AKR1C4 Human
Description
Overview of AKR1C4 Human
AKR1C4 (aldo-keto reductase family 1 member C4) is a liver-specific enzyme encoded by the AKR1C4 gene located on chromosome 10p15.1 . It belongs to the aldo-keto reductase (AKR) superfamily and functions as a 3α-hydroxysteroid dehydrogenase (3α-HSD1), catalyzing the reduction of ketosteroids to hydroxysteroids using NADPH as a cofactor . Its primary roles include:
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Bile acid biosynthesis: AKR1C4 collaborates with AKR1D1 to produce 5β-dihydrosteroids, a critical step in bile acid synthesis .
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Steroid hormone metabolism: Converts neurosteroids (e.g., allopregnanolone) and regulates hormones like testosterone and progesterone .
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Detoxification: Reduces toxic compounds, such as the pesticide chlordecone, to less harmful metabolites .
Catalytic Roles in Steroid Metabolism
AKR1C4 mediates NADPH-dependent reductions at specific positions of steroid molecules:
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3α-reduction: Converts 5α-androstane-3α,17β-diol to 5α-androstane-3α,17β-diol (3α-diol) and vice versa .
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5β-reduction: Partners with AKR1D1 to reduce Δ⁴-3-ketosteroids (e.g., cholesterol derivatives) into 5β-dihydrosteroids, a precursor for bile acids .
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Progesterone metabolism: Reduces progesterone to 20α-hydroxyprogesterone, modulating reproductive hormone signaling .
Disease Associations
Therapeutic Targeting
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Cancer Therapy: Inhibitors targeting AKR1C4 are under investigation for prostate cancer (PCa) and breast cancer, where AKR1C enzymes drive hormone-dependent growth .
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Detoxification: AKR1C4’s role in reducing chlordecone highlights its potential in mitigating pesticide toxicity .
Comparative Analysis of AKR1C Isoforms
| Isoform | Primary Function | Tissue Expression | Key Substrates |
|---|---|---|---|
| AKR1C1 | 20α-hydroxyprogesterone synthesis | Breast, endometrium, liver | Progesterone, aldehydes |
| AKR1C2 | 3α-reduction of DHT to 3α-diol | Mammary gland, liver | 5α-DHT, bile acids |
| AKR1C3 | Testosterone/estradiol biosynthesis | Prostate, breast, liver | Δ⁴-androstene-3,17-dione |
| AKR1C4 | 5β-reduction, bile acid synthesis | Liver-specific | Cholesterol, chlordecone |
Research Challenges and Future Directions
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Tissue-Specific Inhibition: Designing inhibitors that target AKR1C4 without affecting other AKR1C isoforms remains challenging due to high sequence homology .
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Population-Specific Variants: Rare AKR1C4 variants (e.g., rs182498797) show ancestry-specific effects on puberty timing, necessitating diverse cohort studies .
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Non-Catalytic Roles: Emerging evidence suggests AKR1C4 may regulate transcription factors (e.g., AR) independent of enzymatic activity, warranting further investigation .
Key References
Product Specs
Aldo-keto reductase family 1 member C4, also known as AKR1C4, belongs to the aldo/keto reductase superfamily, which comprises over 40 proteins and enzymes. This enzyme plays a crucial role in catalyzing the conversion of aldehydes and ketones into their respective alcohols using NADH and/or NADPH as cofactors. In the liver, AKR1C4 is involved in the bioreduction of chlordecone, a harmful organochlorine pesticide, converting it into chlordecone alcohol.
Recombinant human AKR1C4, produced in E. coli, is a single, non-glycosylated polypeptide chain consisting of 323 amino acids (1-323aa). It has a molecular weight of 37kDa.
The AKR1C4 protein solution is supplied at a concentration of 1mg/ml and is formulated in a buffer containing 20mM Tris-HCl (pH 8.5), 0.1M NaCl, 10% glycerol, and 1mM DTT.
The purity of the protein is determined to be greater than 90.0% using SDS-PAGE analysis.
The enzyme exhibits a specific activity exceeding 700pmol/min/ug. This activity is determined by measuring the rate at which 1.0 picomole of 1-Acenaphthenol is oxidized per minute in the presence of NADP at a pH of 8.8 and a temperature of 25°C.
Aldo-keto reductase family 1 member C4 (chlordecone reductase 3-alpha hydroxysteroid dehydrogenase type I dihydrodiol dehydrogenase 4), 3-alpha-hydroxysteroid dehydrogenase type I, MGC22581, HAKRA, 3 alpha-hydroxysteroid dehydrogenase/dihydrodiol dehydrogenase 4, CDR, DD4, CHDR, 3-alpha-HSD1, C11.
MDPKYQRVEL NDGHFMPVLG FGTYAPPEVP RNRAVEVTKL AIEAGFRHID SAYLYNNEEQ VGLAIRSKIA DGSVKREDIF YTSKLWCTFF QPQMVQPALE SSLKKLQLDY VDLYLLHFPM ALKPGETPLP KDENGKVIFD TVDLSATWEV MEKCKDAGLA KSIGVSNFNC RQLEMILNKP GLKYKPVCNQ VECHPYLNQS KLLDFCKSKD IVLVAHSALG TQRHKLWVDP NSPVLLEDPV LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIREN IQVFEFQLTS EDMKVLDGLN RNYRYVVMDF LMDHPDYPFS DEY.
