The adrenal steroid hormones are synthesized from cholesterol, which is mostly derived from the plasma, but a small portion is synthesized in situ from acetyl-CoA via mevalonate and squalene. Much of the cholesterol in the adrenal is esterified and stored in cytoplasmic lipid droplets. Upon stimulation of the adrenal by ACTH, an esterase is activated, and the free cholesterol formed is transported into the mitochondrion, where a cytochrome P450 side chain cleavage enzyme (P450scc) converts cholesterol to pregnenolone. Cleavage of the side chain involves sequential hydroxylations, first at C22 and then at C20, followed by side chain cleavage (removal of the six-carbon fragment isocaproaldehyde) to give the 21-carbon steroid (Figure 1, top). An ACTH-dependent steroidogenic acute regulatory (StAR) protein is essential for the transport of cholesterol to P450scc in the inner mitochondrial membrane.

Fig1. Cholesterol side chain cleavage and basic steroid hormone structures. The basic sterol rings are identified by the letters A to D. The carbon atoms are numbered 1 to 21, starting with the A ring.

All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reactions that occur in either the mitochondria or endoplasmic reticulum of the producing cell. Hydroxylases that require molecular oxygen and NADPH are essential, and dehydrogenases, an isomerase, and a lyase reaction are also necessary for certain steps. There is cellular specificity in adrenal steroidogenesis. For instance, 18-hydroxylase and 19-hydroxysteroid dehydrogenases, which are required for aldosterone synthesis, are found only in the zona glomerulosa cells (the outer region of the adrenal cortex), so that the biosynthesis of this mineralocorticoid is confined to this region. A schematic representation of the pathways involved in the synthesis of the three major classes of adrenal steroids is presented in Figure 2. The enzymes are shown in the rectangular boxes, and the modifications at each step are shaded.

Fig2. Pathways involved in the synthesis of the three major classes of adrenal steroids (mineralocorticoids, glucocorticoids, and androgens).Enzymes are shown in the rectangular boxes, and the modifications at each step are shaded. Note that the 17α-hydroxylase and 17,20-lyase activities are both part of one enzyme, designated P450c17. (Reproduced with permission from DeGroot LJ: Endocrinology, vol 2. Philadelphia, PA: Grune & Stratton; 1979.)

Mineralocorticoid Synthesis

 Synthesis of aldosterone follows the mineralocorticoid pathway and occurs in the zona glomerulosa. Pregnenolone is con verted to progesterone by the action of two smooth endoplas mic reticulum enzymes, 3β-hydroxysteroid dehydrogenase (3β-OHSD)andΔ5,4-isomerase. Progesterone is hydroxylated at the C21 position to form 11-deoxycorticosterone (DOC), which is an active (Na+-retaining) mineralocorticoid. The next hydroxylation, at C11 , produces corticosterone, which has glucocorticoid activity and is a weak mineralocorticoid (it has <5% of the potency of aldosterone). In some species (eg, rodents), it is the most potent glucocorticoid. C21 hydroxylation is necessary for both mineralocorticoid and glucocorticoid activity, but most steroids with a C17 hydroxyl group have more glucocorticoid and less mineralocorticoid action. In the zona glomerulosa, which does not have the smooth endo plasmic reticulum enzyme 17α-hydroxylase, a mitochondrial 18-hydroxylase is present. The 18-hydroxylase (aldosterone synthase) acts on corticosterone to form 18-hydroxycorti costerone, which is changed to aldosterone by conversion of the 18-alcohol to an aldehyde. This unique distribution of enzymes and the special regulation of the zona glomerulosa by K+ and angiotensin II have led some investigators to suggest that, in addition to the adrenal being two glands, the adrenal cortex is actually two separate organs.

Glucocorticoid Synthesis

 Cortisol synthesis requires three hydroxylases located in the fasciculata and reticularis zones of the adrenal cortex that act sequentially on the C17 , C21 , and C11 positions. The first two reactions are rapid, while C11 hydroxylation is relatively slow. If the C11 position is hydroxylated first, the action of17α-hydroxylase is impeded, and the mineralocorticoid pathway is followed (forming corticosterone or aldosterone, depending on the cell type). 17α-Hydroxylase is a smooth endoplasmic reticulum enzyme that acts on either progesterone or, more commonly, pregnenolone. 17α-Hydroxyprogesterone is hydroxylated at C21 to form 11-deoxycortisol, which is then hydroxylated at C11 to form cortisol, the most potent natural glucocorticoid hormone in humans. 21-Hydroxylase is a smooth endoplasmic reticulum enzyme, whereas 11β-hydroxylase is a mitochondrial enzyme. Steroidogenesis thus involves the repeated shuttling of substrates into and out of the mitochondria.

Androgen Synthesis

The major androgen or androgen precursor produced by the adrenal cortex is dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the glucocorticoid path way, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of 17,20-lyase. The lyase activity is actually part of the same enzyme (P450c17) that catalyzes 17α-hydroxylation. This is therefore a dual-function protein. The lyase activity is important in both the adrenals and the gonads and acts exclusively on 17α-hydroxy-containing molecules. Adrenal androgen pro duction increases markedly if glucocorticoid biosynthesis is impeded by the lack of one of the hydroxylases (adrenogenital syndrome). DHEA is really a prohormone since the actions of 3β-OHSD and Δ5,4-isomerase convert the weak androgen DHEA into the more potentandrostenedione. Small amounts of androstenedione are also formed in the adrenal by the action of the lyase on 17α-hydroxyprogesterone. Reduction of androstenedione at the C17 position results in the formation of testosterone, the most potent adrenal androgen. Small amounts of testosterone are produced in the adrenal by this mechanism, but most of this conversion occurs in the testes.

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مواضيع ذات صلة

Cholesterol Side Chain Cleavage Enzyme (p450scc)

Steroidogenic Acute Regulatory Protein (StAR)

Cytochrome P450 Steroid Hydroxylases

Major Protein Components of Muscle Fibers

The Major Components of Cartilage are Type II Collagen & Certain Proteoglycans

Bone is Affected by many Metabolic & Genetic Disorders

The Assembly of Membranes is Complex

Transport Vesicle Formation and Function Involves SNAREs & Other Factors

Misfolded Proteins Undergo Endoplasmic Reticulum Associated Degradation

Proteoglycans & Glycosaminoglycans

The ER Functions as The Quality Control Compartment of The Cell

Proteins Follow Several Routes to be Inserted Into or Attached to The Membranes of The Endoplasmic Reticulum