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Information on EC 5.3.3.1 - steroid DELTA-isomerase
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EC Tree
5.3.3.1 steroid DELTA-isomeraseIUBMB Comments
This activity is catalysed by several distinct enzymes (cf. EC 1.1.3.6, cholesterol oxidase and EC 1.1.1.145, 3-hydroxy-5-steroid dehydrogenase).
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Word Map
- 5.3.3.1
-
steroidogenic
- progesterone
- adrenal
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steroidogenesis
- androgen
- p450scc
- leydig
- star
- testicular
- pregnenolone
- 17beta-hsd
- lh
- aromatase
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5-3-ketosteroids
- gonad
- testosteroni
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granulosa
- dehydroepiandrosterone
- luteal
- androstenedione
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17beta-hydroxysteroid
- dheas
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theca
- p450arom
- 17alpha-hydroxylase
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neurosteroids
- cyp11a1
- trilostane
- 19-nortestosterone
-
dienolate
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5alpha-reductase
- equilenin
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low-barrier
- 17alpha-hydroxylase/17,20-lyase
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interna
- 3betahsd
- delta5-3beta-hydroxysteroid
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intracrine
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double-bond
- hsd3b1
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talalay
- 20alpha-hsd
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beta-proton
The enzyme appears in viruses and cellular organisms
Synonyms
3beta-hsd, ketosteroid isomerase, delta 5-3-ketosteroid isomerase, steroid isomerase, 3beta-hydroxysteroid dehydrogenase/isomerase, steroid delta-isomerase, gst a3-3, 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase, 3beta-hsd/isomerase, 5-ene-4-ene isomerase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3-Keto-DELTA5-steroid isomerase
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3-Ketosteroid DELTA5-->DELTA4-isomerase
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3-Oxo steroid DELTA4-DELTA5-isomerase
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3-Oxo-delta5 steroid isomerase
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3-Oxosteroid DELTA4-DELTA5-isomerase
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3-Oxosteroid DELTA5-DELTA4-isomerase
3-Oxosteroid isomerase
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3beta-HSD
3beta-HSD/isomerase
5-Ene-4-ene isomerase
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5-Pregnene-3,20-dione isomerase
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delta 5-3-ketosteroid isomerase
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DELTA-3-ketosteroid isomerase
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Delta-5-3-ketosteroid isomerase
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DELTA5(or DELTA4)-3-keto steroid isomerase
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DELTA5-3-keto steroid isomerase
DELTA5-3-ketosteroid isomerase
DELTA5-3-oxosteroid isomerase
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DELTA5-ketosteroid isomerase
DELTA5-steroid isomerase
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Hydroxysteroid isomerase
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Isomerase, steroid DELTA
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ketosteroid isomerase
KSI
Steroid 5-->4-isomerase
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Steroid isomerase
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additional information
3-Oxosteroid DELTA5-DELTA4-isomerase
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DELTA5-3-keto steroid isomerase
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DELTA5-3-ketosteroid isomerase
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DELTA5-ketosteroid isomerase
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additional information
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3beta-hydroxy-5-ene steroid dehydrogenase/isomerase enzyme system
additional information
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3beta-hydroxy-DELTA5-steroid dehydrogenase/3-keto-DELTA5-steroid isomerase
additional information
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3beta-hydroxysteroid dehydrogenase/5-ene--4-ene isomerase
additional information
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beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase
additional information
the enzyme is a member of the short chain dehydrogenase/reductase family, cf. EC 1.1.1.51
additional information
the enzyme is a member of the short chain dehydrogenase/reductase family, cf. EC 1.1.1.51
additional information
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beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase
additional information
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enzyme complex 3beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase
additional information
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DELTA5-3-beta-hydroxysteroid dehydrogenase-isomerase system
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
mechanism in which the transition state for enolization is dienolate-like, characterized by relatively little proton transfer from Tyr14 in the transition state, and the intermediate in the overall reaction is dienol-like. An alternative mechanism in which the intermediate is stabilized by a short, strong hydrogen bond can also be consistent with the data
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a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
"flip-flop" mechanism may be involved
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a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
catalytic mechanism, phenolate binding to the oxyanion hole of ketosteroid isomerase via hydrogen bonding, electrostatic contributions and geometric and electrostatic changes, overview, the KSI reaction involves changes in both geometry and charge distribution as the reaction proceeds from its ground state to its intermediate
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a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
catalytic mechanism, phenolate binding to the oxyanion hole of ketosteroid isomerase via hydrogen bonding, electrostatic contributions and geometric and electrostatic changes, overview, the KSI reaction involves changes in both geometry and charge distribution as the reaction proceeds from its ground state to its intermediate, Tyr16 and Asp103 are important in catalysis
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a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
two-step reaction first, Asp38 acts as a base, abstracting the 4beta-H atom from C-4 of the steroid to form a dienolate as the intermediate, next, the intermediate is reketonized by proton transfer to the 6beta-position, each step goes through its own transition state, catalytic mechanism, theoretical model involving residues Tyr14, Asp38 and Asp99
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a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
enzyme enhances the coupled motion/hydrogen tunneling contribution to the rate acceleration over the solution reaction
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a 3-oxo-DELTA5-steroid = a 3-oxo-DELTA4-steroid
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
intramolecular oxidoreduction
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isomerization
isomerization
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isomerization
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catalysis of the allylic isomerization of a variety of DELTA5-3-ketosteroids by intramolecular transfer of the C4-beta proton to the C6-beta position
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PATHWAY SOURCE
PATHWAYS
KEGG
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, androgen and estrogen metabolism, androgen and estrogen metabolism, androgen and estrogen metabolism, androgen and estrogen metabolism, androgen and estrogen metabolism, androgen and estrogen metabolism, androgen and estrogen metabolism, Microbial metabolism in diverse environments, Microbial metabolism in diverse environments
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SYSTEMATIC NAME
IUBMB Comments
3-oxosteroid DELTA5-DELTA4-isomerase
This activity is catalysed by several distinct enzymes (cf. EC 1.1.3.6, cholesterol oxidase and EC 1.1.1.145, 3-hydroxy-5-steroid dehydrogenase).
