New Insights into the Catalytic Mechanism of Aldose Reductase: A QM/MM Study

Dréanic, Marie-Pierre; Edge, C.; Tuttle, Tell

doi:10.1021/acsomega.7b00815

Cited by 13 publications

(16 citation statements)

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“…The reaction mechanism and the roles of the catalytic tetrad in the AKRs (Asp42, Tyr47, Lys76, His109) have been dissected in detail using crystal structures of numerous apo and holo forms in combination with biochemical and kinetic data from substitution mutants and computational studies involving docking and QM/MM calculations [1,2,23,27,31,[44][45][46][47][48][49][50][51][52][53]. The observed geometry of nonbonded interactions between the enzyme and the adduct is consistent with the general mechanism for erythrose reduction by DnXR (Fig.…”

Section: Substrate-binding Site and Catalytic Mechanismmentioning

confidence: 71%

“…In the absence of relevant complexes, numerous studies of AKRs have utilized molecular modeling of substrates into the putative active sites of holo forms to establish the enzyme–substrate interactions and explain key features, including the enzyme mechanism, substrate specificity, and active site plasticity of the AKRs . In the Dn XR complex, DTT is bound in the substrate‐binding pocket in an orientation expected for a four‐carbon open chain sugar alcohol, reminiscent of a product‐bound form (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

2018

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Aldose reductases (ARs) belonging to the aldo‐keto reductase (AKR) superfamily catalyze the conversion of carbonyl substrates into their respective alcohols. Here we report the crystal structures of the yeast Debaryomyces nepalensis xylose reductase (DnXR, AKR2B10) in the apo form and as a ternary complex with a novel NADP‐DTT adduct. Xylose reductase, a key enzyme in the conversion of xylose to xylitol, has several industrial applications. The enzyme displayed the highest catalytic efficiency for l‐threose (138 ± 7 mm−1·s−1) followed by d‐erythrose (30 ± 3 mm−1·s−1). The crystal structure of the complex reveals a covalent linkage between the C4N atom of the nicotinamide ring of the cosubstrate and the S1 sulfur atom of DTT and provides the first structural evidence for a protein mediated NADP–low‐molecular‐mass thiol adduct. We hypothesize that the formation of the adduct is facilitated by an in‐crystallo Michael addition of the DTT thiolate to the specific conformation of bound NADPH in the active site of DnXR. The interactions between DTT, a four‐carbon sugar alcohol analog, and the enzyme are representative of a near‐cognate product ternary complex and provide significant insights into the structural basis of aldose binding and specificity and the catalytic mechanism of ARs. Database Structural data are available in the PDB under the accession numbers http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZCI and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZCM.

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Section: Substrate-binding Site and Catalytic Mechanismmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

2018

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“…Природа донорів протону є важливою для розуміння механізму каталізу. Методами квантової і молекулярної механіки встановлено, що в активному центрі ензиму є три амінокислотні залишки, віддаль яких до Оксигену карбонільного групи субстрату дозволяє розглядати їх як потенційних донорів протону, зокрема: Tyr-48, His-110 і Cys-298 (Siu et al, 1993;Tarle et al, 1993;Bohren et al, 1994;Lee et al, 1998;Varnai et al, 1999;Cachau et al, 2000;Varnai & Warshel, 2000;Dreanic et al, 2000;Petrash, 2004).…”

Section: рис 2 схема впорядкованого механізму дії алрunclassified

“…Але й вони не дали однозначної відповіді щодо донора протонів. Більшість дослідників вважає ймовірним донором протону Tyr-48 (Wilson et al, 1992;Tarle et al, 1993;Bohren et al, 1994;Varnai & Warshel, 2000;Dreanic et al, 2000), інші дослідники -His-110 (Siu et al, 1993;Lee et al, 1998;Varnai et a1., 1999;Cachau et al, 2000). Крім того, деякі автори вважають, що відсутність єдиної відповіді зумовлена комбінованим ефектом трьох амінокислот Lys-77, Tyr-48, His-110.…”

