Q95JH4 · AK1C4_MACFU
- ProteinAldo-keto reductase family 1 member C4
- GeneAKR1C4
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids323 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Liver specific enzyme that acts as an NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain (PubMed:15618685).
Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (By similarity).
Acts preferentially as a 3-alpha-hydroxysteroid dehydrogenase (HSD) with a subsidiary 3-beta-HSD activity (PubMed:15618685).
Catalyzes efficiently the transformation of the potent androgen 5-alpha-dihydrotestosterone (5alpha-DHT or 17beta-hydroxy-5alpha-androstan-3-one) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol). Catalyzes the reduction of estrone into 17beta-estradiol but with low efficiency. Metabolizes a broad spectrum of natural and synthetic therapeutic steroid and plays an important role in metabolism of androgens, estrogens, progestereone and conjugated steroids. Catalyzes the biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leading to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route (By similarity).
Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (By similarity).
Acts preferentially as a 3-alpha-hydroxysteroid dehydrogenase (HSD) with a subsidiary 3-beta-HSD activity (PubMed:15618685).
Catalyzes efficiently the transformation of the potent androgen 5-alpha-dihydrotestosterone (5alpha-DHT or 17beta-hydroxy-5alpha-androstan-3-one) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol). Catalyzes the reduction of estrone into 17beta-estradiol but with low efficiency. Metabolizes a broad spectrum of natural and synthetic therapeutic steroid and plays an important role in metabolism of androgens, estrogens, progestereone and conjugated steroids. Catalyzes the biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leading to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route (By similarity).
Catalytic activity
- chlordecone alcohol + NADP+ = chlordecone + H+ + NADPH
- 5alpha-androstane-3alpha,17beta-diol + NADP+ = 17beta-hydroxy-5alpha-androstan-3-one + H+ + NADPHThis reaction proceeds in the backward direction.
- (20S)-hydroxypregn-4-en-3-one + NADP+ = H+ + NADPH + progesteroneThis reaction proceeds in the forward and the backward directions.
- (20S)-hydroxypregn-4-en-3-one + NAD+ = H+ + NADH + progesteroneThis reaction proceeds in the forward and the backward directions.
- 3alpha-hydroxy-5alpha-androstane 17-O-(beta-D-glucuronate) + NADP+ = 5alpha-dihydrotestosterone 17-O-(beta-D-glucuronate) + H+ + NADPHThis reaction proceeds in the backward direction.
- (3beta,5alpha,17beta)-3-hydroxy-androstan-17-yl sulfate + NADP+ = 5alpha-dihydrotestosterone sulfate + H+ + NADPHThis reaction proceeds in the backward direction.
- 5alpha-androstane-3alpha,17beta-diol + NAD+ = androsterone + H+ + NADHThis reaction proceeds in the forward direction.
Activity regulation
Potently inhibited by benzbromarone, 3',3'',5',5''-tetrabromophenolphthalein (TBPP) and o-cresolphthalein.
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
0.6 μM | 5alpha-pregnane-3alpha,21-diol-20-one | |||||
0.3 μM | 5-alpha-pregnan-20-alpha-ol-3-one | |||||
0.7 μM | 3alpha-hydroxy-5alpha-androstan-17-one | |||||
0.3 μM | 5-beta-pregnan-20-alpha-ol-3-one | |||||
25 μM | trans-benzene dihydrodiol | |||||
420 μM | (s)-tetralol |
kcat is 4.9 min-1 for 5-beta-pregnan-20-alpha-ol-3-one as substrate. kcat is 4.9 min-1 for 3alpha-hydroxy-5alpha-androstan-17-one as substrate. kcat is 23 min-1 for 5alpha-pregnane-3alpha,21-diol-20-one.
Pathway
Steroid metabolism.
Features
Showing features for binding site, site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 20-24 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: GFGSY | ||||||
Binding site | 50 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Site | 54 | Important for substrate specificity | ||||
Sequence: L | ||||||
Active site | 55 | Proton donor | ||||
Sequence: Y | ||||||
Site | 84 | Lowers pKa of active site Tyr | ||||
Sequence: K | ||||||
Binding site | 117 | substrate | ||||
Sequence: H | ||||||
Binding site | 166-167 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: SN | ||||||
Binding site | 190 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: Q | ||||||
Binding site | 216-221 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: HSALGT | ||||||
Binding site | 270-280 | NADP+ (UniProtKB | ChEBI) | ||||
Sequence: KSYNEQRIREN |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytosol | |
Molecular Function | 5alpha-androstane-3beta,17beta-diol dehydrogenase activity | |
Molecular Function | androstan-3-alpha,17-beta-diol dehydrogenase activity | |
Molecular Function | androsterone dehydrogenase activity | |
Molecular Function | chlordecone reductase activity | |
Molecular Function | dihydrotestosterone 17-beta-dehydrogenase activity | |
Molecular Function | estradiol 17-beta-dehydrogenase [NAD(P)+] activity | |
Molecular Function | testosterone 17-beta-dehydrogenase (NADP+) activity | |
Molecular Function | testosterone dehydrogenase (NAD+) activity | |
Biological Process | lipid metabolic process |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameAldo-keto reductase family 1 member C4
- EC number
- Alternative names
Gene names
Organism names
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Cercopithecidae > Cercopithecinae > Macaca
Accessions
- Primary accessionQ95JH4
Subcellular Location
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000124642 | 1-323 | Aldo-keto reductase family 1 member C4 | |||
Sequence: MDPKYQRVALNDGHFMPVLGFGSYAPPEVPRNRVVEVTKLAIEAGFRHIDSAYLYNNEEQVGLAIRSKIADGSVKREDIFYTSKLWCTFFRPQLVQPALESSLKKLQLDYVDLYLIHFPMALKPGETPLPKDENGKVMFDTVDLCAIWEAMEKCKDAGLAKSIGVSNFNRRQLEMILNNPGLKYKPVCNQVECHPYLNQSKLLDFCKSKDIVLVAHSALGTQRHKLWVDQNSPALLEDPVLCALAKKHKRSPALIALRYQLQRGVVVLAKSYNEQRIRENVQVFEFQLTSEDMKVLDDLNRNFRYVVMDFLVDHPDYPFSDEY |
Expression
Tissue specificity
High expression in liver. Also expressed in kidney.
Interaction
Subunit
Monomer.
Structure
Sequence
- Sequence statusComplete
- Length323
- Mass (Da)37,103
- Last updated2001-12-01 v1
- Checksum38382E7AD7EB7AFA