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CAS REGISTRY NUMBER
COMMENTARY
9031-36-1
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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
(+)-cis-isopulegone
(+)-pulegone
the enzyme also exhibits (+)-cis-isopulegone isomerase activity
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?
androst-5-ene-3,17-dione
androst-4-ene-3,17-dione
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alpha-secondary deuterium kinetic isotope effects at C6 of the steroid. Presence of coupled motion/hydrogen tunneling in the enzyme-catalyzed reaction
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r
17beta-Hydroxy-5(10)-estren-3-one
?
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at 0.25% of the activity compared to 5-androstene-3,17-dione
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?
5(10)-estrene-3,17-dione
estr-4-en-3,17-dione
nonsticky substrate
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?
5-Androstene-3,17-dione
4-Androstene-3,17-dione
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?
5-Androstene-3,17-dione
4-Androstene-3,17-dione
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?
5-Androstene-3,17-dione
4-Androstene-3,17-dione
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residue Asp38 acts as a base to abstract a proton from C-4 of the substrate to form an intermediate dienolate, which is then reprotonated on C-6
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?
5-Androstene-3,17-dione
4-Androstene-3,17-dione
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?
5-Androstene-3,17-dione
4-Androstene-3,17-dione
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the hydrogen-bond network which links the two catalytic residues, Tyr14 and Asp99, to Tyr30, Tyr55, and a water molecule in the highly apolar active site provides the structural support that is needed for the enzyme to maintain the active site geometry optimized for both function and stability
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?
5-Pregnene-3,20-dione
4-Pregnene-3,20-dione
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a 3-oxo-DELTA5-steroid
a 3-oxo-DELTA4-steroid
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phenolates binding to the oxyanion hole of the enzyme via electrostatic interactions, different binding of transition state analogue and substrate, hydrogen bonds shorten with increasing charge localization, overview
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r
a 3-oxo-DELTA5-steroid
a 3-oxo-DELTA4-steroid
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phenolates binding to the oxyanion hole of the enzyme via hydrogen bonding, different binding of transition state analogue and substrate, hydrogen bonds shorten with increasing charge localization, overview
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r
additional information
?
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identification of a putative 3beta-hydroxy-steroid dehydrogenase/DELTA5-DELTA4 isomerase pathway with the ability to handle both dehydroepiansdrosterone as well as C-17 side-chain containing compounds such as pregnenolone and 3beta-hydroxy-16alpha,17alpha-epoxypregn-5-en-20-one. 3beta-HSD/isomerase activity only occurs following lactonization of the steroidal ring-D. Presence of C-7 allylic hydroxylation, in either epimeric form, inhibits 3beta-HSD/isomerase activity. In Aspergillus tamarii, pregnenolone and 3beta-hydroxy-16alpha,17alpha-epoxypregn-5-en-20-one are metabolized solely through the putative 3beta-HSD/isomerase pathway
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?
additional information
?
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identification of a putative 3beta-hydroxy-steroid dehydrogenase/DELTA5-DELTA4 isomerase pathway with the ability to handle both dehydroepiansdrosterone as well as C-17 side-chain containing compounds such as pregnenolone and 3beta-hydroxy-16alpha,17alpha-epoxypregn-5-en-20-one. 3beta-HSD/isomerase activity only occurs following lactonization of the steroidal ring-D. Presence of C-7 allylic hydroxylation, in either epimeric form, inhibits 3beta-HSD/isomerase activity. In Aspergillus tamarii, pregnenolone and 3beta-hydroxy-16alpha,17alpha-epoxypregn-5-en-20-one are metabolized solely through the putative 3beta-HSD/isomerase pathway
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?
additional information
?
