Aldose reductase

Related Reading

Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway of sugar metabolism. In addition to catalyzing the reduction of glucose to sorbitol, it can also catalyze the reduction of aldehydes and their derivatives produced by a large number of lipid peroxidation reactions. Recent studies have shown that, in addition to its role in diabetes complications, AR also plays an important role in many inflammatory diseases, such as atherosclerosis, sepsis, asthma, and uveitis. When inflammation occurs, the presence of AR can promote the expression of pro-inflammatory factors such as iNOS, CD86, etc., and further concentrate the inflammatory response. At the same time, it also regulates the function of the immune system after tissue damage. In addition, AR is overexpressed in human tumors such as lung cancer, colon cancer, lung cancer, cervical cancer, and ovarian cancer, suggesting that AR may play a role in the pathological process of the above-mentioned cancers.

Introductions

Aldose reductase (AR) is a member of the aldose reductase superfamily (aldo-keto reductase, AKR). It is an important rate-limiting enzyme in the glucose metabolism polyol pathway. It reduces glucose to sorbitol and finally produce fructose. In 1956, Holcomb et al. first isolated aldose reductase from seminal vesicles and placental tissues. It is the only catalytic enzyme that reduces aldose to polyol.

Structure

In the research on AR, many researchers cloned genes similar to AR from a variety of biological cells, and then conducted detailed studies on their gene origin, biological evolution, and functional classification. Currently, AR in the aldone reductase superfamily is considered to be the prototypical enzyme of the aldone reductase superfamily. The enzyme has 315 amino acid residues, folded into a β/α-loop structure with a catalytically active binding site, and the nucleic acid cofactor binds to an extended conformation at the top of the β/α structure.

Figure 1. Protein structure of aldose reductase.

Functions

• Pro-inflammatory effect

Most of the research on AR focuses on its role in the development of diabetes. Recent studies have found that when subjected to external inflammatory stimuli, the expression of AR will be significantly up-regulated, affecting the inflammatory response process

• Participate in oxidative stress

Oxidative stress is a potential pathogenic factor of some diseases. Reactive oxygen species are considered to be the basis of oxidative changes in many diseases, and activate PKC and redox-sensitive transcription factors such as NF-κB and AP-1. In diabetic patients, AR expression is up-regulated, exacerbating oxidative stress.

• Participate in sugar metabolism

The polyol pathway involved in AR is another metabolic pathway in the body's sugar metabolism. AR catalyzes the conversion of NADPH-dependent glucose to sorbitol, which is the first step in the polyol pathway of sugar metabolism, and sorbitol dehydrogenase catalyzes NAD-dependent sorbitol to fructose.

• Activated protein kinase C

Many studies have shown that AR acts on some kinase signaling pathways including PKC. The activation of DAG-PKC is considered to be a key signaling pathway in the pathological process of diabetic complications.

Conclusions

With the deepening of research on aldose reductase, it has been found that AR plays an important role in diabetic complications and inflammatory response, and participates in the regulation of multiple signaling pathways in the body, especially inflammatory response. The activation of AR promotes the activity of NF-κB, an important transcription factor in the inflammatory response, and aggravates the inflammatory response. When ARI is used or the AR gene is knocked out, the process of inflammatory response is obviously alleviated. Therefore, in-depth research on the mechanism of action of AR molecules, especially the continuous clarification of the mechanism of action in the inflammatory response, will surely help the development of ARI for clinical treatment applications to provide more and more effective anti-inflammatory methods.

References

1. Wilson DK.; et al. An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications. Science, 1992,257(5066): 81－84.
2. Ramana KV.; et al. Aldose reductase: A novel therapeutic target for inflammatory pathologies. Int J Biochem Cell Biol. 2010，42(1): 17－20.