11β-hydroxysteroid dehydrogenase type 1

Hydroxysteroid (11-beta) dehydrogenase 1

PDB rendering based on 1xu7.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1XU7, 1XU9, 2BEL, 2ILT, 2IRW, 2RBE, 3BYZ, 3BZU, 3CH6, 3CZR, 3D3E, 3D4N, 3D5Q, 3EY4, 3FCO, 3FRJ, 3H6K, 3HFG, 3OQ1, 3PDJ, 3QQP, 3TFQ, 4BB5, 4BB6, 4C7J, 4C7K, 4HFR, 4HX5, 4IJU, 4IJV, 4IJW, 4K1L, 4P38

Identifiers

Symbols

HSD11B1 ; 11-DH; 11-beta-HSD1; CORTRD2; HDL; HSD11; HSD11B; HSD11L; SDR26C1

External IDs

OMIM: 600713 MGI: 103562 HomoloGene: 68471 IUPHAR: 2763 ChEMBL: 4235 GeneCards: HSD11B1 Gene

EC number

1.1.1.146

Gene ontology
Molecular function	• 11-beta-hydroxysteroid dehydrogenase [NAD(P) activity] • 11-beta-hydroxysteroid dehydrogenase (NADP+) activity
Cellular component	• endoplasmic reticulum membrane • membrane • integral component of membrane
Biological process	• glucocorticoid biosynthetic process • steroid metabolic process • lung development • small molecule metabolic process • oxidation-reduction process
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 1:
209.69 – 209.73 Mb

Chr 1:
193.22 – 193.26 Mb

PubMed search

11β-hydroxysteroid dehydrogenase type 1, or 'cortisone reductase' is an NADPH-dependent enzyme highly expressed in key metabolic tissues including liver, adipose tissue, and the central nervous system. In these tissues, HSD11B1 reduces cortisone to the active hormone cortisol that activates glucocorticoid receptors.

Function

The protein encoded by this gene is a microsomal enzyme that catalyzes the conversion of the stress hormone cortisol to the inactive metabolite cortisone. In addition, the encoded protein can catalyze the reverse reaction, the conversion of cortisone to cortisol. Too much cortisol can lead to central obesity, and a particular variation in this gene has been associated with obesity and insulin resistance in children. Two transcript variants encoding the same protein have been found for this gene.^[1]

Clinical significance

11β-HSD1 is inhibited by carbenoxolone, a drug typically used in the treatment of peptic ulcers. Moreover, 18alpha-glycyrrhizic acid from the root of glycyrrhiza glabra was discovered as an inhibitor.^[2]

Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and hence may explain why aspirin improve glycemic control in type 2 diabetes.^[3] Epigallocatechin gallate from green tea can also potently inhibit this enzyme,^[4] which might partly explain the anti-stress properties of green tea consumption.

References

↑ "Entrez Gene: HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1".
↑ Classen-Houben D, Schuster D, Da Cunha T, Odermatt A, Wolber G, Jordis U, Kueenburg B (Feb 2009). "Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid". The Journal of Steroid Biochemistry and Molecular Biology 113 (3-5): 248–52. doi:10.1016/j.jsbmb.2009.01.009. PMID 19429429.
↑ Nixon M, Wake DJ, Livingstone DE, Stimson RH, Esteves CL, Seckl JR, Chapman KE, Andrew R, Walker BR (Apr 2012). "Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization". Diabetes 61 (4): 790–6. doi:10.2337/db11-0931. PMC 3314355. PMID 22357964.
↑ Hintzpeter J, Stapelfeld C, Loerz C, Martin HJ, Maser E (3 January 2014). "Green tea and one of its constituents, Epigallocatechine-3-gallate, are potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1". PLOS ONE 9 (1): e84468. Bibcode:2014PLoSO...984468H. doi:10.1371/journal.pone.0084468. PMID 24404164.

