03: Lipid Metabolism: Cholesterol Synthesis

______ is the main organ of cholesterol synthesis

• Other cells/tissues also synthesize cholesterol

• Cholesterol is the precursor of many steroid hormones

Liver

Cholesterol contains _____ carbon atoms

27

Components of the Biosynthesis of cholesterol process are:

acetyl CoA, NADPH, enzymes

What is/are the source(s) of Acetyl CoA?

• _______ (from Glucose): Under aerobic conditions, pyruvate, which is the end product of glycolysis, is processed through the Pyruvate Dehydrogenase (PDH) complex in the first stage of the tricarboxylic acid (TCA) cycle. For every molecule of pyruvate, one molecule of Acetyl CoA is produced. This conversion also yields one NADH. Since glycolysis of one glucose molecule produces two pyruvate molecules, it means one glucose molecule ultimately yields two Acetyl CoA molecules.

• _____ (Free Fatty Acids): Acetyl CoA can also be generated from the breakdown of fats. Specifically, free fatty acids undergo a process called beta-oxidation, which occurs in the mitochondrial matrix.

  • During beta-oxidation, the fatty acid chain is systematically degraded. Each cycle of beta-oxidation shortens the fatty acid by two carbons, releasing one molecule of Acetyl CoA. For instance, a 16-carbon fatty acid (C16) undergoes seven cycles of beta-oxidation to produce eight molecules of Acetyl CoA.

  • In addition to Acetyl CoA, each round of beta-oxidation also yields one FADH2 and one NADH.

• _______: Acetyl CoA can also come from the catabolism of proteins. Amino acids, derived from protein breakdown, can be funneled into the Krebs cycle, with some forming intermediates that can be converted to Acetyl CoA.

• Once formed, Acetyl CoA enters the TCA cycle (also known as the Krebs cycle or citric acid cycle) to produce significant amounts of ATP equivalents, including NADH, FADH2, and GTP.

Pyruvate, Fats, Proteins

Biosynthesis of cholesterol: Anabolic Process

• Enzymes are located in the:

  ____ and _____

Cytosol, Endoplasmic Reticulum (ER)

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

what is Rate limiting step in the overallsynthesis of cholesterol?

HMG CoA -(HMG CoA reductase)→ mevalonate

HMG CoA reductase (enzyme)

• ______ are HMG CoA reductase inhibitors

Statins

_______ exerts negative feedback

• ______ is further converted to form isopentenylpyrophosphate (IPP)

• IPP is aka an Isoprene unit (5C)

Mevalonate

Synthesis: Isoprene unit creation

1. Mevalonate converted to _____ (6C)

   • Mevalonate kinase

   • Phosphomevalonate kinase

IPP

Synthesis: Isoprene unit creation

2. Pyrophosphomevalonate is decarboxylated to _________

   • ________ (enzyme)

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

isopentenyl pyrophosphate (IPP), Pyrophosphomevalonate decarboxylase

_______ are competitive inhibitors of HMG CoA reductase

• Suppress synthesis of cholesterol

• Lower cholesterol levels improves cardiac health

Statins