Indanol dehydrogenase
Converts progesterone to its inactive form, 20-alpha-dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation.
Reference Protein and Structure
- Sequence
-
Q04828
(1.1.1.-, 1.1.1.51, 1.1.1.53, 1.1.1.62, 1.1.1.112, 1.1.1.149, 1.1.1.209, 1.1.1.210, 1.1.1.357, 1.3.1.20)
(Sequence Homologues)
(PDB Homologues)
- Biological species
-
Homo sapiens (Human)
- PDB
-
1mrq
- Crystal structure of human 20alpha-HSD in ternary complex with NADP and 20alpha-hydroxy-progesterone
(1.59 Å)
- Catalytic CATH Domains
-
3.20.20.100
(see all for 1mrq)
Enzyme Mechanism
Introduction
This enzyme displays a sequential ordered kinetic mechanism, in which the pyridine nucleotide cofactor binds first and leaves last. It is a class A dehydrogenase which catalyses direct hydride transfer of the pro-R hydrogen from the C4 position of the nicotinamide ring to the acceptor carbonyl at C3 of the steroid substrate.
Catalytic Residues Roles
| UniProt | PDB* (1mrq) | ||
| Asp50 | Asp50A | Part of an Asp-Lys-Tyr catalytic triad that lowers the pKa of Tyr55. | electrostatic stabiliser |
| Tyr55 | Tyr55A | Tyr55 forms a hydrogen bond with the C3 ketone of testosterone and acts as a general acid/base. | proton shuttle (general acid/base) |
| Lys84 | Lys84A | Lowers the pKa of the catalytic tyrosine. | modifies pKa |
| His117 | His117A | His117 is highly conserved and forms a second hydrogen bond with the C3 ketone of testosterone. Thought to act as a general acid/base. | proton shuttle (general acid/base) |
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file;
y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain;
C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.
Chemical Components
References
- Penning TM (2011), J Steroid Biochem Mol Biol, 125, 46-56. Human hydroxysteroid dehydrogenases and pre-receptor regulation: insights into inhibitor design and evaluation. DOI:10.1016/j.jsbmb.2011.01.009. PMID:21272640.
- Dhagat U et al. (2008), J Med Chem, 51, 4844-4848. Selectivity determinants of inhibitor binding to human 20alpha-hydroxysteroid dehydrogenase: crystal structure of the enzyme in ternary complex with coenzyme and the potent inhibitor 3,5-dichlorosalicylic acid. DOI:10.1021/jm8003575. PMID:18620380.
- Couture JF et al. (2003), J Mol Biol, 331, 593-604. Human 20α–Hydroxysteroid Dehydrogenase: Crystallographic and Site-directed Mutagenesis Studies Lead to the Identification of an Alternative Binding Site for C21-steroids. DOI:10.1016/s0022-2836(03)00762-9. PMID:12899831.
- Bennett MJ et al. (1997), Structure, 5, 799-812. Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3α-hydroxysteroid/dihydrodiol dehydrogenase. DOI:10.1016/s0969-2126(97)00234-7. PMID:9261071.
- Bennett MJ et al. (1996), Biochemistry, 35, 10702-10711. Structure of 3α-Hydroxysteroid/Dihydrodiol Dehydrogenase Complexed with NADP+ †. DOI:10.1021/bi9604688. PMID:8718859.
- Hoog SS et al. (1994), Proc Natl Acad Sci U S A, 91, 2517-2521. Three-dimensional structure of rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase: a member of the aldo-keto reductase superfamily. DOI:10.1073/pnas.91.7.2517. PMID:8146147.
Catalytic Residues Roles
| Residue | Roles |
|---|---|
| Lys84A | modifies pKa |
| His117A | proton shuttle (general acid/base) |
| Asp50A | electrostatic stabiliser |
| Tyr55A | proton shuttle (general acid/base) |