Tolrestat acts atypically as a competitive inhibitor of the thermostable aldo‐keto reductase Tm1743 from <i>Thermotoga maritima</i>

Zhang, Chenyun; Min, Zhenzhen; Liu, Xuemeng; Wang, Chao; Wang, Zhiguo; Shen, Jiabing; Tang, Wanrong; Zhang, Xin; Liú, Dan; Xu, Xiaoling

doi:10.1002/1873-3468.13630

Cited by 7 publications

(7 citation statements)

References 52 publications

(78 reference statements)

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“…The gene of a multipoint mutant was subjected to site-directed mutagenesis multiple times based on one-point mutation. We selected multiple mutation sites away from the active site (NADP + ) and the active site of AKR, including 110 (Y), 114, 143 (Y), 162 (Q), and 189 (Q) (N-terminal) of pZE21-akr . We selected three mutation sites (114Y–143Y–189Q) and five mutation sites (110Y–114Y–143Y–162Q–189Q) as the number of different mutations of the akr gene and named them akr three-point mutant gene and akr five-point mutant gene.…”

Section: Methodsmentioning

confidence: 99%

Rapidly and Precisely Cross-Linked Enzymes Using Bio-Orthogonal Chemistry from Cell Lysate for the Synthesis of (S)-1-(2,6-Dichloro-3-fluorophenyl) Ethanol

Wang

et al. 2020

ACS Sustainable Chem. Eng.

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To develop a method for preparing rapidly, precisely, and bio-orthogonally cross-linked enzymes (RP-CLEs), nonstandard amino acids (NSAAs) were inserted into the enzyme protein, and microwave irradiation was used to accelerate its site-specific linkage through Cu-free strain-promoted alkyne–azide cycloaddition (SPAAC). To this end, we selected aldehyde ketone reductase (AKR) as model enzyme, and AKR mutants were obtained by five-point insertion of p-azido-l-phenylalanine (pAzF) which were subsequently cross-linked to form RP-CLEs from cell lysate supernatant under microwave irradiation. The AKR five-point mutant and corresponding RP-CLEs were characterized using MALDI-TOF MS, SEM, and FT-IR, respectively. The specific activities of RP-CLEs of three-point and five-point AKR were 1.27 and 2.06 U·mg–1, 1.21- and 2.16-fold those of the corresponding free enzymes, respectively. In the asymmetric synthesis of (S)-1-(2,6-dichloro-3-fluorophenyl) ethanol, the yield was up to 90.8%, and the ee was 99.98%. Moreover, after 6 consecutive 12 h reaction cycles, AKR five-point RP-CLEs still retained 80% of their initial activity. Thus, depending on the enzyme structure analysis, different numbers of NSAAs could be reasonably incorporated into the protein to accurately guide and control the covalent linkage to form RP-CLEs. This green method could be further developed both to generate bio-orthogonally cross-linked enzyme and separate them from nontarget proteins for industrial biocatalysis.

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Section: Methodsmentioning

confidence: 99%

Rapidly and Precisely Cross-Linked Enzymes Using Bio-Orthogonal Chemistry from Cell Lysate for the Synthesis of (S)-1-(2,6-Dichloro-3-fluorophenyl) Ethanol

Wang

et al. 2020

ACS Sustainable Chem. Eng.

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“…From the results obtained, it can be seen that the docking score of the interaction between the AKR1B10 protein and the test ligand tetraprenyltoluquinone is smaller than the native ligand. The native ligand used in this protein, tolrestat, was revealed as a potent inhibitor of AKR1B10 n vitro and in vivo [27], [28]. The Gibbs free energy (G), which represents the strength of the binding between the test ligand and the protein, is used to calculate the docking score.…”

Section: Resultsmentioning

confidence: 99%

Tetraprenyltoluquinone Inhibits the Tumor Marker Aldo-Keto Reductase: An in Silico Study

Hefni¹,

Dachriyanus²,

Susanti³

et al. 2022

Int. J. Adv. Sci. Eng. Inf. Technol.

