AKR1B - Aldo-keto reductase family 1 member B|Elisa - Clia - Antibody - Protein

Background

The aldo-keto reductase (AKR) superfamily comprises enzymes that play critical roles in the reduction of aldehydes and ketones to their respective alcohols. AKR1B is a subfamily within this larger group, which includes enzymes that are essential for the metabolism of sugars, steroids, prostaglandins, and other molecules. These enzymes are involved in various physiological processes, including detoxification of reactive aldehydes, regulation of osmotic stress, and drug metabolism. The AKR1B subfamily is particularly significant due to its involvement in the polyol pathway, which is crucial in the development of diabetic complications.

Protein Structure

AKR1B enzymes, like other members of the AKR superfamily, possess a conserved (β/α)_8-barrel structure. This characteristic fold consists of eight parallel beta-strands surrounded by eight alpha-helices. The structure creates a deep, hydrophobic binding pocket for substrates and cofactors. Key structural features of AKR1B enzymes include:

1. NADPH Binding Site: The AKR1B enzymes utilize NADPH as a cofactor. The NADPH binding site is highly conserved, and it is essential for the catalytic reduction of substrates. The binding involves several amino acid residues that facilitate the correct positioning and stabilization of NADPH.
2. Catalytic Site: The active site of AKR1B enzymes contains critical residues such as tyrosine, lysine, and histidine, which are involved in proton transfer during the reduction process. These residues ensure the proper orientation and activation of the substrate for catalysis.
3. Substrate Specificity: The substrate-binding pocket is flexible, allowing the enzyme to accommodate a variety of aldehyde and ketone substrates. This flexibility is partly due to the presence of mobile loop regions that adjust to fit different substrate sizes and shapes.

Classification and Subtypes

The AKR1B subfamily includes several members, each with specific substrate preferences and tissue distributions. Notable members of this subfamily include:

1. AKR1B1 (Aldose Reductase): This enzyme is widely studied and is primarily involved in the reduction of glucose to sorbitol in the polyol pathway. AKR1B1 is expressed in various tissues, including the lens, retina, kidneys, and nerves, and is implicated in diabetic complications such as neuropathy, retinopathy, and nephropathy.
2. AKR1B10 (Aldo-Keto Reductase Family 1 Member B10): This enzyme is involved in the detoxification of reactive aldehydes and the metabolism of isoprenoid-derived compounds. AKR1B10 is highly expressed in the liver and intestines and has been linked to the development and progression of certain cancers, including hepatocellular carcinoma and colorectal cancer.

Function and Biological Significance

AKR1B enzymes are multifunctional and participate in various physiological and pathological processes:

1. Polyol Pathway: AKR1B1 catalyzes the reduction of glucose to sorbitol, the first step in the polyol pathway. This pathway is especially active under hyperglycemic conditions and contributes to the osmotic and oxidative stress associated with diabetic complications. Excessive accumulation of sorbitol can lead to cellular damage in tissues such as the retina, kidney, and peripheral nerves.
2. Detoxification: AKR1B enzymes play a vital role in detoxifying reactive aldehydes generated from lipid peroxidation and other metabolic processes. By reducing these toxic aldehydes to less reactive alcohols, AKR1B enzymes help maintain cellular redox balance and protect against oxidative stress.
3. Cancer Metabolism: AKR1B10 is involved in the metabolism of lipid-derived reactive aldehydes and has been implicated in cancer biology. It is upregulated in several types of cancer and contributes to the proliferation, survival, and chemoresistance of cancer cells. AKR1B10’s role in detoxifying reactive aldehydes may protect cancer cells from oxidative damage, promoting tumor growth and progression.
4. Drug Metabolism: AKR1B enzymes also metabolize various pharmacologically active compounds. They can influence the pharmacokinetics and pharmacodynamics of drugs, potentially impacting their efficacy and toxicity. This role is particularly relevant in the context of cancer chemotherapy and the development of drug resistance.

Clinical Issues

Abnormal expression or activity of AKR1B enzymes is associated with several clinical conditions:

1. Diabetic Complications: AKR1B1 is a key enzyme in the polyol pathway, and its overactivity under hyperglycemic conditions leads to the accumulation of sorbitol, contributing to diabetic complications such as neuropathy, retinopathy, and nephropathy. Inhibitors of AKR1B1 are being developed as potential therapeutic agents to prevent or mitigate these complications.
2. Cancer: Overexpression of AKR1B10 is observed in various cancers, including liver, colorectal, and lung cancers. This overexpression is associated with poor prognosis and resistance to chemotherapy. AKR1B10’s role in detoxifying reactive aldehydes and modulating lipid metabolism makes it a potential target for cancer therapy.
3. Inflammatory Diseases: AKR1B enzymes are implicated in inflammatory responses. By modulating the levels of reactive aldehydes and prostaglandins, these enzymes can influence inflammation and immune responses. Dysregulation of AKR1B activity may contribute to chronic inflammatory conditions.
4. Drug Resistance: Changes in AKR1B enzyme activity can affect the metabolism and efficacy of drugs. In cancer, upregulation of AKR1B10 can contribute to resistance to chemotherapeutic agents by detoxifying reactive aldehydes and other cytotoxic compounds.

Summary

The AKR1B subfamily of enzymes plays a critical role in various metabolic pathways, including the polyol pathway, detoxification of reactive aldehydes, and drug metabolism. Their structural features, such as the conserved (β/α)_8-barrel fold and flexible substrate-binding pocket, enable them to interact with a wide range of substrates. The biological significance of AKR1B enzymes is underscored by their involvement in diabetic complications, cancer metabolism, and inflammatory diseases. Clinical issues related to abnormal AKR1B activity highlight the therapeutic potential of targeting these enzymes in disease treatment. Ongoing research into the regulation, function, and inhibition of AKR1B enzymes holds promise for developing novel therapeutic strategies for managing diabetes, cancer, and other conditions associated with oxidative stress and metabolic dysregulation.