Cholesterol Synthesis

Stage 1: Mevalonate Synthesis

 

• Two molecules of cytosolic acetyl-CoA condense to form acetoacetyl-CoA.
• The reaction is catalyzed by a thiolase.

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• Acetoacetyl-CoA condenses with another acetyl-CoA forming hydroxymethylglutaryl CoA (HMG-CoA).
• The reaction is catalyzed by HMG-CoA synthase.

 

 

 

• HMG-CoA, a key intermediate in the biosynthesis of cholesterol, is reduced in the endoplasmic reticulum to mevalonic acid. This reduction results in the hydrolysis of the thioester bond of HMG-CoA producing mevalonate and CoA-SH (reduced CoA).
• This is the committed step of cholesterol biosynthesis.
• The reaction is catalyzed by the regulatory enzyme HMG-CoA reductase. This enzyme catalyzes the four-electron reduction of HMG-CoA to coenzyme A and mevalonate, which is the rate limiting step in sterol biosynthesis.

HMG-CoA + 2NADPH + 2H⁺ —› HMGR mevalonate + 2NADP⁺ + CoASH

• HMG-CoA reductase is inhibited by cholesterol. In the liver, it is also inhibited by bile salts.
• The reaction utilizes 2 molecules of NADPH, which is oxidized to NADP.

 

 

Stage 2: Conversion of Mevalonate to Activated Isoprenes

 

 

 

 

• Mevalonic acid is phosphorylated 3 times at C5 (two phosphates forming pyrophosphate) and C3.
• These reactions require 3 molecules of ATP.

 

 

 

 

 

 

 

 

 

 

 

 

• Phosphorylated mevalonate is decarboxylated.

• An activated 5-carbon isoprenoid, isopentenyl pyrophosphate (IPP), is formed.

 

 

 

• IPP is isomerized to another activated isoprene - DPP.

 

 

Stage 3: Condensation of Isoprenoids to Form Squalene

 

 

 

• Two molecules of isopentenyl pyrophosphate (one of them is an isomer) condense, forming a 10-carbon compound, geranyl pyrophosphate.

 

 

 

 

• Geranyl pyrophosphate reacts with another isopentenyl pyrophosphate to form a 15-carbon compound, farnesyl pyrophosphate. The reaction is catalyzed by prenyl transferase.

 

 

  

• Squalene is formed from two 15-carbon units in the reaction catalyzed by squalene synthase. This is the second reaction in the cholesterol synthesis pathway that requires NADPH as a coenzyme.

 

 

 

Stage 4: Conversion of Squalene to Lanosterol and Cholesterol

 

 

 

• Squalene is oxidized by squalene monooxygenase using another molecule of NADPH as a coenzyme.

 

 

 

 

 

 

 

• Cyclization reaction forms lanosterol.

 

 

 

 

 

 

• Lanosterol is converted to cholesterol in the last series of reactions. The conversion of lanosterol to cholesterol requires 19 additional reaction steps.

 

 

 

 

 

 

Value: 1 The committed step in cholesterol synthesis is: a. Synthesis of β-hydroxy-β-methylglutaryl coenzyme A b. Reduction of β-hydroxy-β-methylglutaryl coenzyme A c. Decarboxylation of pyrophosphate mevalonate to isopentenyl pyrophosphate d. Condensation of activated isoprenes to form squalene e. Phosphorylation of mevalonate	Value: 1 Which of the following enzymes is not involved in cholesterol synthesis? a. Thiolase b. Mevalonate kinase c. Prenyl transferase d. Squalene monooxygenase e. Acyl transferase
Value: 1 The product of condensation of three acetyl groups in cholesterol biosynthesis is called:	Value: 1 The 30-cabon intermediate in cholesterol synthesis resulting from condensation of 6 activated isoprenes units is called:
Value: 1 Which two enzymes involved in the synthesis of cholesterol require NADPH as a coenzyme? a. HMG-CoA reductase, squalene synthase b. HMG-CoA reductase, HMG-CoA synthase c. HMG-CoA synthase, mevalonate kinase d. mevalonate kinase, thiolase e. thiolase, HMG-CoA reductase	Value: 1 Decarboxylation of mevalonate is preceded by 3 __________ reactions.

 

 

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