Lecture 14: chol and phospholipid metabolism

Question 1

Cholesterol Synthesis occurs mainly in ____, Intestin, and ______ ______

Answer 1

Cholesterol Synthesis occurs mainly in Liver, Intestine, and Gonads/Adrenals

Question 2

Cholesterol synthesis starts in _____ and is completed in ____

Answer 2

Cholesterol synthesis starts in Cytosol and is completed in Rough ER

Question 3

Step 1 of Cholesterol Synthesis:

• 3 Acetyl CoA (2c) to _______
• Occurs in ________
  
  • acetyl CoA trasnported from mitchochondria by _______
• Catalysed by ________\_ which is the rate limiting step

Answer 3

Step 1 of Cholesterol Synthesis:

• 3 Acetyl CoA (2c) to Mevalonate
• Occurs in Cytoplasm
  
  • acetyl CoA trasnported from mitchochondria by Citrate Shuttle
• Catalysed by HMG CoA Reductase which is rate limiting

Question 4

Enzyme responsible for rate-limiting step in Cholesotorl Synthesis: ________________\_

• phosphorylation by cAMP-dependent protein kinases __________ the enzyme (reversed by phosphatases)
• High cholesterol reduces levels of enzyme t_1/2 and reduces levels of the enzyme’s RNA

Answer 4

Enzyme responsible for rate-limiting step in Cholesotorl Synthesis: HMG-CoA Reductase

• phosphorylation by cAMP-dependent protein kinases inactivates the enzyme (reversed by phosphatases)
• High cholesterol reduces levels of enzyme t_1/2 and reduces levels of the enzyme’s RNA

Question 5

__________ are cholesterol-lowering drugs that act as transition-state analogs, binding like transition states to the HMG-CoA reductase.

Answer 5

Statins are cholesterol-lowering drugs that act as transition-state analogs, binding like transition states to the HMG-CoA reductase

Question 6

Step 2 of Cholesterol Synthesis:

• 6C Mevalonate is converted to 5C _____________ by decarboxylation
• This molecule is an important intermediary for other molecules, including those in the _________

Answer 6

Step 2 of Cholesterol Synthesis:

• 6C Mevalonate is converted to 5C Isopentenyl Pyrophosphate by carboxylation
• This molecule is an important intermediary for other molecules, including those in the ETC

Question 7

Step 3 of Cholesterol Synthesis: # of (5C) Isopentenyl Pyrophospahte units are converted to __________(#C)

• Isopentenyl Pyrophosphate–> Geranyl Pyrophosphate–> Farnesyl Pyrophosphate–>Squaline

Answer 7

Step 3 of Cholesterol Synthesis:

• # of (5C) IPP units is converted to Squaline (30C)
• Isopentenyl Pyrophosphate (5C) –> Geranyl Pyrophosphate (10C) –> Farnesyl Pyrophosphate (15C) X2–> Squaline

Question 8

Step 4 Cholesterol Synthesis:

• Squalene undergoes multiple enzyme catalyzed _________ reactions to yield lanosterol
• Lanosterol goes through 19 step reaction, _________ is formed

Answer 8

Step 4 Cholesterol Synthesis:

• Squalene undergoes multiple enzyme-catalyzed Cyclicization reactions to yield lanosterol
• Lanosterol goes through 19 step reaction, Cholesterol is formed

Question 9

HMG CoA Reductase is ________ in the presence of a lot of cholestorol

Answer 9

HMG CoA Reductase is downregulated in the presence of a lot of cholesterol

Question 10

Formation of __________ from cholesterol represents the only pathway for cholesterol elimination from the body

Answer 10

Formation of Bile Salts from cholesterol represents the only pathway for cholesterol elimination from the body

Question 11

_____________:

• Polar carboxylic acid derivatives of cholesterol
• amphipathic molecules (biological detergents)
• Emulsification of ingested fats in duodenum
• synthesised in _____ and stored in ________
• _____ % is excreted in faeces and remainder reabsorbed and recycled to liver

Answer 11

Bile Salts:

• Polar carboxylic acid derivatives of cholesterol
• amphipathic molecules (biological detergents)
• Emulsification of ingested fats in the duodenum
• synthesisedin Liver and stored in Gall Bladder
• 5-10% is excreted in feces and remainder reabsorbed and recycled to liver

Question 12

Deooxyxholic Acid is a ____________ and yeilds the ____________ GLycocholic Acid and Taurocholic acid

Answer 12

Deoxycholic Acid is a Bile Acid and yeilds the Bile Salts GLycocholic Acid and Taurocholic Acid

Question 13

___\_ fatty acids are precursors of prostaglandins, thromboxanes, and leukotrienes. They are _____-_inflammatory

Answer 13

ω6 fatty acids are precursors of prostaglandins, thromboxanes, and leukotrienes. They are Pro-inflammatory

Question 14

____\_fatty acids are cardioprotective, __\_-inflammatory, and ___________\_

Answer 14

ω3 fatty acids are cardioprotective, anti-inflammatory, and anticarcinogenic

Question 15

___________\_ Acid:

• Derived from C20 essential ω6 PUFA C20:4
• Incorporated into membrane glycerophospholipids
• Exert its actions by binding to specific plasma membrane receptors
• Functions as__________ ___________ molecule and plays important role in _________ and _________

Answer 15

Arachonic Acid:

• Derived from C20 essential ω6 PUFA C20:4
• Incorporated into membrane glycerophospholipids
• Exert its actions by binding to specific plasma membrane receptors
• Functions as a Local Signaling molecule and plays important role in Inflammation and Thrombosis

