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Information on EC 1.3.1.3 - DELTA4-3-oxosteroid 5beta-reductase and Organism(s) Digitalis lanata and UniProt Accession Q6PQJ9
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1.3.1.3 DELTA4-3-oxosteroid 5beta-reductaseIUBMB Comments
The enzyme from human efficiently catalyses the reduction of progesterone, androstenedione, 17alpha-hydroxyprogesterone and testosterone to 5beta-reduced metabolites; it can also act on aldosterone, corticosterone and cortisol, but to a lesser extent . The bile acid intermediates 7alpha,12alpha-dihydroxy-4-cholesten-3-one and 7alpha-hydroxy-4-cholesten-3-one can also act as substrates .
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The taxonomic range for the selected organisms is: Digitalis lanata
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
akr1d1, 5beta-por, h5beta-red, progesterone 5beta-reductase, p5betar, steroid 5beta-reductase, srd5beta, aldo-keto reductase 1d1, 3-oxo-delta4-steroid 5beta-reductase, akr1d4, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
4,5beta-dihydrocortisone:NADP+ DELTA4-oxidoreductase
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5-beta-reductase
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androstenedione 5beta-reductase
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cortisone 5beta-reductase
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cortisone beta-reductase
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DELTA 4-5beta-reductase
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DELTA4-3-ketosteroid 5beta-reductase
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DELTA4-hydrogenase
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reductase, cholestenone 5beta.-
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reductase, cortisone DELTA4-5beta-
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steroid 5beta.-reductase
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testosterone 5-beta-reductase
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testosterone 5beta-reductase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
reduction
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
5beta-cholestan-3-one:NADP+ 4,5-oxidoreductase
The enzyme from human efficiently catalyses the reduction of progesterone, androstenedione, 17alpha-hydroxyprogesterone and testosterone to 5beta-reduced metabolites; it can also act on aldosterone, corticosterone and cortisol, but to a lesser extent [8]. The bile acid intermediates 7alpha,12alpha-dihydroxy-4-cholesten-3-one and 7alpha-hydroxy-4-cholesten-3-one can also act as substrates [9].
CAS REGISTRY NUMBER
COMMENTARY
37255-35-9
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9029-08-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
4-androstene-3,17-dione + NADPH
5beta-androstan-3,17-dione + NADP+
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?
cortexone + NADPH
21-trihydroxy-5beta-pregnane-3,20-dione + NADP+
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?
cortisol + NADPH
11beta,17,21-trihydroxy-5beta-pregnane-3,20-dione + NADP+
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?
testosterone + NADPH + H+
(5beta,17beta)-17-hydroxyandrostan-3-one + NADP+
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?
progesterone + NADPH + H+
5beta-pregnane-3,20-dione + NADP+
5alpha-pregnane-3,20-dione, the 5alpha-isomer of the pregnane-3,20-dione is not formed
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ir
progesterone + NADPH + H+
5beta-pregnane-3,20-dione + NADP+
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stereospecific reduction of the 4-double-bond in cardenolide biosynthesis
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?
additional information
?
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pregnenolone, 21-OH-pregenenolone and isoprogesterone are not accepted by recombinant 5beta-POR
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?
additional information
?
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pregnenolone, 21-OH-pregenenolone and isoprogesterone are not accepted by recombinant 5beta-POR
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?
additional information
?
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AKR1D1 catalyzes the stereospecific reduction of the delta4-double-bond of circulating steroid hormones that contain the delta4-3-ketosteroid functionality, e.g. the reduction of testosteron, progesterone and cortisol to yield the corresponding 5-dihydrosteroid
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?
additional information
?
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aldo-keto reductases are a major superfamily of monomeric NADPH-dependent carbonyl oxidoreductases, active site contains conserved residues D50, Y55, K84, and H117
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?
additional information
?
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the steroid 5beta-reductases catalyze a reaction that is unique in steroid enzymology since the resultant product contains a cis-A/B ring configuration and accordingly contains a 90° bend, the cis-A/B ring configuration is an essential characteristic of cardiac glycosides, e.g. digioxin and bile acids and their precursors
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
progesterone + NADPH + H+
5beta-pregnane-3,20-dione + NADP+
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stereospecific reduction of the 4-double-bond in cardenolide biosynthesis
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?
additional information
?
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AKR1D1 catalyzes the stereospecific reduction of the delta4-double-bond of circulating steroid hormones that contain the delta4-3-ketosteroid functionality, e.g. the reduction of testosteron, progesterone and cortisol to yield the corresponding 5-dihydrosteroid
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?
additional information
?
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aldo-keto reductases are a major superfamily of monomeric NADPH-dependent carbonyl oxidoreductases, active site contains conserved residues D50, Y55, K84, and H117
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?
additional information
?
