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.