Cholesterol Biosynthesis

CHOLESTEROL SYNTHESIS
  • About 1 g of cholesterol is synthesized per day in adults. Almost all the tissues of the body participate in cholesterol biosynthesis. The
  • largest contribution is made by liver (5O%), intestine (15%), skin, adrenal cortex, reproductive tissue etc.
  • The enzymes involved in cholesterol synthesis are found in the cytosol and microsomal fractions of the cell.
  • Acetate of acetyl CoA provides all the carbon atoms in cholesterol.
  • The reducing equivalents are supplied by NADPH while ATP provides energy.
  • For the production of one mole of cholesterol, 18 moles of acetyl CoA, 36 moles of ATP and 16 moles of NADPH are required.
STEPS OF CHOLESTEROL SYNTHESIS
  • Synthesis of beta-hydroxy beta-methylglutaryl CoA (HMG CoA): Two moles of acetyl CoA condense to form acetoacetyl CoA. Another molecule of acetyl CoA is then added to produce HMG CoA.
  • Both cholesterol and ketone bodies are synthesize from beta hydroxyl beta methyl glutary CoA (HMG CoA). So enzymes, thiolase & HMG CoA synthase involved in conversion of acetyl CoA to HMG CoA are common to synthesis of cholesterol and ketone bodies both. However, cytoplasmic HMG CoA synthase is involved in cholesterol synthesis, whereas mitochondrial HMG CoA synthase is involved in Ketone body synthesis.
  • Formation of mevalonate : HMG CoA reductase is the rate limiting enzyme in cholesterol biosynthesis .This enzyme is present in endoplasmic reticulum and catalyses the reduction of HMC CoA to mevalonate.
  • Production of isoprenoid units : In a three step reaction catalysed by kinases, mevalonate is converted to 3-phospho 5-pyrophosphomevalonate which on decarboxylation forms isopentenyl pyrophosphate (lPP). The latter isomerizes to dimethylallyl pyrophosphate(DPP).Presence of Magnesium is required during this step.
  • Synthesis of squalene : IPP and DPP condense to produce a 10-carbon geranyl pyrophosphate( GPP).Another molecule of IPP condenses with GPP to form a 15-carbon farnesyl pyrophosphate (FPP). Two units of farnesyl pyrophosphate unite and get reduced to produce a 30-carbon squalene.
  • Conversion of squalene to cholesterol : Squalene undergoes hydroxylation and cyclization utilizing 02 and NADPH and gets converted to lanosterol. The formation of cholesterol from lanosterol is a multistep process with a series of about 19 enzymatic reactions,which takes place in the membranes of the endoplasmic reticulum.
REGULATION OF CHOLESTEROL SYNTHESIS
  • Cholesterol biosynthesis is controlled by the rate limiting enzyme HMG CoA reductase. HMG CoA reductase is found in association with endoplasmic reticulum, and is subjected to different metabolic controls.
  • Feedback control : Increase in the cellular concentration of cholesterol reduces the synthesis of the enzyme HMG CoA reductase.
  • Hormonal regulation : The enzyme HMG CoA reductase exists in two interconvertible forms. The dephosphorylated form of HMC
  • CoA reductase is more active while the phosphorylated form is less active. Glucagon and glucocorticoids favour the
  • formation of inactive HMG CoA reductase (phosphorylated form) and, thus, decrease cholesterol synthesis.On the other hand, insulin
  • and thyroxine increase cholesterol production by enhancing the formation of active HMC CoA reductase( dephosphorylated form).
  • Inhibition by drugs : Compactin and lovastatin are competitive inhibitors of the enzyme HMG CoA reductase and, therefore, reduce cholesterol synthesis.
  •  HMG CoA reductase activity is inhibited by bile acids. Fasting also reduces the activity of this enzyme.
Exam Question
  • Rate limiting step in cholesterol synthesis is HMG CoA reductase.
  • Lovastatin acts by inhibiting which enzyme Hydroxymethylglutaryl-CoA reductase(HMG CoA reductase).
  • HMG-Co-A Synthase enzyme is common to the synthesis of cholesterol and ketone bodies.
  • Cholesterol is synthesized from Acetyl Co-A.
  • Mineral required for cholesterol biosynthesis is Mg.
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