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the steroid 5beta-reductases catalyze a reaction that is unique in steroid enzymology since the resultant product contains a cis-A/B ring configuration and accordingly contains a 90° bend, the cis-A/B ring configuration is an essential characteristic of cardiac glycosides, e.g. digioxin and bile acids and their precursors
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
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the enzyme belongs to the aldoketo reductase (AKR) family, sequence comparisons, overview
additional information
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residues Tyr156, Asp205, and Ser248 are responsible for the low catalytic efficiency of the enzyme, substrate binding pocket structure, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). 5BPOR_DIGLA
389
0
44071
Swiss-Prot
other Location (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
5beta-POR, in the presence and absence of the cofactor NADP+, hanging drop vapour diffusion method, using 15% polyethylene glycol 4000, 0.1 M ammonium acetate, and 0.1 M sodium citrate, pH 5.6
by the hanging-drop method, at 2.7 A resolution, crystals belong to space group P43212, contain a single 5beta-POR molecule in the asymmetric unit and tend to diffract anisotropically, identification of six out of eight possible Se-atom positions
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recombinant wild-type and mutant enzymes from Escherichia coli strain M15 by nickel affinity chromatography
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the crystal structure of the 5beta-POR-NADP+ binary complex reveals that 5beta-POR exhibits a characteristic short-chain dehydrogenase fold with an N-terminal domain consisting of a double Rossmann fold for cofactor binding and an insertional domain between strands betaF and betaG of about 100 residues for substrate binding, crystal structure of the 5beta-POR-NADP+ binary complex reveals that the side chain of K147 is found in a similar position to the lysine residue of the YXX(S)K motif in standard short-chain dehydrogenases
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C352G
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site-directed mutagenesis, mutation at the substrate binding site, the mutant shows reduced activity compared to the wild-type enzyme
D181T/L182Q
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site-directed mutagenesis, mutation at motif V, the mutant shows reduced activity compared to the wild-type enzyme
F353M
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site-directed mutagenesis, mutation at the substrate binding site, the mutant shows similar activity as the wild-type enzyme
F353P
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site-directed mutagenesis, mutation at the substrate binding site, the mutant shows similar activity as the wild-type enzyme
G204N
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site-directed mutagenesis, mutation at motif IV, the mutant shows reduced activity compared to the wild-type enzyme
L182Q
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site-directed mutagenesis, mutation at motif V, the mutant shows similar activity as the wild-type enzyme
M150L
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site-directed mutagenesis, mutation at motif IV, the mutant shows similar activity as the wild-type enzyme
N205A
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site-directed mutagenesis, mutation at the substrate binding site, the mutant shows increased activity compared to the wild-type enzyme
N205M
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site-directed mutagenesis, mutation at the substrate binding site, the mutant shows increased activity compared to the wild-type enzyme
N205M/Y156V
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site-directed mutagenesis, double mutation at the substrate binding site, the mutant shows increased activity compared to the wild-type enzyme
R146T
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site-directed mutagenesis, mutation at motif IV, the mutant shows similar activity as the wild-type enzyme
S248M
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site-directed mutagenesis, mutation near the substrate binding site, inactive mutant
T65P
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site-directed mutagenesis, mutation at near motif II, the mutant shows similar activity as the wild-type enzyme
Y156V
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site-directed mutagenesis, mutation at the substrate binding site, the mutant shows increased activity compared to the wild-type enzyme
Y302F
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site-directed mutagenesis, mutation at motif IV, the mutant shows similar activity as the wild-type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
nickel-Sepharose affinity column chromatography and Superdex 75 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
Sph1/Sal1 5beta-POR fragment cloned into the pQE vector and transformed into Escherichia coli strain M15(pREP4)
DNA and amino acid sequence determination and analysis, sequence comparisons, expression of wild-type and mutant enzymes in Escherichia coli strain M15
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overproduced by the pQE expression system and transformed into Escherichia coli strain B834(DE3)
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
5beta-POR is highly conserved within the genus Digitalis and the respective genes and proteins share considerable homology to putative progesterone reductases from other plant species
additional information
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5beta-POR is highly conserved within the genus Digitalis and the respective genes and proteins share considerable homology to putative progesterone reductases from other plant species
additional information
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inspection of the MAD-phased electron-density map shows that 5beta-POR is a Rossmann-type reductase and the quality of the map is such that it is anticipated that a complete atomic model of 5beta-POR may readily be built
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Egerer-Sieber, C.; Herl, V.; Mller-Uri, F.; Kreis, W.; Muller, Y.A.
Crystallization and preliminary crystallographic analysis of selenomethionine-labelled progesterone 5beta-reductase from Digitalis lanata Ehrh
Acta Crystallogr. Sect. F
62
186-188
2006
Digitalis lanata
Herl, V.; Fischer, G.; Mller-Uri, F.; Kreis, W.
Molecular cloning and heterologous expression of progesterone 5beta-reductase from Digitalis lanata Ehrh.
Phytochemistry
67
225-231
2006
Digitalis lanata (Q6PQJ9), Digitalis lanata
Di Costanzo, L.; Penning, T.M.; Christianson, D.W.
Aldo-keto reductases in which the conserved catalytic histidine is substituted
Chem. Biol. Interact.
178
127-133
2009
Digitalis lanata
Thorn, A.; Egerer-Sieber, C.; Jaeger, C.; Herl, V.; Mueller-Uri, F.; Kreis, W.; Muller, Y.
The crystal structure of progesterone 5beta-reductase from Digitalis lanata defines a novel class of short chain dehydrogenases/reductases
J. Biol. Chem.
283
17260-17269
2008
Digitalis lanata (Q6PQJ9), Digitalis lanata
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