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Y Biochemistry 2 > Midterm II: Cholesterol (Ben) > Flashcards

Midterm II: Cholesterol (Ben) Flashcards

1
Q

What is the first step in the synthesis of mevalonate?

Reactants?

Enzyme?

Products?

A

Condensation…

Reactants: 2x Acetyl-CoA

Enzyme: Thiolase

Products: Acetoacetyl-CoA + CoA-SH

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2
Q

What is the 2nd step in the synthesis of m__evalonate?

Reactants?

Enzyme?

Products?

A

A second condensation…

Reactants: Acetoacetyl-CoA + Acetyl-CoA

Enzyme: HMG-CoA Synthase

Products: HMG-CoA + CoA-SH

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3
Q

What is the 3rd and final step in the synthesis of mevalonate?

Reactants?

Enzyme?

Products?

A

Reduction…

Reactants: HMG-CoA + 2 NADPH + 2 H+

Enzyme: HMG-CoA Reductase

Products: Mevalonate + 2 NADP+ + CoA-SH

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4
Q

After formation of mevalonate…

what is the next (2nd) step of cholesterol synthesis?

(generally, no specific enzymes etc.)

A

formation of isoprenoid units from mevalonate by loss of CO2

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5
Q

After formation of isoprenoid units…

what is the next (3rd) step in cholesterol synthesis?

(generally, no specific enzymes)

A

condensation of six isoprenoid units to form squalene

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6
Q

After squalene formation…

what is the next (4th) step in cholesterol synthesis?

(generally, no specific enzymes)

A

cyclization of squalene to form lanosterol

(lanosterol goes on to form cholesterol)

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7
Q

What is the main step for regulation of cholesterol synthesis?

A

the HMG-CoA Reductase step creating mevalonate near the beginning of synthesis

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8
Q

What endogenous substances directly inhibit HMG-CoA Reductase?

And what drugs inhibit it?

A
  • Bile Acid
  • Cholesterol
  • Mevalonate

(Direct + downstream products of HMG-CoA Reductase activity)

  • Statin drugs​
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9
Q

How do cholesterol + its metabolites repress transcription of HMG-CoA Reductase?

A

by repressing activation of SREBP (steroid regulatory element-binding protein)

  • cholesterol blocks SREBP from moving to the golgi where its HLH domain can be cleaved and sent to the nucleus to upregulate cholesterol synthesis genes
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10
Q

What protein keeps SREBP from moving from to the golgi for cleavage of its HLH domain?

And how else does this protein decrease cholesterol synthesis?

A

Insig (Insulin induced gene)

  • binds to sterol-sensing domain of SCAP and keeps SCAP/SREBP in the ER
  • also directly increases degradation of HMG-CoA Reductase
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11
Q

What protein promotes activation of SREBP and thus its presence in the nucleus as an upregulator of HMG-CoA reductase?

A

SCAP

SREBP Cleavage-Activating Protein

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12
Q

What two enzymes cleave SREBP and allow it to travel to the nucleus?

A

S1P - cleaves the HLH domain off of the rest of the protein

S2P - remove the HLH domain from the golgi membrane for transport to the nucleus

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13
Q

What are the 3 steps of cholesterol absorption from the intestine?

A
  1. Uptake - of hydrolyzed cholesterol esters as free cholesterol via NPC1L1 transporter into enterocyte
  2. Resynthesis - of cholesterol esters
  3. Secretion - of cholesterol esters into chylomicrons in the lymph
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14
Q

What protein is important in absorption of free cholesterol from the intestine?

What drug blocks it?

A

NPC1L1

Niemann-Pick C1-Like Protein 1

  • blocked by ezetimibe
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15
Q

What enzyme is responsible for cholesterol esterification?

Two isoforms… which one is where (types of cells)?

