Cholesterol Synthesis and Lipid Metabolism Notes

_____ is the main organ of cholesterol synthesis

• Other cells/tissues also synthesize cholesterol

Liver

______ is the precursor of many steroid hormones

Cholesterol

Cholesterol contains _____ carbon atoms

27

Components of the biosynthesis of cholesterol process are:

Acetyl CoA (2C building block), NADPH (redox steps), Enzymes

Biosynthesis of cholesterol: Anabolic Process

• Enzymes are located in the _____ and ______

cytosol and endoplasmic reticulum

How/Why does cholesterol synthesis occur:

• Low levels of cholesterol in cell (cause for synthesis)

• Regulatory pathways are invoked

• Enzyme catalyzed reactions; many steps

• Cholesterol is synthesized

• Synthesis is switched off once desired cellular levels are reached

• Cholesterol exerts ____ feedback on pathway enzymes

negative

Synthesis: Role of HMG CoA

• Step 1: Two molecules of acetyl CoA (2C) condense to form _______ (4C)

• Enzyme: ______

acetoacetyl CoA, B-ketothiolase

Synthesis: Role of HMG CoA

• Step 2: Another unit of acetyl CoA (2C) is linked to acetoacetyl CoA (4C) to form _____ (6C)

• Enzyme: _____

HMG CoA, HMG-CoA synthase

HMG CoA synthase catalyzes _____ and ____ synthesis

ketone bodies, cholesterol

Synthesis of Mevalonate

• Reduction of HMG CoA to mevalonate

• ______ in the overallsynthesis of cholesterol

• Affect the step, affect cholesterolsynthesis (statins work this way)

Rate limiting step

Synthesis of Mevalonate

• HMG CoA reductase (enzyme)

HMG CoA reductase

Synthesis of Mevalonate

• _____ are HMG CoA reductase

  inhibitors

Statins

Mevalonate exerts negative feedback

• Mevalonate is further converted to form _______

  • is aka an Isoprene unit (5C)

IPP

Synthesis: Isoprene unit creation

• Mevalonate converted to 5-pyrophosphomevalonate (6C)

  • Mevalonate kinase

  • Phosphomevalonate kinase

• _________ is decarboxylated to isopentenyl pyrophosphate (IPP)

• _________(enzyme)

• 5C isoprene unit is important in the synthesis of medicinal natural products

Pyrophosphomevalonate, Pyrophosphomevalonate decarboxylase

List the key intermediates in the synthesis of isoprene ro lanosterol

• ______ is converted to _____

• ______ is converted to _____

Isopentenyl pyrophosphate to squalene to lanosterol

Lanosterol is converted to ______

• Many steps

• = final product

cholesterol

After Lanosterol is converted to cholesterol, it is converted to cholesterol esters

• _______ (enzyme)

• Acid counterpart is Fatty acid CoA

• ______ catalyzes the synthesis of cholesterol esters from cholesterol

Acyl CoA cholesterol acyltransferase (ACAT)

Cholesterol is “protected” as CE → ______(CE)

• Prevents oxidation of 2^o alcohol

• CE is hydrolyzed to obtain Cholesterol
  (also enzyme catalyzed)

Cholesterol esters

Why are statins prescribed? → To lower cholesterol

• Statins are ___________

• Suppress synthesis of cholesterol

• Lower cholesterol levels improves cardiac health

competitive inhibitors of HMG CoA reductase

Storage of fatty acids

• Fatty acids esterified with glycerol → triacylglycerol (TAG)

• Recall: TAGs are the storage form of fatty acids

• Reduction of dihydroxyacetone phosphate yields glycerol 3-phosphate (alcohol)

  • ___________(enzyme)

  • Reaction occurs in the liver and adipose tissue

Glycerol 3-phosphate dehydrogenase