12α-Hydroxysteroid Dehydrogenase

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Introductions

12α-hydroxysteroid dehydrogenase (12α-HSD) is an enzyme that plays a key role in the metabolism of glucocorticoids, hormones involved in the regulation of immune function, metabolism and stress responses. 12α-HSD catalyzes the conversion of cortisol to its inactive metabolite cortisone in tissues such as the liver and kidney. This process prevents overactivation of glucocorticoid receptors and protects them from the deleterious effects of cortisol overexposure.

Structure

12α-HSD is a member of the short-chain dehydrogenase/reductase (SDR) superfamily of enzymes. It consists of two structural domains: the catalytic domain and the cofactor-binding domain. The catalytic structural domain contains a conserved NAD(P)+ binding pattern and a catalytic triad consisting of serine, tyrosine and lysine residues. The cofactor-binding domain interacts with the cofactor NAD(P)+, which is essential for the enzyme activity.

Function

12α-HSD plays a key role in the regulation of glucocorticoid activity in various tissues. Glucocorticoids bind to intracellular glucocorticoid receptors (GR), triggering a range of downstream effects, including anti-inflammatory, immunosuppressive and metabolic responses. However, chronic exposure to high levels of glucocorticoids can lead to adverse effects such as muscle wasting, osteoporosis and impaired glucose tolerance. Therefore, the local metabolism of glucocorticoids by 12α-HSD helps to maintain a balance between the beneficial and detrimental effects of these hormones.

Regulation

The activity of 12α-HSD is regulated by several factors, including substrate availability, cofactor availability, and post-translational modifications. Cortisol is the preferred substrate for 12α-HSD, and its availability is determined by the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts cortisone to cortisol. 11β-HSD1 activity is regulated by various factors, including cytokines, growth factors, and nutritional status.

Applications

• In the field of drug discovery, 12α-HSD is the target of several classes of drugs, including glucocorticoid receptor antagonists, which block the activity of glucocorticoids in tissues such as the liver and kidney. For example, mifepristone, a selective glucocorticoid receptor antagonist, has been used to treat disorders such as Cushing's syndrome and depression.
• In addition to its application in drug discovery, 12α-HSD has been used as a diagnostic marker for several diseases. For example, alterations in 12α-HSD activity have been observed in patients with metabolic diseases such as obesity and diabetes mellitus.
• In addition, 12α-HSD has been implicated in the pathogenesis of several diseases, including hypertension, osteoporosis, and Alzheimer's disease.

Clinical significance

The clinical significance of 12α-HSD is related to its role in regulating glucocorticoid activity in various tissues. alterations in 12α-HSD activity can lead to a range of disorders associated with dysregulation of glucocorticoid signaling.

• Cushing's syndrome: This is a disorder characterized by excessive cortisol secretion from the adrenal glands. In some cases, Cushing's syndrome may be caused by mutations in genes encoding enzymes involved in cortisol metabolism, including 12α-HSD.
• Diabetes and obesity: Altered expression or activity of 12α-HSD is associated with the development of insulin resistance, a key feature of type 2 diabetes and obesity. 12α-HSD deficiency is associated with reduced adiposity and improved glucose tolerance in mice.
• Hypertension: Glucocorticoids have been shown to play a role in the regulation of blood pressure. Due to impaired 12α-HSD activity, excessive activation of glucocorticoid receptors is associated with hypertension.