AKR1D- Aldo-keto reductase family 1 member D | Elisa - Clia - Antibody - Protein

Background:

AKR1D1, or Aldo-keto reductase family 1 member D1, is an enzyme that plays a crucial role in steroid metabolism. Specifically, it is involved in the conversion of bile acids from cholesterol. Bile acids are essential for the digestion and absorption of fats in the intestine. AKR1D1 catalyzes the NADPH-dependent reduction of Δ4-3-oxo steroids, including cortisol, cortisone, and testosterone, to their respective 3β-hydroxy steroids. This enzyme also converts 7α-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one, an important intermediate in bile acid synthesis. Mutations or deficiencies in AKR1D1 can lead to bile acid deficiency syndromes, which are characterized by impaired synthesis of bile acids, leading to liver and metabolic problems. Deficiencies in AKR1D1 can also result in accumulation of toxic intermediates, causing liver damage.

Protein Structure:

• Domains: AKR1D1 has a typical (α/β)8-barrel structure, characteristic of the aldo-keto reductase family.
• Active Site: Contains a conserved catalytic tetrad (Tyr, Lys, His, Asp), which is crucial for its enzymatic activity.
• NADP(H) Binding Site: Like other AKR family members, AKR1D1 binds NADP(H) as a cofactor necessary for its reductase activity.
• Isoforms: AKR1D1 is a specific isoform within the AKR1 subfamily, with its unique substrate specificity and functional roles.

Classification and Subtypes:

• Family: Aldo-keto reductase (AKR) superfamily.
• Subfamily: AKR1, which includes several members with diverse functions in metabolism.
• AKR1D1: Specifically known as Δ^4-3-oxosteroid 5β-reductase, reflecting its role in steroid and bile acid metabolism.

Function and Biological Significance:

• Steroid Metabolism: AKR1D1 reduces Δ^4-3-ketosteroids, an essential step in the metabolism of steroids. This reduction is critical for the inactivation and clearance of steroid hormones.
• Bile Acid Metabolism: Plays a vital role in the conversion of 7α-hydroxycholest-4-en-3-one to 3α,7α-dihydroxy-5β-cholestan-24-oic acid, a key step in bile acid biosynthesis.
• Detoxification: By participating in the metabolism of steroids and bile acids, AKR1D1 helps detoxify these compounds, preventing their accumulation and potential toxicity.
• Hormone Regulation: Through its role in steroid metabolism, AKR1D1 indirectly influences hormone levels and activity, impacting various physiological processes.

Interactions:

• Cofactors: Binds to NADP(H), which is essential for its enzymatic activity.
• Substrates: Specifically reduces Δ^4-3-oxosteroids and other related compounds.
• Protein-Protein Interactions: May interact with other enzymes and proteins involved in steroid and bile acid metabolism, influencing metabolic pathways.

Clinical Issues:

• Bile Acid Metabolism Disorders: Mutations or deficiencies in AKR1D1 can lead to disorders of bile acid metabolism, resulting in conditions such as congenital bile acid synthesis defect type 2.
• Steroid Metabolism Disorders: Impairments in AKR1D1 activity can disrupt steroid hormone metabolism, potentially leading to hormonal imbalances and related disorders.
• Liver Diseases: Given its role in bile acid metabolism, AKR1D1 dysfunction can contribute to liver diseases, including cholestasis and liver fibrosis.
• Cancer: Abnormal expression or activity of AKR1D1 has been implicated in certain cancers, where it may influence tumor progression and drug metabolism.

Summary:

Aldo-keto reductase family 1 member D (AKR1D1) is an enzyme integral to the metabolism of steroids and bile acids. With a conserved (α/β)8-barrel structure and a catalytic tetrad, AKR1D1 functions to reduce Δ^4-3-oxosteroids, facilitating the proper metabolism and detoxification of these compounds. It plays critical roles in maintaining hormonal balance and bile acid homeostasis. Clinical implications of AKR1D1 include bile acid metabolism disorders, liver diseases, and potential roles in cancer progression. Understanding and targeting AKR1D1 can provide insights into therapeutic approaches for related metabolic and liver disorders.