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properties of the steroid-enzyme aduct
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?
additional information
?
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the 2.3 A structure indicates that Phe101 is not a catalytic residue and that Tyr14 and Asp99 COOH should be directly involved in the stabilization of the dienolate intermediate
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?
additional information
?
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the 2.3 A structure indicates that Phe101 is not a catalytic residue and that Tyr14 and Asp99 COOH should be directly involved in the stabilization of the dienolate intermediate
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?
additional information
?
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equilenin geometrically and electrostatically resembles the dienolate reaction intermediate and transition state, binding structure to enzyme mutant D40N, overview
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?
additional information
?
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mechanism of KSI-catalyzed steroid isomerization, overview
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?
additional information
?
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the reaction occurs by a two-step general acid-base mechanism involving a dienolate intermediate. Hybrid quantum/classical molecular dynamics simulations elucidating the geometrical, conformational, and electrostatic changes occurring during the isomerization reaction catalyzed by KSI, calculation of rate constants and modeling of the KSI active site, overview. Electrostaic and conformational changes during the proton transfer reactions, rearrangements, overview
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?
additional information
?
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in pregnancy placental 3beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5--4 isomerase produce progesterone from pregnenolone and metabolize fetal dehydroepiandrosterone sulfate to androstenedione, an estrogen precursor
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?
additional information
?
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the conversion of 3beta-hydroxy-5-ene steroids by the enzyme complex 3beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase is an obligatory step in the biosynthesis of all classes of hormonal steroids in classical steroidogenic as well as in peripheral tissues
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?
additional information
?
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the bifunctional enzyme possesses 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity, the enzyme is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones
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?
additional information
?
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the bifunctional enzyme possesses 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity, the enzyme is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones
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?
additional information
?
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the bifunctional enzyme possesses 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity, the enzyme is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones
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?
additional information
?
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structure-function relations, analysis of three dimensional model of a ternary complex of human 3beta-HSD type 1 with an NAD+ cofactor and androstenedione product, reaction of EC 1.1.1.51, to elucidate the key substrate binding residues in the active site as well as the basis for dual function of the 3beta-HSD_1 enzyme, Asn100 and Glu126 residues are key residues that participate in the dehydrogenase and isomerization reactions, respectively, isomerase substrate binding structure, overview
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?
additional information
?
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structure-function relations, analysis of three dimensional model of a ternary complex of human 3beta-HSD type 1 with an NAD+ cofactor and androstenedione product, reaction of EC 1.1.1.51, to elucidate the key substrate binding residues in the active site as well as the basis for dual function of the 3beta-HSD_1 enzyme, Asn100 and Glu126 residues are key residues that participate in the dehydrogenase and isomerization reactions, respectively, isomerase substrate binding structure, overview
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?
additional information
?
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structure-function relations, analysis of three dimensional model of a ternary complex of human 3beta-HSD type 1 with an NAD+ cofactor and androstenedione product, reaction of EC 1.1.1.51, to elucidate the key substrate binding residues in the active site as well as the basis for dual function of the 3beta-HSD_1 enzyme, Asn100 and Glu126 residues are key residues that participate in the dehydrogenase and isomerization reactions, respectively, isomerase substrate binding structure, overview
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?
additional information
?
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human GST A3-3 does not stabilize a dienolate by an oxyanion hole in the active site
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?
additional information
?
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human GST A3-3 does not stabilize a dienolate by an oxyanion hole in the active site
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?
additional information
?
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the conversion of 3beta-hydroxy-5-ene steroids by the enzyme complex 3beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase is an obligatory step in the biosynthesis of all classes of hormonal steroids in classical steroidogenic as well as in peripheral tissues
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?
additional information
?
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the aromatic residues Phe54, Phe82 and Trp116 in the hydrophobic substrate-binding pocket of the enzyme contribute differentially to steroid species including substrate, intermediate and product
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?
additional information
?
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enzyme can be induced by various steroids
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?
additional information
?
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mechanism of KSI-catalyzed steroid isomerization, direct detection of physical coupling between the Y16 and D103 hydrogen bonds, ligand binding, overview
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?
additional information
?
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the enzyme catalyzes a C-H bond cleavage and formation through an enolate intermediate. Conversion of the ketone substrate to the enolate intermediate is simulated by a photoacid bound to the active site oxyanion hole. The lack of a significant solvation response in KSI suggests a preorganized active site
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?
additional information
?
