AKR1D1 aldo-keto reductase family 1 member D1 [Homo sapiens (human)] - Gene

Summary

Official Symbol: AKR1D1provided by HGNC
Official Full Name: aldo-keto reductase family 1 member D1provided by HGNC
Primary source: HGNC:HGNC:388
See related: Ensembl:ENSG00000122787 MIM:604741; Vega:OTTHUMG00000155787
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CBAS2; SRD5B1; 3o5bred
Summary: The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]
Expression: Restricted expression toward liver (RPKM 96.8) See more
Orthologs: mouse all

Genomic context

Location:: 7q33

Exon count:: 9

Annotation release	Status	Assembly	Chr	Location
109	current	GRCh38.p12 (GCF_000001405.38)	7	NC_000007.14 (138076432..138118304)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	7	NC_000007.13 (137761178..137803050)

Chromosome 7 - NC_000007.14 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Jun 15 11:32:44 2016

Bibliography

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

infant proved to be a compound heterozygote of the AKR1D1 variants c.579+2delT and c.853C>T(p.Q285X), two novel mutations originated from his mother and father, respectively
Title: [Clinical feature and genetic analysis of a family affected by congenital bile acid synthesis defect type 2: identification of 2 novel mutations in AKR1D1 gene].
Impaired NADPH binding and hydride transfer is the molecular basis for bile acid deficiency in patients with the P133R mutation in AKR1D1.
Title: In-Depth Dissection of the P133R Mutation in Steroid 5β-Reductase (AKR1D1): A Molecular Basis of Bile Acid Deficiency.
When different steroid substrates were used in single turnover experiments with AKR1D1.
Title: The rate-determining steps of aldo-keto reductases (AKRs), a study on human steroid 5β-reductase (AKR1D1).
AKR1D1 generates all 5beta-dihydrosteroids in the C19-C27 steroid series.
Title: 5β-Reduced steroids and human Δ(4)-3-ketosteroid 5β-reductase (AKR1D1).
Despite having high kchem values with steroid hormones, the kinetic control of AKR1D1 is consistent with the enzyme catalysing the slowest step in the catabolic sequence of steroid hormone transformation in the liver.
Title: Rate of steroid double-bond reduction catalysed by the human steroid 5β-reductase (AKR1D1) is sensitive to steroid structure: implications for steroid metabolism and bile acid synthesis.
Studies indicate that mutations in aldo-keto reductase family 1 (AKR1) enzymes AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.
Title: Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism.
Novel homozygous frameshift mutations in the AKR1D1 gene and in the SKIV2L gene were found in a family with severe infantile liver disease.
Title: A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease.
Consistent with AKR1D1's putative role as a driver of the P450 subnetwork, the AKR1D1 3'-UTR SNP was significantly associated with increased hepatic mRNA expression of multiple P450s
Title: Genetic variation in aldo-keto reductase 1D1 (AKR1D1) affects the expression and activity of multiple cytochrome P450s.
These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.
Title: Conversion of human steroid 5β-reductase (AKR1D1) into 3β-hydroxysteroid dehydrogenase by single point mutation E120H: example of perfect enzyme engineering.
all five mutations identified in patients with functional bile acid deficiency strongly affected AKR1D1 enzyme functionality and therefore may be causal for this disease
Title: The effect of disease associated point mutations on 5β-reductase (AKR1D1) enzyme function.

Submit: New GeneRIF Correction See all GeneRIFs (20)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Bile acid synthesis defect, congenital, 2 MedGen: C1856127 OMIM: 235555 GeneReviews: Not available	Compare labs

NHGRI GWAS Catalog

Description
An atlas of genetic influences on human blood metabolites. NHGRI GWA Catalog NHGRI GWA CatalogPubMed
Genome-wide association of mood-incongruent psychotic bipolar disorder. NHGRI GWA Catalog NHGRI GWA CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Pathways from BioSystems

