This is the Highlights page for the lecture entitled Steroid Metabolism.
This lecture encompasses biosynthesis of cholesterol, bile acids, steroid hormones, prostaglandins, leukotrienes, and thromboxanes. Key points:
1. Isoprene - 5 carbon units - 1) isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Each is made from acetyl-CoA molecules. Synthesis of isopentenyl pyrophosphate and dimethylallyl pyrophosphate comes from HMG-CoA, so isoprenoid biosynthesis overlaps partly with ketone body synthesis.
2. The most important enzyme in cholesterol biosynthesis is HMG-CoA reductase. It is the primary regulatory enzyme in cholesterol biosynthesis. Cholesterol is a feedback inhibitor of the enzyme. The enzyme is a target of the drug called Lovastatin.
3. Reaction of isopentenyl pyrophospahte with dimethylallyl pyrophosphate yields a 10-carbon intermediate, geranyl pyrophosphate
4. Reaction of geranyl pyrophosphate with isopentenyl pyrophosphate yields a 15 carbon intermediate - farnesyl pyrophosphate.
5. Reaction of two farnesyl pyrophosphates yields a 30 carbon intermediate - squalene.
6. Further reaction of squalene yields a multi-cyclic intermediate, lanosterol.
7. Lanosterol is converted to cholesterol in a multi-step process.
8. Instead of leading to synthesis of cholesterol ( a cyclic compound), squalene can also lead to synthesis of other isoprenes, such as Vitamin A (retinol)., Vitamin E (alpha-tocopherol), and Vitamin K.
9. Vitamin D is derived from cholesterol and the predominant intermediate, cholecalciferol is synthesized in reaction that requires ultraviolet (UV) light.
10. Retinol is the alcohol form of vitamin A. The aldehyde form, called retinal, is important in vision. Detection of light is a product of isomerization of a cis-double bond (position 11) in the retinal-opsin complex in the eye. (Opsin is a protein that reacts with 11-cis retinal).
11. Vitamin E is an antioxidant that may have an important function protecting membranes from oxidation.
12. Vitamin K is involved in carboxylation of glutamate residues in proteins. One place where this is important is in blood clotting.
13. Cholesterol is a precursor of the bile acids. These include cholate (cholic acid), chenodeoxycholate, glycocholate, and taurocholate.
14. Cholesterol is also a precursor of the steroid hormones. There are five groups of steroid hormones. These are all derived from pregnenolone and include Androgens (male sex hormones), Estrogens (female sex hormones,which are derived from male sex hormones), Mineralocorticoids, Glucocorticoids, and Progestins. The only way sex hormones are released from the body is via the urine.
15. Eicosanoids are 20 carbon compounds derived from or related to arachidonic acid.
16. Eicosanoids are involved in responses, such as localized pain, smooth muscle contraction, blood pressure control, inflammation, platelet "stickiness", and others.
17. Synthesis of prostaglandins from arachidonic acid arises by cleavage of arachidonic acid from glycerophospholipids by enzymes called phospholipases. These can be stimulated, for example, by things such as bee stings, and many other mechanisms.
18. The second step of prostaglandin synthesis involves the enzyme called PGH synthase. PGH synthase is a complicated enzyme with activities called cyclooxygenases. There are different types of cyclooxygenases.
19. The cyclooxygenase activity of PGH synthase is essential for formation of prostaglandins. Pain relievers, such as aspirin or ibuprofen, act by inhibiting the cyclooxygenase activity and thus inhibiting prostaglandin biosynthesis.
20. Another way to prevent prostaglandin biosynthesis is by inhibiting the phospholipases that release prostaglandins from glycerophospholipids. Molecules which inhibit phospholipases include the corticosteroids.
21. Aspirin and ibuprofen are called Non-Steroidal Anti-Inflammatory Drugs or NSAIDs, in contrast to corticosteroids mentioned in #20.
22. Leukotrienes are made from arachidonic acid via a different pathway than prostaglandins. This involves action of an enzyme called a lipoxygenase.