Structure of a glutathione conjugate bound to the active site of aldose reductase

2006 ◽  
Vol 64 (1) ◽  
pp. 101-110 ◽  
Author(s):  
Ranvir Singh ◽  
Mark A. White ◽  
Kota V. Ramana ◽  
J. Mark Petrash ◽  
Stanley J. Watowich ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Active Site ◽  
Glutathione Conjugate

Kinetic and Spectroscopic Evidence for Active Site Inhibition of Human Aldose Reductase†,‡

Biochemistry ◽  
1996 ◽  
Vol 35 (34) ◽  
pp. 11196-11202 ◽  
Author(s):  
Takayuki Nakano ◽  
J. Mark Petrash
Keyword(s):  
Aldose Reductase ◽  
Active Site ◽  
Spectroscopic Evidence

scholarly journals Aldose Reductase Differential Inhibitors in Green Tea

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1003 ◽  
Author(s):  
Francesco Balestri ◽  
Giulio Poli ◽  
Carlotta Pineschi ◽  
Roberta Moschini ◽  
Mario Cappiello ◽  
...  
Keyword(s):  
Gallic Acid ◽  
Green Tea ◽  
Aldose Reductase ◽  
Active Site ◽  
Inhibitory Action ◽  
Computational Study ◽  
Epigallocatechin Gallate ◽  
Polyol Pathway ◽  
Differential Inhibition ◽  
Tea Extract

Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been proposed to counteract the damaging effects linked to the activity of the enzyme while preserving its detoxifying ability. Here, we show that epigallocatechin gallate (EGCG), one of the most representative catechins present in green tea, acts as a differential inhibitor of human recombinant AKR1B1. A kinetic analysis of EGCG, and of its components, gallic acid (GA) and epigallocatechin (EGC) as inhibitors of the reduction of L-idose, 4-hydroxy2,3-nonenal (HNE), and 3-glutathionyl l-4-dihydroxynonanal (GSHNE) revealed for the compounds a different model of inhibition toward the different substrates. While EGCG preferentially inhibited L-idose and GSHNE reduction with respect to HNE, gallic acid, which was still active in inhibiting the reduction of the sugar, was less active in inhibiting HNE and GSHNE reduction. EGC was found to be less efficient as an inhibitor of AKR1B1 and devoid of any differential inhibitory action. A computational study defined different interactive modes for the three substrates on the AKR1B1 active site and suggested a rationale for the observed differential inhibition. A chromatographic fractionation of an alcoholic green tea extract revealed that, besides EGCG and GA, other components may exhibit the differential inhibition of AKR1B1.

Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase

1997 ◽  
Vol 7 (14) ◽  
pp. 1897-1902 ◽  
Author(s):  
Giulio Rastelli ◽  
Paola Vianello ◽  
Daniela Barlocco ◽  
Luca Costantino ◽  
Antonella Del Corso ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Active Site

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

2020 ◽  
Vol 22 (99) ◽  
pp. 125-142
Author(s):  
Y. M. Makukh ◽  
T. M. Gryvul ◽  
A. Ya. Krasnevich ◽  
D. S. Vignan
Keyword(s):  
Aldose Reductase ◽  
Conformational Changes ◽  
Mechanism Of Action ◽  
Active Site ◽  
Mammalian Cells ◽  
Polyol Pathway ◽  
The Body ◽  
Biological Role ◽  
Binary Complex ◽  
Sorbitol Pathway

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.

Active site modification of aldose reductase by nitric oxide donors

1997 ◽  
Vol 1341 (2) ◽  
pp. 217-222 ◽  
Author(s):  
Animesh Chandra ◽  
Sanjay Srivastava ◽  
J.Mark Petrash ◽  
Aruni Bhatnagar ◽  
Satish K Srivastava
Keyword(s):  
Nitric Oxide ◽  
Aldose Reductase ◽  
Active Site ◽  
Nitric Oxide Donors

scholarly journals Charge-density analysis of human aldose reductase active site

2008 ◽  
Vol 64 (a1) ◽  
pp. C368-C368 ◽  
Author(s):  
B. Guillot ◽  
C. Jelsch ◽  
A. Podjarny ◽  
C. Lecomte
Keyword(s):  
Charge Density ◽  
Aldose Reductase ◽  
Active Site ◽  
Density Analysis

ChemInform Abstract: Structure-Based Design of an Inhibitor Modeled at the Substrate Active Site of Aldose Reductase.

ChemInform ◽  
2010 ◽  
Vol 28 (49) ◽  
pp. no-no
Author(s):  
G. RASTELLI ◽  
P. VIANELLO ◽  
D. BARLOCCO ◽  
L. COSTANTINO ◽  
A. DEL CORSO ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Active Site ◽  
Abstract Structure
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