White PC, Mune T, Agarwal AK (Feb 1997). "11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess". Endocrine Reviews 18 (1): 135–56. doi:10.1210/er.18.1.135. PMID 9034789.
Agarwal AK (Nov 2003). "Cortisol metabolism and visceral obesity: role of 11beta-hydroxysteroid dehydrogenase type I enzyme and reduced co-factor NADPH". Endocrine Research 29 (4): 411–8. doi:10.1081/ERC-120026947. PMID 14682470.
Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM (Oct 2004). "11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response". Endocrine Reviews 25 (5): 831–66. doi:10.1210/er.2003-0031. PMID 15466942.
Wake DJ, Walker BR (Feb 2006). "Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity". Endocrine 29 (1): 101–8. doi:10.1385/ENDO:29:1:101. PMID 16622297.
Tannin GM, Agarwal AK, Monder C, New MI, White PC (Sep 1991). "The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization". The Journal of Biological Chemistry 266 (25): 16653–8. PMID 1885595.
Graham DL, Oram JF (Jun 1987). "Identification and characterization of a high density lipoprotein-binding protein in cell membranes by ligand blotting". The Journal of Biological Chemistry 262 (16): 7439–42. PMID 3034894.
Whorwood CB, Mason JI, Ricketts ML, Howie AJ, Stewart PM (Apr 1995). "Detection of human 11 beta-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase-polymerase chain reaction and localization of the type 2 isoform to renal collecting ducts". Molecular and Cellular Endocrinology 110 (1-2): R7–12. doi:10.1016/0303-7207(95)03546-J. PMID 7545619.
Mune T, Rogerson FM, Nikkilä H, Agarwal AK, White PC (Aug 1995). "Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase". Nature Genetics 10 (4): 394–9. doi:10.1038/ng0895-394. PMID 7670488.
Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM (Apr 1998). "Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues". The Journal of Clinical Endocrinology and Metabolism 83 (4): 1325–35. doi:10.1210/jc.83.4.1325. PMID 9543163.
Calvo D, Gómez-Coronado D, Suárez Y, Lasunción MA, Vega MA (Apr 1998). "Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL". Journal of Lipid Research 39 (4): 777–88. PMID 9555943.
Odermatt A, Arnold P, Stauffer A, Frey BM, Frey FJ (Oct 1999). "The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane". The Journal of Biological Chemistry 274 (40): 28762–70. doi:10.1074/jbc.274.40.28762. PMID 10497248.
Sriskanda V, Schwer B, Ho CK, Shuman S (Oct 1999). "Mutational analysis of Escherichia coli DNA ligase identifies amino acids required for nick-ligation in vitro and for in vivo complementation of the growth of yeast cells deleted for CDC9 and LIG4". Nucleic Acids Research 27 (20): 3953–63. doi:10.1093/nar/27.20.3953. PMC 148661. PMID 10497258.
Schutte BC, Bjork BC, Coppage KB, Malik MI, Gregory SG, Scott DJ, Brentzell LM, Watanabe Y, Dixon MJ, Murray JC (Jan 2000). "A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41". Genome Research 10 (1): 81–94. doi:10.1101/gr.10.1.81 (inactive 2015-02-15). PMC 310500. PMID 10645953.
Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM (Sep 2000). "Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone". Bone 27 (3): 375–81. doi:10.1016/S8756-3282(00)00344-6. PMID 10962348.
Reddy ST, Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopadhyay A, Shih DM, Lusis AJ, Navab M, Fogelman AM (Apr 2001). "Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids". Arteriosclerosis, Thrombosis, and Vascular Biology 21 (4): 542–7. doi:10.1161/01.ATV.21.4.542. PMID 11304470.
Pácha J, Lisá V, Miksík I (Feb 2002). "Effect of cellular differentiation on 11beta-hydroxysteroid dehydrogenase activity in the intestine". Steroids 67 (2): 119–26. doi:10.1016/S0039-128X(01)00143-X. PMID 11755176.
Albertin G, Tortorella C, Malendowicz LK, Aragona F, Neri G, Nussdorfer GG (May 2002). "Human adrenal cortex and aldosterone secreting adenomas express both 11beta-hydroxysteroid dehydrogenase type 1 and type 2 genes". International Journal of Molecular Medicine 9 (5): 495–8. doi:10.3892/ijmm.9.5.495. PMID 11956655.
Mazzocchi G, Malendowicz LK, Aragona F, Tortorella C, Gottardo L, Nussdorfer GG (Jul 2002). "11beta-Hydroxysteroid dehydrogenase types 1 and 2 are up- and downregulated in cortisol-secreting adrenal adenomas". Journal of Investigative Medicine : The Official Publication of the American Federation for Clinical Research 50 (4): 288–92. doi:10.2310/6650.2002.33012. PMID 12109593.

PDB gallery

1xu9: Crystal Structure of the Interface Closed Conformation of 11b-hydroxysteroid dehydrogenase isozyme 1

2bel: STRUCTURE OF HUMAN 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN COMPLEX WITH NADP AND CARBENOXOLONE

1xu7: Crystal Structure of the Interface Open Conformation of Tetrameric 11b-HSD1

2ilt: Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and Adamantane Sulfone Inhibitor

2irw: Human 11-beta-Hydroxysteroid Dehydrogenase (HSD1) with NADP and Adamantane Ether Inhibitor

Oxidoreductases: alcohol oxidoreductases (EC 1.1)

1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3 Beta 3-beta-HSD NSDHL 11 Beta HSD11B1 HSD11B2 17 Beta

1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)

1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase

1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)

1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase

1.1.99: other acceptors	Choline dehydrogenase L2HGDH

Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism

Mevalonate pathway

To HMG-CoA	Acetyl-Coenzyme A acetyltransferase HMG-CoA synthase (regulated step)

Ketogenesis	HMG-CoA lyase 3-hydroxybutyrate dehydrogenase Thiophorase

To Mevalonic acid	HMG-CoA reductase

To DMAPP	Mevalonate kinase Phosphomevalonate kinase Pyrophosphomevalonate decarboxylase Isopentenyl-diphosphate delta isomerase

Geranyl-	Dimethylallyltranstransferase Geranyl pyrophosphate

To cholesterol

To lanosterol	Farnesyl-diphosphate farnesyltransferase Squalene monooxygenase Lanosterol synthase

7-Dehydrocholesterol path	Lanosterol 14α-demethylase Sterol-C5-desaturase-like 7-Dehydrocholesterol reductase

Desmosterol path	24-dehydrocholesterol reductase

To Bile acids

Steroidogenesis

To pregnenolone

Side-chain cleavage

To corticosteroids

aldosterone: 18-hydroxylase

To sex hormones

To androgens	17α-hydroxylase/17,20 lyase 3β dehydrogenase 17β dehydrogenase 5α reductase 1 2

To estrogens	Aromatase

Other/ungrouped

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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11β-hydroxysteroid dehydrogenase type 1

Function

Clinical significance

See also

References

Further reading