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Bile acid and bile salt metabolism, organism-specific biosystem (from REACTOME)
Bile acid and bile salt metabolism, organism-specific biosystemIn a healthy adult human, about 500 mg of cholesterol is converted to bile salts daily. Newly synthesized bile salts are secreted into the bile and released into the small intestine where they emulsi...
Bile acid biosynthesis, cholesterol => cholate/chenodeoxycholate, organism-specific biosystem (from KEGG)
Bile acid biosynthesis, cholesterol => cholate/chenodeoxycholate, organism-specific biosystemPathway module; Carbohydrate and lipid metabolism; Sterol biosynthesis
Bile acid biosynthesis, cholesterol => cholate/chenodeoxycholate, conserved biosystem (from KEGG)
Bile acid biosynthesis, cholesterol => cholate/chenodeoxycholate, conserved biosystemPathway module; Carbohydrate and lipid metabolism; Sterol biosynthesis
Metabolic pathways, organism-specific biosystem (from KEGG)
Metabolic pathways, organism-specific biosystem
Metabolic pathways
Metabolism, organism-specific biosystem (from REACTOME)
Metabolism, organism-specific biosystemMetabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as th...
Metabolism of lipids and lipoproteins, organism-specific biosystem (from REACTOME)
Metabolism of lipids and lipoproteins, organism-specific biosystemLipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphi...
Metapathway biotransformation, organism-specific biosystem (from WikiPathways)
Metapathway biotransformation, organism-specific biosystem
Metapathway biotransformation
Primary bile acid biosynthesis, organism-specific biosystem (from KEGG)
Primary bile acid biosynthesis, organism-specific biosystemBile acids are steroid carboxylic acids derived from cholesterol in vertebrates. The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver and conjugated with taurin...
Primary bile acid biosynthesis, conserved biosystem (from KEGG)
Primary bile acid biosynthesis, conserved biosystemBile acids are steroid carboxylic acids derived from cholesterol in vertebrates. The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver and conjugated with taurin...
Steroid hormone biosynthesis, organism-specific biosystem (from KEGG)
Steroid hormone biosynthesis, organism-specific biosystemSteroid hormones derived from cholesterol are a class of biologically active compounds in vertebrates. The cholesterol side-chain cleavage enzyme CYP11A1 catalyzes conversion of cholesterol, a C27 co...
Steroid hormone biosynthesis, conserved biosystem (from KEGG)
Steroid hormone biosynthesis, conserved biosystemSteroid hormones derived from cholesterol are a class of biologically active compounds in vertebrates. The cholesterol side-chain cleavage enzyme CYP11A1 catalyzes conversion of cholesterol, a C27 co...
Synthesis of bile acids and bile salts, organism-specific biosystem (from REACTOME)
Synthesis of bile acids and bile salts, organism-specific biosystemIn a healthy adult human, about 500 mg of cholesterol is converted to bile salts daily (Russell 2003). The major pathway for bile salt synthesis in the liver begins with the conversion of cholesterol...
Synthesis of bile acids and bile salts via 24-hydroxycholesterol, organism-specific biosystem (from REACTOME)
Synthesis of bile acids and bile salts via 24-hydroxycholesterol, organism-specific biosystemIn the body, 24-hydroxycholesterol is synthesized in the brain, exported to the liver, and converted there to bile acids and bile salts. This pathway is only a minor source of bile acids and bile sal...
Synthesis of bile acids and bile salts via 27-hydroxycholesterol, organism-specific biosystem (from REACTOME)
Synthesis of bile acids and bile salts via 27-hydroxycholesterol, organism-specific biosystemIn the body, 27-hydroxycholesterol is synthesized in multiple tissues, exported to the liver, and converted there to bile acids and bile salts. This pathway is only a minor source of bile acids and b...
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol, organism-specific biosystem (from REACTOME)
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol, organism-specific biosystemIn the liver, synthesis of bile acids and bile salts is initiated with the conversion of cholesterol to 7alpha-hydroxycholesterol and of 7alpha-hydroxycholesterol to 4-cholesten-7alpha-ol-3-one. The ...
bile acid biosynthesis, neutral pathway, organism-specific biosystem (from BIOCYC)
bile acid biosynthesis, neutral pathway, organism-specific biosystemGeneral Background The biosynthesis of bile acids is a major route of : CHOLESTEROL catabolism. It converts the hydrophobic, insoluble : CHOLESTEROL molecule into soluble bile acids. Accumulation ...

