AKR1C- Aldo-keto reductase family 1 member C | Elisa - Clia - Antibody - Protein

Background

The aldo-keto reductase (AKR) superfamily encompasses enzymes that catalyze the reduction of aldehydes and ketones to their corresponding alcohols. The AKR1C subfamily, part of this larger group, consists of enzymes that play essential roles in steroid metabolism, prostaglandin synthesis, and the detoxification of reactive aldehydes and ketones. These enzymes are ubiquitously expressed across various tissues and are involved in multiple physiological processes, including hormone regulation, detoxification, and cellular redox balance.

Protein Structure

AKR1C enzymes share a conserved structure typical of the AKR superfamily. They are characterized by a beta-alpha-beta fold, which forms a central beta-sheet surrounded by alpha-helices. This configuration creates a large, deep, and hydrophobic active site suitable for binding a wide range of substrates. The key features of the AKR1C enzyme structure include:

1. NAD(P)H Binding Site: AKR1C enzymes require NADH or NADPH as a cofactor for their reductase activity. The binding site for these cofactors is highly conserved and involves several residues that facilitate the correct positioning of the nicotinamide ring for hydride transfer.
2. Substrate Binding Pocket: The active site pocket can accommodate a variety of substrates, including steroids, prostaglandins, and xenobiotic compounds. The plasticity of this pocket is achieved through a flexible loop region that adjusts to the shape and size of the substrate.
3. Catalytic Residues: Typically, the AKR1C active site includes key residues such as tyrosine, histidine, and lysine, which are crucial for the catalytic reduction process. These residues facilitate the transfer of hydride ions from NADPH/NADH to the substrate.

Classification and Subtypes

The AKR1C subfamily includes several members, each with specific substrate preferences and physiological roles. The primary members of the AKR1C subfamily include:

1. AKR1C1 (20α-Hydroxysteroid Dehydrogenase): Involved in the metabolism of progesterone and other steroids, converting them into their inactive forms.
2. AKR1C2 (3α-Hydroxysteroid Dehydrogenase Type 3): Plays a role in androgen metabolism, converting dihydrotestosterone (DHT) to 3α-androstanediol.
3. AKR1C3 (17β-Hydroxysteroid Dehydrogenase Type 5): Functions in the metabolism of androgens and estrogens, and is also involved in prostaglandin synthesis.
4. AKR1C4 (3α-Hydroxysteroid Dehydrogenase Type 4): Predominantly expressed in the liver, where it participates in bile acid synthesis and steroid metabolism.

Function and Biological Significance

AKR1C enzymes are multifunctional proteins with roles extending across various biological pathways:

1. Steroid Metabolism: AKR1C enzymes are critical in the interconversion of active and inactive steroid hormones. For example, AKR1C2 converts potent androgens like DHT into less active forms, thereby regulating androgenic activity in tissues.
2. Prostaglandin Metabolism: AKR1C3 is involved in the reduction of prostaglandin D2 (PGD2) to 9α,11β-PGF2, a crucial step in prostaglandin metabolism. This activity influences inflammatory responses and other physiological processes mediated by prostaglandins.
3. Detoxification: AKR1C enzymes help in detoxifying reactive aldehydes and ketones produced during oxidative stress. By reducing these reactive compounds to less harmful alcohols, AKR1C enzymes protect cells from damage and maintain redox homeostasis.
4. Drug Metabolism: AKR1C enzymes also play a role in the metabolism of various drugs and xenobiotics. They can reduce ketone-containing drugs, influencing their pharmacokinetics and activity.

Clinical Issues

Dysregulation or genetic variations in AKR1C enzymes are linked to several diseases and clinical conditions:

1. Cancer: Overexpression of AKR1C3 is observed in various cancers, including prostate, breast, and endometrial cancers. AKR1C3’s role in androgen and estrogen metabolism contributes to the proliferation and survival of hormone-dependent tumors.
2. Endocrine Disorders: Mutations or abnormal expression of AKR1C enzymes can lead to disorders of steroid metabolism, affecting reproductive health and endocrine function.
3. Inflammation: Given their role in prostaglandin metabolism, AKR1C enzymes are implicated in inflammatory diseases. Aberrant prostaglandin levels due to altered AKR1C activity can exacerbate inflammatory responses.
4. Drug Resistance: Changes in AKR1C enzyme activity can influence the efficacy and metabolism of drugs, leading to drug resistance. This is particularly relevant in cancer treatment, where AKR1C3 can affect the metabolism of chemotherapeutic agents.

Summary

The AKR1C subfamily of enzymes is crucial for maintaining physiological balance through their roles in steroid metabolism, prostaglandin synthesis, and detoxification. Their structural features enable them to interact with a wide range of substrates, reflecting their diverse biological functions. The clinical significance of AKR1C enzymes is underscored by their involvement in cancer, endocrine disorders, inflammation, and drug resistance. Understanding the molecular mechanisms and regulatory pathways of AKR1C enzymes can offer insights into novel therapeutic strategies for treating related diseases and conditions. Continued research in this field holds promise for advancing our knowledge of these versatile enzymes and their impact on human health.