Section: рис 2 схема впорядкованого механізму дії алрunclassified

Aldosereductase: structure, mechanism of action, biological role and functioning according to normo and hyperglycemia

et al. 2020

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The review summarizes the literature on the structure, biological role and mechanism of action of aldose reductase at different blood glucose levels. Aldosereductase is the first enzyme of the sorbitol (polyol) pathway to glucose metabolism. In mammals, it is a monomeric protein with a molecular weight of 32–56 kDa, has 347–370 amino acid remainders. Its secondary structure consists of α-helices and β-bends, which alternate in 8 units. The active site of the enzyme is located at the C-terminus of the β-bend and contains a glutathione-binding domain. The active site of aldose reductase consists of two sites: substrate-binding and catalytic. The first is formed mainly by the residues of hydrophilic amino acids, and the second, by hydrophobic ones. The interaction of the enzyme with a coenzyme causes conformational changes in aldose reductase. It is believed that the enzyme functions according to the principle of an ordered “bi-bi” mechanism, that is, the coenzyme binds first, and the oxidized product is released last. The reduction of aldehydes of aldose reductase includes several stages: the interaction of the enzyme with NADPH and the formation of a binary complex, the acceptance of the substrate and the formation of a ternary complex (enzyme-coenzyme-substrate) and the separation of the alcohol-reaction product and the oxidized coenzyme. According to normoglycemia in mammalian cells via the sorbitol pathway, up to 1–3 % of intracellular glucose is restored. Under these conditions, it reduces the content of toxic and reactive aldehydes such as: 4-hydroxy-trans-2-nonenal, malondialdehyde, glyoxal, acrolein and their conjugates with reduced glutathione and carnosine, which are also toxic. Before being excreted from the body, they are reduced by aldose reductase to non-toxic compounds. Thus, the enzyme is one of the components of the body's antioxidant system. Hyperglycemia, which is most pronounced in diabetes, significantly increases the flow of glucose through the sorbitol pathway. The activation of aldosereductase and sorbitol dehydrogenase causes the use of a significant amount of NADPH, which leads to a decrease in antioxidant protection, and the excessive formation of NADH leads to a violation of the ratio of reduced and oxidized forms, known as “pseudohypoxia”. Metabolites of the sorbitol pathway, which are formed in excessive amounts, get toxic effects on metabolism and cellular structures, in particular: sorbitol, as an osmotically active component, causes lens edema, leads to the formation of cataracts, and fructose, fructose-phosphate and 3-deoxyglucasone underlie the pathogenesis of secondary diabetic complications.

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“…Studies have been carried out which shows that the effects drugs have hydrophilic and hydrophobic groups (one or two aromatic groups); hydrophilic groups bind to the His110 or Tyr 48 of the anion binding pocket which hinders the proton transfer to the carbonyl group whereas the hydrophobic groups bind to the specific pocket. Moreover, inhibitors specific to ALR2 interact with C-terminal residues that are not conserved in the homologous aldehyde reductase (ALR1) [30].…”

Section: Docking Analysis Of Alpha-glucosidase With Secondary Metabolmentioning

confidence: 99%

In-Silico Analysis of Natural Products That Modulates Enzymes of Diabetic Target

Aryal¹,

Basnet²,

Marasini³

et al. 2020

Preprint

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Metabolic enzymes are often targeted for drug development programs of metabolic diseases such as diabetes and its complications. Many secondary metabolites isolated from natural products have shown therapeutic action against these enzymes. However, some commercially available synthetic drugs have shown unfriendly impacts with various side effects. Thus, this research has focused on a comprehensive study of secondary metabolites showing better inhibitory activities towards metabolic enzymes such as α-amylase, α-glucosidase, aldose reductase, and lipase. Further receptor-based virtual screening was performed against the various secondary metabolites database designed in-silico. Using Gold combined with subsequent post-docking analyses, the score was obtained as methyl xestospongic ester (Gold score 65.83), 2,″4″-O-diacetylquercitrin (Gold score 65.15), kaempferol-3-O-neohesperidoside (Gold score 53.37) and isosalvianolic acid C methyl ester (Gold score 53.44) for lipase, aldol reductase, α-amylase, and α-glucosidase, respectively. Besides, vitexin and isovitexin for α-amylase; N-trans-Caffeoyl-tyramin for α-glucosidase; purpurolide F and schaftoside for lipase; acteoside and orientin for aldose reductase could be potential drugs for respective enzymes based on in-silico analyses, supported by experimental IC50 values reported. They could bind to the competitive sites of the various targets of metabolic enzymes, and finally, toxicity analysis using ProTox-II was also performed.

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New Insights into the Catalytic Mechanism of Aldose Reductase: A QM/MM Study

Cited by 13 publications

References 51 publications

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis

Aldosereductase: structure, mechanism of action, biological role and functioning according to normo and hyperglycemia

In-Silico Analysis of Natural Products That Modulates Enzymes of Diabetic Target

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