugs. Thus, growing evidence supports AKR1B10 as a potential target for diagnosing and treating these diseases. Herein, we reviewed the literature on the roles of AKR1B10 in a healthy gastrointestinal tract, the development and progression of cancers and acquired chemoresistance, in addition to its gene regulation, functions, and inhibitors.
... Most genes in this cluster are involved in cell energy production and metabolic regulations, suggesting the pivotal roles of metabolic reprogramming in CSC feature maintenance. Out of the 11 genes, 5 have known roles in cancer initiation and progression, i.e., the regulatory role of SH3YL1 together with DOCK4 on breast carcinoma cell migration [36], the early prognostic value of ATP6V1C2 for colorectal cancers [37], the promotive functionalities of PRKAR2B on EMT and oncogenic role in prostate cancers [38,39], the association of MYO5B with gastric cancers [40,41], and the physiological role of AKR1B15 and its involvement in cancer development [42]. Among the rest six members in the cluster, FAT2 encodes a cadherin family member and is aliased as FAT tumor suppressor homolog 2, MYO5C encodes a member of the same family with MYO5B that has already been implicated in cancers, ATP6V1B1, ATP6V1C2, and ATP2C2 encode ATPase subunits, and FA2H encodes fatty acid 2-hydroxylase, where the association between FA2H and cancers has been recently reported [6]. ...
Background
Breast carcinomas are heterogeneous diseases with distinct clinical outcomes and cancer stem cell (CSC) percentages. Exploring breast carcinoma stem cell landscape could help understand the heterogeneity of such cancers with profound clinical relevance.
Methods
We conducted transcriptional profiling of CSCs and non-stem cancer cells isolated from three triple-negative breast carcinoma cell lines, analyzed the CSC transcriptome landscape that drives breast carcinoma heterogeneity through differentially expressed gene identification, gene ontology (GO) and pathway enrichment analyses as well as network construction, and experimentally validated the network hub gene.
Results
We identified a CSC feature panel consisting of 122 and 381 over-represented and under-expressed genes capable of differentiating breast carcinoma subtypes. We also underpinned the prominent roles of the PI3K-AKT pathway in empowering carcinoma cells with uncontrolled proliferative and migrative abilities that ultimately foster cancer stemness, and revealed the potential promotive roles of ATP6V1B1 on breast carcinoma stemness through functional in vitro studies.
Conclusions
Our study contributes in identifying a CSC feature panel for breast carcinomas that drives breast carcinoma heterogeneity at the transcriptional level, which provides a reservoir for diagnostic marker and/or therapeutic target identification once experimentally validated as demonstrated by ATP6V1B1.
... Most genes in this cluster are involved in cell energy production and metabolic regulations, suggesting the pivotal roles of metabolic reprogramming in CSC feature maintenance. Out of the 11 genes, 5 have known roles in cancer initiation and progression, i.e., SH3YL1 together with DOCK4 regulate breast cancer cell migration [35], ATP6V1C2 is an early prognostic marker for colorectal cancers [36], PRKAR2B promotes EMT and is oncogenic in prostate cancers [37,38], MYO5B is associated with gastric cancers [39,40], and the physiological role of AKR1B15 and its involvement in cancer development has been characterized in [41]. Among the rest 6 members in the cluster, FAT2 encodes a cadherin family member and is aliased as FAT tumor suppressor homolog 2, MYO5C encodes a member of the same family with MYO5B that has already been implicated in cancers, ATP6V1B1, ATP6V1C2 and ATP2C2 encode ATPase subunits, and FA2H encodes fatty acid 2hydroxylase, where the association between FA2H and cancers has been recently reported [15]. ...
Background
Breast cancers are heterogeneous diseases with distinct clinical outcomes and cancer stem cell percentages. Exploring breast cancer stem cell landscape could help understand the heterogeneity of such cancers with profound clinical relevance.Methods
We conducted transcriptional profiling of cancer stem cells and non-cancer stem cells isolated from 3 triple negative breast cancer cell lines, analyzed the cancer stem cell transcriptome landscape that drives breast cancer heterogeneity through differential expressed gene analysis, gene ontology and pathway enrichment as well as network construction, and performed experimental validations on the network hub gene.ResultsWe identified a cancer stem cell feature panel consisting of 122 and 381 over-represented and under-expressed genes capable of differentiating breast cancer subtypes. We also underpin the prominent roles of the PI3K-AKT pathway in empowering cancer cells with uncontrolled proliferative and migrative abilities that ultimately foster cancer stemness, and reveal the potential promotive roles of ATP6V1B1 on breast tumor stemness through functional in vitro studies. Conclusions
Our study contributes in identifying a cancer stem cell feature panel for breast tumors that drives breast cancer heterogeneity at the transcriptional level, which provides a reservoir for diagnostic marker and/or therapeutic target identification once experimentally validated as demonstrated by ATP6V1B1 .
... A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, which exhibits high sequence identity with human aldo-keto reductase (AKR1B1) is identified as a biomarker of lung cancer [17]. Human aldoketo reductase 1B15 (AKR1B15), a newly discovered enzyme j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 7 ( 2 0 1 9 ) 7 9 3 e8 0 4 that shares 92% amino acid sequence identity with AKR1B10 also showed higher catalytic activity than AKR1B10 [18]. We searched the targets of the three diseases from OMIM, TTD, DisGeNET and DrugBank, and got 89 targets relative with bronchitis, 105 targets relative with pneumonia and 161 targets relative with influenza. ...
Jinzhen oral liquid (JZ) is a classical traditional Chinese medicine formula used for the treatment of children lung disease. However, the effective substance of JZ is still unclear. In this study, we used lung injury rat model to study the protective effect of JZ, through UPLC-Q-TOF/MS detection coupled with metabolic research and network pharmacology analysis. Fortunately, 31 absorbed prototype constituents and 41 metabolites were identified or tentatively characterized based on UPLC-Q-TOF/MS analysis, and the possible metabolic pathways were hydroxylation, sulfation and glucuronidation. We optimized the data screening in the early stage of network pharmacology by collecting targets based on adsorbed constituents, and further analyzed the main biological processes and pathways. 24 selected core targets were frequently involved in reactive oxygen species metabolic process, dopaminergic synapse pathway and so on, which might play important roles in the mechanisms of JZ for the treatment of lung injury. Overall, the absorbed constituents and their possible metabolic pathways, as well as the absorbed constituent-target-disease network provided insights into the mechanisms of JZ for the treatment of lung injury. Further studies are needed to validate the biological processes and effect pathways of JZ. Keywords: Metabolic research, TCM, Network pharmacology
... The use of enzyme inhibitors has been proposed as a good therapeutic strategy to treat diseases associated to the action of AKR1B1, and the aforementioned recent findings have renewed the interest for AKR1B1 as a target. Since AKR1B1 and other members of the AKR superfamily, such as AKR1B10 and AKR1B15, have a very similar active-site topology, selective inhibitors are needed to discriminate between them [4,[6][7][8][9][10]. Noteworthy, almost all AKR1B1 inhibitors (ARIs) possess a negatively charged group, e.g, the carboxylic acid function of the acetic acid class of inhibitors, or the imide group of hydantoins and their isosteres. ...
... substitutedquinoline-4-carboxylic acids (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). ...
Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Kiappvs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs.
