Sphingolipid metabolism

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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

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Ceramide is a precursor for numerous
glycosphingolipids
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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

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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

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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

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Steroid metabolism

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

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Simplicity to complexity
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Cholesterol is made from acetyl-CoA

• Mevalonate formation is
• the first stage of cholesterol
• synthesis

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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

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Mevalonate is converted to isoprene-containing
molecules
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A momentary diversion

• Isoprenoids are
• precursors for several
• important biomolecules

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Back to cholesterol biosynthesis
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Head to tail condensations ultimately result in a
30 carbon intermediate, squalene
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Squalene is cyclized to cholesterol
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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

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Lipids and proteins

• Proteins mediate lipid
• transport between tissues
• Proteins are also modified
• by lipids

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Proteins and lipids produce particles with
distinct densities
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These particles facilitate transport
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Cholesterol is taken up by receptor-mediated
endocytosis
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Cholesterol synthesis is balanced with uptake
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Acyl-CoAcholesterol acyltransferase (ACAT)
generates cholesteryl esters
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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

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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

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Cholate and chenodeoxycholate acid are prominent
bile salts

• Note cytochrome
• P450

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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)

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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

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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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