Description: Homo sapiens aldo-keto reductase family 1, member C4 (AKR1C4), mRNA. RefSeq Summary (NM_001818): This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]. Transcript (Including UTRs) Position: hg19 chr10:5,238,798-5,260,910 Size: 22,113 Total Exon Count: 9 Strand: + Coding Region Position: hg19 chr10:5,238,831-5,260,723 Size: 21,893 Coding Exon Count: 9
ID:AK1C4_HUMAN DESCRIPTION: RecName: Full=Aldo-keto reductase family 1 member C4; EC=1.1.1.-; AltName: Full=3-alpha-HSD1; AltName: Full=3-alpha-hydroxysteroid dehydrogenase type I; EC=1.1.1.50; AltName: Full=Chlordecone reductase; Short=CDR; EC=1.1.1.225; AltName: Full=Dihydrodiol dehydrogenase 4; Short=DD-4; Short=DD4; AltName: Full=HAKRA; FUNCTION: Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha- androstan-3-alpha,17-beta-diol (3-alpha-diol). Also has some 20- alpha-hydroxysteroid dehydrogenase activity. The biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leads to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route. CATALYTIC ACTIVITY: Chlordecone alcohol + NADP(+) = chlordecone + NADPH. CATALYTIC ACTIVITY: Androsterone + NAD(P)(+) = 5-alpha-androstane- 3,17-dione + NAD(P)H. SUBUNIT: Monomer. SUBCELLULAR LOCATION: Cytoplasm. TISSUE SPECIFICITY: Liver specific. PTM: The N-terminus is blocked. POLYMORPHISM: The allele with Cys-145/Val-311 shows a three- to five-fold decrease in catalytic efficiency for xenobiotic and steroidal substrates compared to the Ser-145/Leu-311 allele. DISEASE: Defects in AKR1C4 are a cause of 46,XY sex reversal type 8 (SRXY8) [MIM:614279]. A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. Note=AKR1C4 mutations may act as modifier of disease severity in SRXY8 patients. A splicing mutation resulting in loss of exon 2 has been found in affected individuals also carrying mutation Val-79 in AKR1C2 (PubMed:21802064). SIMILARITY: Belongs to the aldo/keto reductase family. SEQUENCE CAUTION: Sequence=AAA35658.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): AKR1C4 CDC HuGE Published Literature: AKR1C4 Positive Disease Associations: Cholesterol, LDL Related Studies:
Cholesterol, LDL Sekar Kathiresan et al. BMC medical genetics 2007, A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study., BMC medical genetics.
[PubMed 17903299]
Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
MalaCards Disease Associations
MalaCards Gene Search: AKR1C4 Diseases sorted by gene-association score: 46xy sex reversal 8* (424) * = Manually curated disease association
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P17516
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Mouse
Rat
Zebrafish
D. melanogaster
C. elegans
S. cerevisiae
No ortholog
No ortholog
No ortholog
No ortholog
No ortholog
No ortholog
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0001758 retinal dehydrogenase activity GO:0004033 aldo-keto reductase (NADP) activity GO:0009055 electron carrier activity GO:0015125 bile acid transmembrane transporter activity GO:0016491 oxidoreductase activity GO:0016655 oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor GO:0047023 androsterone dehydrogenase activity GO:0047743 chlordecone reductase activity
Biological Process: GO:0001523 retinoid metabolic process GO:0006699 bile acid biosynthetic process GO:0008202 steroid metabolic process GO:0008209 androgen metabolic process GO:0015721 bile acid and bile salt transport GO:0022900 electron transport chain GO:0044597 daunorubicin metabolic process GO:0044598 doxorubicin metabolic process GO:0055114 oxidation-reduction process GO:0071395 cellular response to jasmonic acid stimulus
AK314988 - Homo sapiens cDNA, FLJ95910. LP747419 - Sequence 6 from Patent WO2018009939. BC020744 - Homo sapiens aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehydrogenase 4), mRNA (cDNA clone MGC:22581 IMAGE:4734943), complete cds. S68287 - chlordecone reductase {clone HAKRa} [human, liver, mRNA, 1167 nt]. CU676682 - Synthetic construct Homo sapiens gateway clone IMAGE:100022237 5' read AKR1C4 mRNA. KJ896595 - Synthetic construct Homo sapiens clone ccsbBroadEn_05989 AKR1C4 gene, encodes complete protein. KR711253 - Synthetic construct Homo sapiens clone CCSBHm_00021501 AKR1C4 (AKR1C4) mRNA, encodes complete protein. DQ894598 - Synthetic construct Homo sapiens clone IMAGE:100009058; FLH176796.01L; RZPDo839H06121D aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehy> (AKR1C4) gene, encodes complete protein. AB031085 - Homo sapiens mRNA for dihydrodiol dehydrogenase 4, complete cds. DQ891424 - Synthetic construct clone IMAGE:100004054; FLH176800.01X; RZPDo839H06122D aldo-keto reductase family 1, member C4 (chlordecone reductase; 3-alpha hydroxysteroid dehydrogenase, type I; dihydrodiol dehy> (AKR1C4) gene, encodes complete protein. AB045829 - Homo sapiens mRNA for 3alpha-hydroxysteroid dehydrogenase variant, complete cds. M33375 - Human chlordecone reductase mRNA, complete cds. D26125 - Homo sapiens mRNA for 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase DD4, partial cds. MB486559 - JP 2019531699-A/6: METHODS FOR DIAGNOSING AND TREATING CANCER. JD136992 - Sequence 118016 from Patent EP1572962. JD496865 - Sequence 477889 from Patent EP1572962.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa00120 - Primary bile acid biosynthesis hsa00140 - Steroid hormone biosynthesis hsa00980 - Metabolism of xenobiotics by cytochrome P450 hsa01100 - Metabolic pathways
Reactome (by CSHL, EBI, and GO)
Protein P17516 (Reactome details) participates in the following event(s):
R-HSA-2855252 AKRs reduce RBP2:atRAL to RBP2:atROL R-HSA-192036 5Beta-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha, 12alpha-triol R-HSA-192160 5beta-cholestan-7alpha-ol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha-diol R-HSA-193758 5beta-cholestan-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,24(S)-triol R-HSA-193781 5Beta-cholestan-7alpha,12alpha,24(S)-triol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol R-HSA-193800 5Beta-cholestan-7alpha,12alpha,27-triol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol R-HSA-193841 5beta-cholestan-7alpha,27-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,27-triol R-HSA-975634 Retinoid metabolism and transport R-HSA-193368 Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol R-HSA-193775 Synthesis of bile acids and bile salts via 24-hydroxycholesterol R-HSA-193807 Synthesis of bile acids and bile salts via 27-hydroxycholesterol R-HSA-2187338 Visual phototransduction R-HSA-6806667 Metabolism of fat-soluble vitamins R-HSA-192105 Synthesis of bile acids and bile salts R-HSA-418594 G alpha (i) signalling events R-HSA-196854 Metabolism of vitamins and cofactors R-HSA-194068 Bile acid and bile salt metabolism R-HSA-388396 GPCR downstream signalling R-HSA-1430728 Metabolism R-HSA-8957322 Metabolism of steroids R-HSA-372790 Signaling by GPCR R-HSA-556833 Metabolism of lipids R-HSA-162582 Signal Transduction
US Server
