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 10-13) Uses UDP activated sugars, but not CTP activated head groups

Ceramide is a precursor for numerous glycosphingolipids

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

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

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

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

Simplicity to complexity

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

Acetate  Mevalonate Catalyzed by thiolase,  -hydroxy-  - 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

Mevalonate is converted to isoprene- containing molecules

A momentary diversion: Isoprenoids are precursors for several important biomolecules

Back to cholesterol biosynthesis:

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

Squalene is cyclized to cholesterol

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

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

Proteins and lipids produce particles with distinct densities

These particles facilitate transport

Cholesterol is taken up by receptor-mediated endocytosis

Cholesterol synthesis is balanced with uptake

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

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

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

Cholate and chenodeoxycholate acid are prominent bile salts Note cytochrome P450

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)

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

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.