Q&A
What is AKR1C4 and what is its primary function in human physiology?
AKR1C4 is one of four human enzymes in the aldo-keto reductase family 1C subfamily (AKR1C1-AKR1C4). These enzymes share high amino acid sequence identity (84-98%) and catalyze NADPH-dependent reductions of various substrates . The primary function of AKR1C4 in human physiology is metabolizing steroid hormones through its activity as a hydroxysteroid dehydrogenase. It catalyzes NADPH-dependent reductions at the C3, C5, C17, and C20 positions on the steroid nucleus and side-chain, thus playing essential roles in steroid hormone homeostasis .
AKR1C4 efficiently catalyzes the reduction of 5α-pregnane-3,20-dione to yield 3α-hydroxy-5α-pregnan-20-one (allopregnanolone), which is a precursor of androsterone . Through these enzymatic activities, AKR1C4 contributes to the regulation of steroid hormone levels and activity in the body.
Where is AKR1C4 primarily expressed in humans, and how does this differ from other AKR1C family members?
Unlike other members of the AKR1C subfamily that are expressed in various tissues, AKR1C4 is predominantly liver-specific . This distinct tissue-specific expression pattern highlights its specialized role in hepatic metabolism, particularly in steroid hormone processing in the liver.
The other AKR1C isoforms (AKR1C1-AKR1C3) have broader tissue distribution patterns, which contributes to their involvement in diverse physiological processes throughout the body. The liver-specific expression of AKR1C4 makes it uniquely positioned to participate in first-pass metabolism of steroid hormones and potentially other substrates as they pass through the liver.
What is the genomic location and structure of the AKR1C4 gene?
The AKR1C4 gene is located on chromosome 10p15-p14 in humans . It is part of a gene cluster that includes all four AKR1C family members (AKR1C1-AKR1C4). The gene comprises 12 exons, which is consistent with the structure of other AKR1C genes .
The protein encoded by AKR1C4 has an average molecular weight of approximately 34-42 kDa . The close chromosomal proximity of all AKR1C genes suggests they likely arose through gene duplication events during evolution, which explains their high sequence similarity and related functions in steroid hormone metabolism.
What is the role of AKR1C4 in age at menarche, particularly in populations of African ancestry?
A trans-ethnic meta-analysis of age at menarche (AAM) identified a novel association with AKR1C4, particularly in populations of African ancestry . The lead variant (rs182498797) in AKR1C4 was significantly associated with age at menarche (P = 1.7 × 10^-8) specifically in African-ancestry studies . This variant has a minor allele frequency (MAF) of approximately 1% in African-ancestry populations but is extremely rare in European ancestry women (MAF = 4 × 10^-6) and monomorphic (invariant) in East and South Asian populations .
The association was replicated in an independent sample of African-ancestry women, with meta-analysis results showing a beta of 0.51 and P = 3.2 × 10^-9 . This discovery highlights the importance of conducting genetic studies in diverse populations, as this AKR1C4 variant would likely have been missed in studies restricted to European or Asian populations.
The biological plausibility for AKR1C4's role in puberty timing stems from its function in steroid hormone metabolism. By metabolizing various steroid hormones, AKR1C4 could influence the hormonal milieu that triggers puberty onset. Notably, quantitative trait loci (QTL) for pig reproductive traits, including age of puberty, have been identified on pig chromosome 10q near a region homologous to human chromosome 10p15, which contains the AKR gene cluster .
How do catalytic-dependent and catalytic-independent functions of AKR1C4 differ in cellular biology?
The functions of AKR1C4 can be classified into catalytic-dependent and catalytic-independent roles, each contributing to different aspects of cellular biology.
Catalytic-dependent functions primarily involve AKR1C4's enzymatic activity as a hydroxysteroid dehydrogenase. These include:
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NADPH-dependent reduction of steroid hormones at specific positions (C3, C5, C17, and C20)
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Contribution to steroid hormone homeostasis and intermediary metabolism
Catalytic-independent functions of AKR1C isoforms have been increasingly recognized, though most studies have focused on other family members rather than AKR1C4 specifically. The search results mention that AKR1C isoforms can function as:
The paper specifies that "accumulating clues showed that catalytic-independent functions also played critical roles in regulating biological events" . While AKR1C4-specific catalytic-independent functions require further investigation, its structural similarities with other AKR1C family members suggest it might share some of these non-enzymatic roles.
What are the implications of AKR1C4 variants in disorders of steroid hormone metabolism?
AKR1C4 variants have been implicated in several disorders related to steroid hormone metabolism. The search results highlight several associations:
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Reproductive timing disorders: An AKR1C4 variant (rs182498797) is associated with age at menarche in African-ancestry populations, suggesting a role in puberty timing regulation .
