11-Beta hydroxysteroid dehydrogenase

Not to be confused with Steroid 11-beta-hydroxylase.
11-beta-hydroxysteroid dehydrogenase (NADP+)
Identifiers
EC number 1.1.1.146
CAS number 9041-46-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

11β-Hydroxysteroid dehydrogenase (HSD-11β or 11β-HSD) is the name of a family of enzymes that catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa,[1] thus regulating the access of glucocorticoids to the steroid receptors:

11β-hydroxysteroid + NADP+ \rightleftharpoons an 11-oxosteroid + NADPH + H+

Thus, the two substrates of this enzyme are 11beta-hydroxysteroid and NADP+, whereas its 3 products are 11-oxosteroid, NADPH, and H+.

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 11beta-hydroxysteroid:NADP+ 11-oxidoreductase. Other names in common use include corticosteroid 11β-dehydrogenase, β-hydroxysteroid dehydrogenase, 11β-hydroxy steroid dehydrogenase, corticosteroid 11-reductase, and dehydrogenase, 11β-hydroxy steroid. This enzyme participates in c21-steroid hormone metabolism and androgen and estrogen metabolism.

Structural studies

As of late 2007, 8 structures have been solved for this class of enzymes, with PDB accession codes 1XSE, 1XU7, 1XU9, 1Y5M, 1Y5R, 2BEL, 2ILT, and 2IRW.

Function

Cortisol. Note the OH at the 11 position on ring C. (The other differences between the diagrams are not of consequence.)

Cortisol, a glucocorticoid, binds the glucocorticoid receptor. However, because of its molecular similarity to aldosterone it is also capable of binding the mineralcorticoid receptor. Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, there is vastly more cortisol in circulation than aldosterone. To prevent over-stimulation of the mineralocorticoid receptor by cortisol, HSD-11β converts the biologically active cortisol to the inactive cortisone, which can no longer bind to the mineralocorticoid receptor. 11β-HSD co-localizes with intracellular adrenal steroid receptors. Licorice, which contains glycyrrhetinic acid, or Carbenoxolone can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome.

Isoforms

In humans, there are two HSD11B isoforms:[2][3]

HSD11B1 NADPH-dependent 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.
HSD11B2 NAD+-dependent Expressed in aldosterone-selective tissues, including kidneys, liver, lungs, colon, salivary glands, HSD2 neurons and placenta. In these tissues, HSD11B2 oxidizes cortisol to cortisone and prevents illicit activation of the mineralocorticoid receptor.

Inhibition of HSD11B1 has been suggested as a possible therapy for treatment of obesity and metabolic syndrome.[3]

See also

References

  1. Seckl JR, Walker BR (April 2001). "Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action". Endocrinology 142 (4): 1371–6. doi:10.1210/en.142.4.1371. PMID 11250914.
  2. Seckl JR (January 1997). "11beta-Hydroxysteroid dehydrogenase in the brain: a novel regulator of glucocorticoid action?". Front Neuroendocrinol 18 (1): 49–99. doi:10.1006/frne.1996.0143. PMID 9000459.
  3. 1 2 Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP (2009). "Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis". The Journal of Clinical Endocrinology and Metabolism 94 (8): 2692–2701. doi:10.1210/jc.2009-0370. PMID 19470627.

External links

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