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Cancer is one of the most common causes of death in the globe. The development of new cancer medicines and the identification of new therapeutic targets is still a pressing necessity. The protein AKR1B10 was discovered to be a valuable biomarker for the diagnosis and prognosis of some malignancies. Over expression of the AKR1B10 gene is found in lung cancer, oral squamous cell carcinoma, breast cancer, cholangiocarcinoma, pancreatic cancer and liver cancer. AKR1B10 is implicated in detoxification, retinoic acid metabolism, and lipid synthesis, among other pathological actions. AKR1B10 is known to be carcinogenic and can be utilized as a tumor marker, according to research. The tetraprenyltoluquinone compound is an isolate from the bark of kandis (Garcinia cowa, Roxb) which has been reported to have anticancer activity in vivo and in vitro and has the potential to be developed as an anticancer drug derived from natural ingredients. This study aims to determine the activity of the tetraprenyltoluquinone compound in silico with the target of the AKR1B10 protein. The method used is molecular docking using PLANTS (Protein Ligand ANT System) for protein visualization and preparation and Ligplus program for visualizing amino acids. The docking score results showed that the AKR1B10 protein interaction with the test ligand tetraprenyltoluquinone is lower than the native ligand, which means the binding energy of tetraprenyltoluquinone to the AKR1B10 (PDB ID: 1ZUA) protein was higher than the native ligand tolrestat. These results indicate that tetraprenyltoluquinone is a potential inhibitor of the AKR1B10 protein in the pathway of cancer.

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“…The AKR superfamily of NADP(H)-dependent aldehyde and ketone reductases has already been explored extensively as drug targets in pharmaceutical and clinical trials. For example, AKR inhibitors, such as tolrestat and epalrestat, were developed to target AKR1B1 for treating type two diabetes complications [37]. AKR1B1 inhibitors may be promising pharmacological agents that prevent cataracts in diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

AKR1B1-Induced Epithelial–Mesenchymal Transition Mediated by RAGE-Oxidative Stress in Diabetic Cataract Lens

Chen

Chang

et al. 2020

Antioxidants

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Purpose: Cataracts are a major cause of visual acuity deterioration in diabetes mellitus (DM) in developed and developing countries. Studies have demonstrated that overproduction of AKR1B1 and receptor for advanced glycation end products (RAGE) plays a major role in the pathogenesis of diabetic cataracts, but it is unclear whether the prevalence of diabetic cataracts is related to epithelial–mesenchymal transition (EMT) in lens epithelial cells. This study aimed to analyze the role of EMT in cataract formation of DM patients. Methods: Immunofluorescence and immunohistochemistry assays were used to estimate AKR1B1, RAGE, AMPK, and EMT levels in epithelial human lens of DM or non-DM cataracts. Results: Immunohistochemical staining demonstrated that pathologic phases and N-cadherin expression levels were significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Immunofluorescent staining showed that AKR1B1 and RAGE were significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Interestingly, acetyl superoxide dismutase 2 (AcSOD2) levels were significantly higher in DM patients’ lens epithelial cells (LECs), whereas AMPKT172 phosphorylation was significantly increased in non-DM patients. This indicates that AMPKT172 might be related to superoxide reduction and diabetic cataract formation. Conclusions: Our results suggest that AKR1B1 overexpression can decrease AMPK activation, thereby increasing AcSOD2 and RAGE-induced EMT in epithelial human lens of DM cataracts. These novel findings suggest that AKR inhibitors may be candidates for the pharmacological prevention of cataracts in patients with DM.

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Tolrestat acts atypically as a competitive inhibitor of the thermostable aldo‐keto reductase Tm1743 from Thermotoga maritima

Cited by 7 publications

References 52 publications

Rapidly and Precisely Cross-Linked Enzymes Using Bio-Orthogonal Chemistry from Cell Lysate for the Synthesis of (S)-1-(2,6-Dichloro-3-fluorophenyl) Ethanol

Rapidly and Precisely Cross-Linked Enzymes Using Bio-Orthogonal Chemistry from Cell Lysate for the Synthesis of (S)-1-(2,6-Dichloro-3-fluorophenyl) Ethanol

Tetraprenyltoluquinone Inhibits the Tumor Marker Aldo-Keto Reductase: An in Silico Study

AKR1B1-Induced Epithelial–Mesenchymal Transition Mediated by RAGE-Oxidative Stress in Diabetic Cataract Lens

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