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Mood disorders: AKR1C4 has been linked to manic/hypomanic irritability in males, potentially through its role in neurosteroid metabolism . Specifically, it efficiently catalyzes the formation of allopregnanolone, which has known effects on mood regulation through GABA receptor modulation.
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Metabolic parameters: AKR1C4 genetic variants have been associated with blood metabolite ratios, triglycerides levels, and hemoglobin levels in various genome-wide association studies .
The mechanisms behind these associations likely involve AKR1C4's role in steroid hormone metabolism. By altering the balance of active steroid hormones, AKR1C4 variants could influence various physiological processes that depend on precise hormonal regulation.
The products of AKR activity have been implicated in various conditions including prostate disease, breast cancer, obesity, polycystic ovary disease, and delayed onset of puberty in humans . While not all of these conditions have been directly linked to AKR1C4 specifically, the enzyme's role in steroid metabolism suggests potential involvement in a range of hormone-dependent disorders.
How does AKR1C4 genetic variation contribute to inter-individual differences in steroid hormone metabolism?
Genetic variation in AKR1C4 can significantly influence steroid hormone metabolism, contributing to inter-individual differences in hormone levels and potentially disease susceptibility. The search results provide several examples of AKR1C4 genetic variants with functional consequences:
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Population-specific variants: The rs182498797 variant in AKR1C4 is primarily found in individuals of African ancestry (MAF~1%) but is extremely rare in European ancestry populations (MAF = 4 × 10^-6) and absent in East and South Asian populations . This population specificity highlights the importance of studying diverse populations to capture the full spectrum of AKR1C4 genetic variation.
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Functional effects on steroid metabolism: Different AKR1C4 variants may alter enzyme activity, substrate specificity, or expression levels, leading to changes in steroid hormone metabolism. While the specific functional effects of most AKR1C4 variants remain to be characterized, their associations with phenotypes like age at menarche suggest functional consequences for steroid hormone regulation .
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Broader metabolic implications: AKR1C4 variants have been associated with triglyceride levels and blood metabolite ratios , suggesting that genetic variation in this enzyme may have broader metabolic consequences beyond steroid hormone metabolism alone.
The research on AKR1C4 genetic variation underscores the complex relationship between genotype and phenotype in steroid hormone metabolism. Given AKR1C4's role in metabolizing multiple steroid hormones, variants in this gene could potentially influence numerous hormone-dependent processes throughout the body.
What associations exist between AKR1C4 and other physiological parameters?
Beyond its role in steroid hormone metabolism, AKR1C4 has been associated with several other physiological parameters:
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Triglyceride levels: Genetic variants in AKR1C4 have been reported to be associated with triglyceride levels in European-ancestry and trans-ethnic genome-wide association studies . This suggests a potential role for AKR1C4 in lipid metabolism, though the precise mechanisms remain to be elucidated.
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Hemoglobin levels: AKR1C4 has been associated with hemoglobin levels in genomic studies . This unexpected association might reflect complex interactions between steroid hormone metabolism and erythropoiesis.
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Blood metabolite ratios: AKR1C4 variants have been linked to blood metabolite ratios , highlighting its potential involvement in broader metabolic pathways beyond steroid hormone metabolism.
These diverse associations suggest that AKR1C4 may have pleiotropic effects on multiple physiological systems. Given its liver-specific expression and role in metabolism, AKR1C4 could influence various metabolic pathways that converge in the liver, explaining its associations with parameters like triglycerides and blood metabolites.
The table below summarizes key studies involving AKR1C4 in diverse populations:
Product Science Overview
Aldo-Keto Reductase Family 1 Member C4, also known as AKR1C4, is a member of the aldo-keto reductase superfamily. This superfamily consists of more than 40 known enzymes and proteins that catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors . AKR1C4 is a protein-coding gene that plays a significant role in various biochemical pathways, including the metabolism of steroid hormones and bile acids .
The AKR1C4 gene is located on chromosome 10p15-p14 and shares high sequence identity with three other gene members clustered in the same region . The gene encodes a protein that consists of 323 amino acids and has a molecular weight of approximately 37 kDa . The protein structure includes a conserved NADPH-binding domain, which is essential for its enzymatic activity .
AKR1C4 catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in the liver . This enzyme also exhibits 3-alpha-hydroxysteroid dehydrogenase activity, which is crucial for the metabolism of steroid hormones . Specifically, it transforms the potent natural androgen dihydrotestosterone into 5-alpha-androstan-3-alpha,17-beta-diol, a compound with much lower activity .
The enzymatic activities of AKR1C4 are vital for maintaining the balance of steroid hormones and bile acids in the body . It plays a role in the synthesis and clearance of testosterone, thereby influencing various physiological processes . Additionally, AKR1C4 is involved in the metabolism of xenobiotics, which are foreign compounds that enter the body .
Recombinant human AKR1C4 is widely used in research to study its enzymatic properties and potential therapeutic applications . Understanding the function and regulation of this enzyme can provide insights into the treatment of diseases related to steroid hormone imbalances and xenobiotic metabolism .
