Chem*4520 Metabolic Processes Fall Semester 2000 Modified October 2000
schematic view of the enzyme citrate synthase, with bound acetyl-CoA analog in green	Department of Chemistry and Biochemistry Home Page Back to Chem*4520 Home Page

The adrenal cortex produces corticosteroids hydroxylated at C-21

Steroid synthesis in the adrenal glands involves mono-oxygenase catalysed hydroxylations at C-17, C-21 and C-11 in that order. The hydroxyl at C-3 of pregnenolone may be oxidized to a ketone before or after the first C-17 hydroxylation, giving two pathways to 17-hydroxyprogesterone.

The pathway differs from sex steroid synthesis by the hydroxylations at C-21 and C-11 which follow. This produces cortisol, the major active glucocorticoid (about 10-30 mg/day in humans). A second pathway starts from progesterone and skips 17-hydroxylation. Hydroxylation at C-21 and C-11 gives corticosterone.

Another mono-oxygenase now oxidizes the methyl group at C-18 of corticosterone to an aldehyde, to give aldosterone, the major mineralocorticoid (about 0.1-0.2 mg/day). Aldosterone spontaneously converts to the hemiacetal form, which is active.

The activity of cortisol may be modulated by reversible conversion to the less active form cortisone. The aldosterone pathway is confined to the outer layer of adrenal cortex, while glucocorticoids are produced by cells in the inner layers.

Small amounts of testosterone and estradiol are produced in the adrenal as well. This is exacerbated if the activity of C-21 hydroxylase is weak, and may result in unusually high testosterone levels in females who have this deficiency.

Steroids exert their effects through control of gene expression

Responses to glucocorticoids include:

Liver:	enhanced levels of gluconeogenesis	elevated expression of glucose-6-phosphatase and pyruvate carboxylase
	more amino acid breakdown (anti-anabolic effect)	elevated expression of transaminases
	liver glycogen build-up	elevated expression of glycogen synthase
Peripheral tissues	diminished insulin response
	diminished protein synthesis (anti-anabolic effect)
Lymphoid cells	diminished inflammatory response
	reduced prostaglandin synthesis	reduced expression of phospholipase A2
General	reduced stress response	negative effects on stress response genes

Responses to mineralocorticoids include:

Effects in distal tubules of kidney, sweat glands, intestinal epithelia

Increased Na+ retention and reabsorption increased K+ and NH4+ secretion increased Mg2+ and Ca2+ excretion.

Excessive levels of mineralocorticoids have adverse effects on heart and brain function.

Prostaglandin synthesis

Prostaglandins are named for a substance originally found in ram semen which triggered contraction of smooth (involuntary) muscle. These substances were isolated and characterised by researchers in the Karolinska Institute in Sweden in 1950-1970. Since then they have been found to be very widely distributed locally-acting intercellular signalling molecules.

	The C20 skeleton of prostaglandins is derived from the polyunsaturated fatty acid arachidonate. The major pool of arachidonate chains exists as the C-2 acyl chain of phospholipids, and arachidonate is released as needed by the action of phospholipase A2.
	The double bonds of arachidonate (20:4 5,8,11,14) are allylic, that is they are spaced apart by one -CH2- group between adjacent double bonds. The allylic arrangement forms a fairly stable free radical by loss of H. from the middle -CH2, with the odd electron remaining delocalized over the five C-H atoms of the allylic system.

An allylic grouping is prone to attack by free radicals from either end, resulting in double bond shift. In this example, the double bond moves into a position conjugated with its neighbour.

Most of the work is done by a single enzyme, prostaglandin PGH2 synthase, which contains two catalytic centers, a cyclo-oxygenase and a peroxidase. The reaction is initiated by the cyclo-oxygenase. A first molecule of O2, which is a diradical, attacks the allylic system from C-11 to C-15 at the C-11 double bond, with loss of H. at C-13. Then follows a two pronged attack by the other end of the O-O at C-9 concomitantly with attack by a second O2 diradical at C-15. This results in cyclization across the gap from C-8 to C-12, forming a five member ring. The end product of cyclo-oxygenase reaction is the the unstable peroxide, prostaglandin G2, PGG2. Finally, the peroxidase component reduces the peroxide at C-15 to a stable hydroxyl group in prostaglandin H2.

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