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bifunctional enzyme possessing 3-beta-hydroxy-DELTA5-steroid dehydrogenase, EC 1.1.1.145, and steroid DELTA-isomerase activity
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?
additional information
?
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the enzyme is involved in synthesis of sex steroids influencing the development and function of the songbird brain, overview
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?
additional information
?
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bifunctional enzyme possessing 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity
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?
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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
5-Androstene-3,17-dione
4-Androstene-3,17-dione
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?
additional information
?
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in pregnancy placental 3beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5--4 isomerase produce progesterone from pregnenolone and metabolize fetal dehydroepiandrosterone sulfate to androstenedione, an estrogen precursor
-
-
?
additional information
?
-
-
the conversion of 3beta-hydroxy-5-ene steroids by the enzyme complex 3beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase is an obligatory step in the biosynthesis of all classes of hormonal steroids in classical steroidogenic as well as in peripheral tissues
-
-
?
additional information
?
-
the bifunctional enzyme possesses 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity, the enzyme is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones
-
-
?
additional information
?
-
the bifunctional enzyme possesses 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity, the enzyme is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones
-
-
?
additional information
?
-
-
the bifunctional enzyme possesses 3beta-hydroxysteroid dehydrogenase activity, EC 1.1.1.51, and steroid DELTA-isomerase activity, the enzyme is a key steroidogenic enzyme that catalyzes the first step of the multienzyme pathway conversion of circulating dehydroepiandrosterone and pregnenolone to active steroid hormones
-
-
?
additional information
?
-
-
the conversion of 3beta-hydroxy-5-ene steroids by the enzyme complex 3beta-hydroxysteroid dehydrogenase/DELTA5-DELTA4 isomerase is an obligatory step in the biosynthesis of all classes of hormonal steroids in classical steroidogenic as well as in peripheral tissues
-
-
?
additional information
?
-
-
enzyme can be induced by various steroids
-
-
?
additional information
?
-
-
the enzyme is involved in synthesis of sex steroids influencing the development and function of the songbird brain, overview
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADPH
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D36A/K37R mutation shifts the cofactor preference of both 3-beta-hydroxysteroid dehydrogenase and isomerase from NAD(H) to NADP(H)
NADH
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the isomerase activity of the wild-type enzyme and the deletion mutant enzyme DELTA283-310 requires allosteric activation by NADH, Km for wild-type enzyme and deletion mutant enzyme is 0.0046 mM
NADH
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wild-type 1 isomerase is activated only by NADH with NADPH producing no isomerase activity. D36A/K37R mutation shifts the cofactor preference of both 3-beta-hydroxysteroid dehydrogenase and isomerase from NAD(H) to NADP(H)
NADH
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isomerase activity of enzyme requires NADH, Km- and kcat-value of isoform 1 wild-type are 0.0046 mM and 45 per min, resp. Km- and kcat-value of isoform 2 wild-type are 0.0126 mM and 99.1 per min, resp
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(17S)-Spiro[5alpha-androstane-17,2'-oxiran]-3-one
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potent irreversible active-site directed
(17S)-Spiro[estra-1,3,5(10),6,8-pentaene-17,2'-oxiran]-3-ol
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active-site-directed, irreversible
(17S)-Spiro[estra-1,3,5(10)-triene-17,2'-oxiran]-3-ol
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potent irreversible active-site directed
10beta-(1-Oxoprop-2-ynyl)oestr-4-ene-3,17-dione
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irreversible, time-dependent, active-site directed
17beta-(1-Oxoprop-2-ynyl)androst-4-en-3-one
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irreversible, time-dependent, active-site directed
17beta-Hydroxy-5,10-seco-oestr-4-yne-3,10-dione
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irreversible, time-dependent, active-site directed
5,10-Seco-oestr-4-yne-3,10,17-trione
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irreversible, time-dependent, active-site directed
coumarin 183
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binds tightly in the oxyanion hole of the enzyme and chemically resemble the intermediate in the catalytic cycle. Upon photoexcitation, the pKa of the hydroxyl group changes substantially. This light-activated change in electron density around the photoacid hydroxyl group simulates the change in substrate pKa during the catalytic cycle. When the light-driven reaction analog occurs in the KSI active site, the electrostatic environment changes little
Halothane
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allosteric modulation of dynamics-function relationship without direct competition, halothane occupancy at the dimer interface disrupts intersubunit hydrogen bonding
N,N-Dimethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide
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non-competitive inhibition of isomerase, competitive inhibition of 3beta-hydroxysteroid dehydrogenase
Spiro-17beta-oxiranyl-DELTA4-androsten-3-one(4beta)
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active site-directed, irreversible
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Spiro-17beta-oxiranylestra-1,3,5(10),6,8-pentaene-3-ol
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active site-directed, irreversible