Question 16

___________ are formed from arachidonate oxidation and cyclization in ER

Answer 16

Prostaglandins are formed from arachidonate by oxidation and cyclization in ER

Question 17

Thromboxanes synthesized from _____\_ by thromboxane synthase

Answer 17

Thromboxanes synthesized from PGH₂ by thromboxane synthase

Question 18

___________: The most widely NSAID used medications in world

• Is an ___________ inhibitor of COX1 and modifies activity of COX2
• Downregulates ___________ pathway and lessens risk of thrombosis

Answer 18

Aspirin (Acetylsalicylate): The most widely NSAID used medication in the world

• Is an Irreversible inhibitor of COX1 and modifies the activity of COX2
• Downregulates Prostaglandin pathway and lessens the risk of thrombosis

Question 19

Simplest GlyceroPhospholipid (GPL) is _______

Answer 19

Simplest GlyceroPhospholipid (GPL) is Phosphatidate

Question 20

GlyceroPhospholipid (GPL) Structure

Answer 20

Question 21

What is Phosphatidylinositol important for?

Broken into Diaglyerol which activates _________ and Inositol which releases ____________

Answer 21

Important for Cell Signaling.

Broken into Diaglyerol which activates Protein Kinase C and Inositol which releases Ca_²⁺ from the Endoplasmic Reticulum

Question 22

Sphingolipids are components of all membranes but are particularly abundant in the ______\_

Answer 22

Sphingolipids are components of all membranes but are particularly abundant in the myelin sheath

Question 23

_______________________\_ have been shown to be important mediators in the signaling cascades involved in apoptosis, proliferation, necrosis, inflammation, senescence, and differentiation

Answer 23

Sphingolipid metabolites(eg. ceramide and sphingosine) have been shown to be important mediators in the signaling cascades involved in apoptosis, proliferation, necrosis, inflammation, senescence, and differentiation

Question 24

Sphingosine+ 1 FA = ________

Answer 24

Sphingosine+ 1 FA = ceramide

Question 25

______________ are ceramides with one or more added sugars:

• Particularly abundant in nerve cell membranes

Answer 25

Glycosphingolipids are ceramides with one or more added sugars:

• Particularly abundant in nerve cell membranes

Question 26

Ceramide with one added sugar?

Answer 26

C__erebrosides

Question 27

Ceramides with more than 1 sugar (not including sialic acid, NANA)

Answer 27

Globoside

Question 28

Ceramide with 3 or more sugars (one of which is sialic acid, NANA)

Answer 28

Ganglioside

Question 29

Glycosphingolipid Breakdown

• Occurs mainly in ________
• Most active in ________ tissues
• Enzyme deficiency causes the accumulation of intermediates that results in _________
  
  • Known as sphingolipidoses, lysosomal storage diseases or lipid storage diseases

Answer 29

Glycosphingolipid Breakdown

• Occurs mainly in Lysosomes
• Most active in Neural tissues
• Enzyme deficiency causes the accumulation of intermediates that results in Cell Death
  
  • Known as sphingolipidoses, lysosomal storage diseases or lipid storage diseases

Question 30

___________________ Disease:

• Failure of Glycosphingolipid breakdown
• Deficiency of ß-hexosaminidase A activity and the lysosomal accumulation of GM2 gangliosides
• Autosomal recessive disorder 1 in 30,000 in the general population, much higher (10-20X) in some ethnic groups:
  
  • _______\_, __________\_, ______________\_
• 3 clinical subtypes (associated with particular mutations)
  
  • infantile (progressive neurological degeneration, blindness, death by age 3)
  • juvenile
  • adult

Answer 30

Tay Sachs Disease:

• Failure of Glycosphingolipid breakdown
• Deficiency of ß-hexosaminidase A activity and the lysosomal accumulation of GM2 gangliosides
• Autosomal recessive disorder 1 in 30,000 in the general population, much higher (10-20X) in some ethnic groups:
  
  • Ashkenazi jews, French-Canadian, Louisiana Cajuns
• 3 clinical subtypes (associated with particular mutations)
  
  • infantile (progressive neurological degeneration, blindness, death by age 3)
  • juvenile
  • adult

Question 31

_____________ Disease:

• Failure of Glycosphingolipid breakdown
• Deficiency of lysosomal enzyme b-galactosidase leading to accumulation of glucosylceramides
  
  • infiltration of bone marrow, hepatosplenomegaly, skeletal and CNS complications
• Autosomal recessive disorder (approx. 1 in 20,000) in general population, much higher prevalence in ___________\_
• 3 clinical subtypes
  
  • type 1 -adult, non-neuropathic form (>95%)
  • type 2 -infantile, acute neuropathic form
  • type 3 –juvenile form
• Successfully treated with __________________\_ (Ceredase)

Answer 31

Gaucgers Disease:

• Failure of Glycosphingolipid breakdown
• Deficiency of lysosomal enzyme b-galactosidase leading to accumulation of glucosylceramides
  
  • infiltration of bone marrow, hepatosplenomegaly, skeletal and CNS complications
• Autosomal recessive disorder (approx. 1 in 20,000) in general population, much higher prevalence in Ashkenazi Jews
• 3 clinical subtypes
  
  • type 1 -adult, non-neuropathic form (>95%)
  • type 2 -infantile, acute neuropathic form
  • type 3 –juvenile form
• Successfully treated with enzyme replacement therapy (Ceredase)