AKR1D1

Last update 08 May 2025

Basic Info

Synonyms

3-oxo-5-beta-steroid 4-dehydrogenase, AKR1D1, aldo-keto reductase family 1 member D1

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Introduction

Catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. Capable of reducing a broad range of delta-(4)-3-ketosteroids from C18 (such as, 17beta-hydroxyestr-4-en-3-one) to C27 (such as, 7alpha-hydroxycholest-4-en-3-one).

100 Clinical Results associated with AKR1D1

100 Translational Medicine associated with AKR1D1

0 Patents (Medical) associated with AKR1D1

149

Literatures (Medical) associated with AKR1D1

01 Apr 2025·Toxicology Letters

Discovery of non-steroidal aldo-keto reductase 1D1 inhibitors through automated screening and in vitro evaluation

Article

Author: Kȩdzierski, Jacek ; Odermatt, Alex ; van Diest, Rianne E ; Allard, Julien A ; Smieško, Martin

Steroid hormones regulate a wide range of physiological processes in the human body. However, exposure to xenobiotics can disrupt the hormonal balance by inhibition of enzymes involved in hormone synthesis or metabolism. Aldo-keto reductase 1D1 (AKR1D1) plays a key role in bile acid and steroid hormone metabolism by catalyzing the reduction of the double bond between C4 and C5 atoms of Δ(4)-steroids. In our previous work, we developed a model to screen for steroid-like xenobiotics that inhibit AKR1D1. In the current study, we used this model to screen for novel non-steroidal inhibitors. By applying an automatized screening approach, based on molecular docking and scoring in combination with post-docking refinement, 45 compounds were detected as potential hits and selected for in vitro evaluation. Among them, zardaverine was identified as the most potent inhibitor, with an IC₅₀ value of 2.32 ± 1.27 μM. Other moderate inhibitors included carbamazepine, larotrectinib, endosulfan II, megastigmatrienone A, and mizolastine. The structural diversity of the identified inhibitors demonstrates that the binding site of AKR1D1 is rather promiscuous and can accommodate a broad range of ligands. These findings underscore the importance of toxicity screening and potential to identify structurally different AKR1D1 inhibitors.

01 Mar 2025·Acta Pharmaceutica

Cloning, expression, and purification of recombinant AKR1D1 for therapeutic applications

Article

Author: Nestorovska, Aleksandra Kapedanovska ; Shutevska, Kristina

AbstractAKR1D1, a key enzyme in the aldo-keto reductase superfamily, plays a dual role in both steroid metabolism and bile acid synthesis by catalyzing the NADPH-dependent reduction of carbon-carbon double bonds, specifically converting 3-ketosteroid hormones into 5β-steroids. Positioned at the critical intersection of steroid hormone and bile acid metabolism, AKR1D1 has the potential to profoundly influence metabolic homeostasis and drug metabolism. Despite its importance, the enzyme’s therapeutic implications and role in drug metabolism remain underexplored. This study presents an optimized methodology for the cloning, expression, and purification of AKR1D1 using an Escherichia coli expression system. We identified optimal conditions for ligation and precise DNA sequencing, emphasizing the need for lower DNA concentrations and higher purity. Protein expression was evaluated in E. coli strains BL21 and Rosetta, with the highest yields achieved under extended incubation at 25 °C with controlled IPTG concentrations. Using freshly transformed cells was essential for maintaining consistent protein expression. The enzyme’s activity was confirmed using a spectrofluorometric assay, demonstrating efficient reduction of testosterone to 5β-DHT. This optimized methodology facilitates the production of AKR1D1 with high specific activity, establishing a valuable platform for future research. It enables a deeper investigation into AKR1D1’s contributions to drug metabolism and its therapeutic potential.

01 Feb 2025·Cell Metabolism

AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity

Article

Author: Chen, Liang ; He, Qiwei ; Zhong, Xiuying ; Li, Zhikun ; Yan, Ronghui ; Cao, Jie ; Wong, Chun-Ming ; Shen, Shengqi ; Yu, Yingxuan ; Suo, Caixia ; Bian, Zhenhua ; Gu, Xuemei ; Zhang, Tong ; Gao, Ping ; Jia, Weidong ; Dong, Zhongjun ; Wei, Haoran ; Yang, Zhiyi ; Yan, Kai ; Zhang, Huafeng ; Lin, Kashuai ; Zhu, Chuxu ; Liu, Rui ; Sun, Linchong ; He, Junming

Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of Bacteroidetes ovatus (B. ovatus), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by B. ovatus might be a promising strategy to activate NK cell cytotoxicity to treat HCC.

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AKR1D1

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