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

NoName (e-PCR)
- UniSTS:481825

D8S2279 (e-PCR)
- UniSTS:473907

SHGC-35425 (e-PCR)
- UniSTS:41341

NoName (e-PCR)
- UniSTS:486834

NoName (e-PCR)
- UniSTS:482513

Homology

Homologs of the AKR1D1 gene: The AKR1D1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and frog.
Orthologs from Annotation Pipeline: 193 organisms have orthologs with human gene AKR1D1
The Hierarchical Catalog of Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
alcohol dehydrogenase (NADP+) activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
alditol:NADP+ 1-oxidoreductase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
aldo-keto reductase (NADP) activity	TAS Traceable Author Statement more info
delta4-3-oxosteroid 5beta-reductase activity	IEA Inferred from Electronic Annotation more info
ketosteroid monooxygenase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
oxidoreductase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
steroid binding	TAS Traceable Author Statement more info	PubMed
steroid dehydrogenase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed

Process	Evidence Code	Pubs
C21-steroid hormone metabolic process	IDA Inferred from Direct Assay more info	PubMed
androgen metabolic process	IBA Inferred from Biological aspect of Ancestor more info	PubMed
androgen metabolic process	IDA Inferred from Direct Assay more info	PubMed
bile acid biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
bile acid biosynthetic process	TAS Traceable Author Statement more info
bile acid catabolic process	IEA Inferred from Electronic Annotation more info
cholesterol catabolic process	IDA Inferred from Direct Assay more info	PubMed
digestion	IDA Inferred from Direct Assay more info	PubMed
oxidation-reduction process	IDA Inferred from Direct Assay more info	PubMed
steroid metabolic process	IBA Inferred from Biological aspect of Ancestor more info	PubMed

Component	Evidence Code	Pubs
cytosol	IDA Inferred from Direct Assay more info	PubMed
cytosol	TAS Traceable Author Statement more info

General protein information

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Preferred Names: 3-oxo-5-beta-steroid 4-dehydrogenase

Names: delta(4)-3-ketosteroid 5-beta-reductase; delta(4)-3-oxosteroid 5-beta-reductase; steroid-5-beta-reductase, beta polypeptide 1 (3-oxo-5 beta-steroid delta 4-dehydrogenase beta 1)

NP_001177835.1

EC 1.3.1.3

NP_001177836.1

EC 1.3.1.3

NP_005980.1

EC 1.3.1.3

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_023342.1 RefSeqGene

Range

5001..46873

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001190906.1 → NP_001177835.1 3-oxo-5-beta-steroid 4-dehydrogenase isoform 2

See identical proteins and their annotated locations for NP_001177835.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (2) has the same N- and C-termini but is shorter compared to isoform 1.

Source sequence(s)

AC083867, AK298421, AK298428

Consensus CDS

CCDS55170.1

UniProtKB/Swiss-Prot

P51857

Related

ENSP00000402374.2, OTTHUMP00000208643, ENST00000411726.6, OTTHUMT00000341636

Conserved Domains (1) summary

COG0656
Location:9 → 268

ARA1; Aldo/keto reductase, related to diketogulonate reductase [Secondary metabolites biosynthesis, transport and catabolism]
NM_001190907.1 → NP_001177836.1 3-oxo-5-beta-steroid 4-dehydrogenase isoform 3

See identical proteins and their annotated locations for NP_001177836.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate exon compared to variant 1, that causes a frameshift. The resulting isoform (3) has a shorter and distinct C-terminus compared to isoform 1.

Source sequence(s)

AC083867, AK298421

Consensus CDS

CCDS55169.1

UniProtKB/Swiss-Prot

P51857

Related

ENSP00000389197.1, OTTHUMP00000208645, ENST00000432161.5, OTTHUMT00000341643

Conserved Domains (1) summary

COG0656
Location:9 → 288

ARA1; Aldo/keto reductase, related to diketogulonate reductase [Secondary metabolites biosynthesis, transport and catabolism]
NM_005989.3 → NP_005980.1 3-oxo-5-beta-steroid 4-dehydrogenase isoform 1

See identical proteins and their annotated locations for NP_005980.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).

Source sequence(s)

AC083867, AK298421, Z28339

Consensus CDS

CCDS5846.1

UniProtKB/Swiss-Prot

P51857

Related

ENSP00000242375.3, OTTHUMP00000208644, ENST00000242375.7, OTTHUMT00000341637

Conserved Domains (1) summary

COG0656
Location:9 → 309

ARA1; Aldo/keto reductase, related to diketogulonate reductase [Secondary metabolites biosynthesis, transport and catabolism]