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Sphingolipid metabolism

Sphingolipid metabolism. Starts with palmitoyl-CoA and serine, which is reduced and undergoes a transacylation and desaturation to yield ceramide (containing sphingosine; refer to figure 10-12) Uses UDP activated sugars, but not CTP activated head groups.

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Sphingolipid metabolism

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  1. Sphingolipid metabolism • Starts with palmitoyl-CoA and serine, which is reduced and undergoes a transacylation and desaturation to yield ceramide (containing sphingosine; refer to figure 10-12) • Uses UDP activated sugars, but not CTP activated head groups

  2. Ceramide is a precursor for numerous glycosphingolipids

  3. Role of sphingolipids • Abundant component of myelin sheath (25% in humans) • Also widely distributed in membranes of plants (use phytosphingosine), and lower eukaryotes (yeast) • These lipids are in a continuous state of turnover, defects in this metabolism leads to various diseases

  4. However, little is known about their specific biochemical function • Gangliosides are receptors for specific agents such as influenza virus • Some gangliosides promote growth of neural tissue in cell cultyre • Biological signaling agents, possibly apoptosis as we will see in near future

  5. Fatty acid  lipid  membrane • After lipids are synthesized in the ER, polar lipids are delivered to the Golgi apparatus, which serves as a clearinghouse sending specific lipids to specific targets using membrane vesicles

  6. Steroid metabolism • Sterols (steroids) are class of lipids that are derivatives of a tetracyclic hydrocarbon

  7. Simplicity to complexity

  8. Cholesterol is made from acetyl-CoA • Mevalonate formation is the first stage of cholesterol synthesis

  9. Acetate  Mevalonate • Catalyzed by thiolase, b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) synthase and reductase • The reductase is the first committed step in this pathway; regulatory point • This last step is a four electron reduction

  10. Mevalonate is converted to isoprene-containing molecules

  11. A momentary diversion: • Isoprenoids are precursors for several important biomolecules

  12. Back to cholesterol biosynthesis:

  13. Head to tail condensations ultimately result in a 30 carbon intermediate, squalene

  14. Squalene is cyclized to cholesterol

  15. Regulation of cholesterol biosynthesis • HMG-CoA reductase is a major target for regulation. • Hormonal regulation by insulin and glucagon • Ingestion of cholesterol inhibits endogenous cholesterol synthesis (control exerted at both transcriptional and translational levels) • Additional sophistication in vertebrates

  16. Lipids and proteins • Proteins mediate lipid transport between tissues • Proteins are also modified by lipids

  17. Proteins and lipids produce particles with distinct densities

  18. These particles facilitate transport

  19. Cholesterol is taken up by receptor-mediated endocytosis

  20. Cholesterol synthesis is balanced with uptake

  21. Acyl-CoA:cholesterol acyltransferase (ACAT) generates cholesteryl esters

  22. Fate of cholesterol • Cholesterol is used by cells to decrease fluidity of cell membrane • Used in steroid hormone and bile salt biosynthesis • Cholesterol can also be exported from liver as bile acids, cholesteryl esters, or biliary cholesterol • Bile acids aid in digestion • Cholesteryl esters are transported to other other tissues to use cholesterol

  23. Bile acids are steroid derivatives with detergent properties • Emulsify dietary lipids • Secreted from liver, stored in gall bladder, passed through bile duct into intestine • Bile acids represent a major metabolic fate of cholesterol, accounting for more than half of the 800 mg/day of cholesterol metabolized (steroid hormones represent about 50 mg of cholesterol per day) • Bile acids are recycled through small intestine

  24. Cholate and chenodeoxycholate acid are prominent bile salts • Note cytochrome P450

  25. Cholesterol is the biosynthetic source of all steroid hormones • Five major classes of hormones • Progestins (regulate events during pregnancy and are precursors to all other steroid hormones) • Glucocorticoids (promote gluconeogenesis, and in certain doses suppress inflammation rxns) • Mineralocorticoids (regulate ion balance in kidney) • Androgens (male sexual characteristic development and maintenance) • Estrogens (female sexual characteristics development and maintenance)

  26. What stands out about steroid hormone biosynthesis? • Role of cytochrome P450 and side chain cleavage in mitochondria • Multiple hydroxylations • Central role of pregnenolone • Mammalian cells lack capacity for complete degradation of steroids. Although a number of catabolic reactions occur, most are conjugated through their hydroxyl groups to glucuronate or sulfate, increasing solubility and allowing elimination through urine

  27. Other isoprenoid compounds: • Vitamin A, D, K, E • Terpenes – generic term for all compounds biosynthesized from isoprene precursors; hence all the molecules we have discussed today are terpenes.

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