11beta hidroxiesteroide deshidrogenasa

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Cortisol is a glucocorticoid that can bind the glucocorticoid receptor. The molecule of cortisol is similar to aldosterone that can bind the mineralcorticoid receptor. Since mineralocorticoid shares much similarity with glucocorticoid, HSD-11β oxidizes cortisol to inactive cortisones to prevent the illicit activation of mineralocorticoid or glucocorticoid receptors in different tissues. HSD-11β co-localizes with intracellular adrenal steroid receptors. Deficiency of HSD-11β will cause severe conditions known as apparent mineralocorticoid excess syndrome (AME), which is characterized as low potassium level, hypertension and reduced plasma renin. Polycystic ovary syndrome (PCOS) is also believed to relate to the deficiency of cortisone conversion to cortisol. In human, there are two HSD-11β isoforms, including type 1 11β-HSD (11β-HSD1, NADPH-dependent) and type 2 11β-HSD (11β-HSD2, NAD + -dependent). It has been reported that 11β-HSD1 has bidirectional activity, while 11β-HSD2 mainly converts cortisol into cortisone. 11β-HSD1 is highly expressed in key metabolic tissues, including liver, adipose tissue, and the central nervous system. 11β-HSD2 is expressed in aldosterone-selective tissues, including kidneys, liver, lungs, colon, salivary glands, HSD2 neurons and placenta. HSD 11β play crucial roles in blood pressure regulation and yndrome of apparent mineralocorticoid excess.

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of 11-dehydrocorticosterone to its active form corticosterone in rodents (or cortisone to cortisol in humans). The reductive reaction of the 11-keto to 11-hydroxyl is the pivotal switch in the activation of glucocorticoids. An excess of active glucocorticoids has been shown to play a key role in metabolic disorders such as diabetes and obesity. Therefore, 11beta-HSD1 represents an important therapeutic target for the treatment of these diseases. To facilitate the iterative design of inhibitors, we have crystallized and determined the three-dimensional structures of a binary complex of murine 11beta-HSD1 with NADP(H) to a resolution of A and of a ternary complex with corticosterone and NADP(H) to a resolution of A by X-ray crystallography. The enzyme forms a homodimer in the crystal and has a fold similar to those of other members of the family of short chain steroid dehydrogenases/reductases (SDRs). The structure shows a novel folding feature at the C-terminus of the enzyme. The C-terminal helix insertions provide additional dimer contacts, exert an influence on the conformations of the substrate binding loops, and present hydrophobic regions for potential membrane attachment. The structure also reveals how 11beta-HSD1 achieves its selectivity for its substrate.

11beta hidroxiesteroide deshidrogenasa

11beta hidroxiesteroide deshidrogenasa


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