A

ACAT (Acetyl-CoA Acetyltransferase)

  1. ACAT1 - in macrophages and Kupfer cells of the liver
  2. ACAT2 - in hepatocytes and enterocytes
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16
Q

What enzyme is responsible for the conversion of cholesterol esters into free cholesterol?

2 names

A

CEH (Cholesteryl Ester Hydrolase)

AKA Hormone-Sensitive Lipase

  • in all the cells where ACAT can catalyze the opposite rxn ( FC —> cholesterol ester)
17
Q

What enzymes are responsible for the synthesis of TAGs that contribute to lipid droplets in lipoproteins?

A

DGAT (Diglyceride Acyltransferase)

  • forms TAGs from diacylglycerol and acyl-CoA
18
Q

How does lanosterol effect HMG-CoA Reductase activity?

A

it inhibits it via ubiquitination which marks HMG-CoA Reductase for degradation in p__roteasomes

19
Q

Describe post-translational regulation of HMG-CoA Reductase

What hormones affect it and how?

A
  • Insulin - activates protein phosphatases which dephoshporylate/deactivate AMPK, keeping HMG-CoA Reductase dephosphorylated and thus active
  • Glucagon - deactivates the same protein phosphatases
  • essentially, phosphorylation via AMPK deactivates HMG-CoA Reductase
20
Q

What key enzyme plays a role in regulating LDL levels and how?

A

PCSK9

(Proprotein Convertase Subtilisin/Kexin Type 9)

  • binds to LDL Receptors and induces their degradation
  • this leads to a decrease in LDL metabolism + increase in circulating LDL
21
Q

What is the receptor with a dual role in HDL metabolism?

What are its two roles in different tissue types?

A

SR-B1

(Class B Scavenger Receptor B1)

  1. Liver/Steroidogenic Tissues - binds HDL via Apo A-I and delivers cholesteryl esters to cells
  2. Other Tissues - accepts cholesterol efflux from cell to HDL, then HDL goes to liver and cholesterol is excreted in bile
22
Q

What is IDOL?

A

Inducible Degrader of LDL Receptor** **(IDOL)

  • ligates ubiquitin to the LDLR in response to high intracellular cholesterol
  • this leads to LDLR degradation
23
Q

What is reverse cholesterol transport?

What receptor plays a major role + how?

What 2 transporters also play a major role?

(the ‘how’ for the transporters is in another card)

A

transport of cholesterol from peripheral tissues back to the liver via plasma

Receptor: SR-B1

  • mediates efflux of cholesterol to HDL from peripheral tissues AND uptake of cholesterol from HDL (via Apo A-I binding) into the liver

Transporters: ATP-binding cassette transporters A1 + G1 (ABCA1 + ABCG1)

24
Q

How are ABCA1 and ABCG1 involved in reverse cholesterol transport?

A

ABCA1 - promotes cholesterol efflux from tissues specifically to poorly-lipidated particles (ie preβ-HDL + Apo-A1) to convert them to HDL3

ABCG1 - mediates transport of cholesterol from cells to (already lipidated?) HDL

25
Q

What is the enzyme responsible for conversion of discoidal HDL to HDL3 ?

How?

Where is it?

A

LCAT (Lecithin:Cholesterol Acyltransferase)

(in the plasma)

  • binds to discoidal particles with Apo A-I and converts their cholesterol to cholesteryl esters
  • non-polar cholesteryl esters move into the interior of the bilayer, forming a nonpolar core surrounded by a now spherical phospholipid layer
26
Q

How does HDL3 become HDL2 ?

A
  • by accepting cholesterol from tissues via SR-B1 and esterifying it via LCAT
  • this increases particle size and forms the less dense HDL2
27
Q

How does HDL2 convert back to HDL3?

2 mechanisms

And what is this whole HDL2/3 interconversion mechanism called?

A
  1. Delivery of cholesterol ester to liver via SR-B1
  2. Hydrolysis of its phospholipids + TAGs by hepatic + endothelial lipase

Known as the HDL cycle

Y Biochemistry 2 (24 decks)

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