The reaction catalyzed by HMG Co-A Reductase

Case Details

A 40 -year-old man presents with chest pain that radiates to his left jaw and shoulder. He is diagnosed with a myocardial infarct (heart attack) and is prescribed statin medication. Statins are competitive inhibitors of HMG CoA reductase, which converts HMG Co A to which of the following?

1. Isopentenyl pyrophosphate
2. Mevalonate
3. Geranyl pyrophosphate
4. Farnesyl pyrophosphate
5. Cholesterol.

The correct answer is B- Mevalonate.

Basic concept

Biosynthesis of cholesterol

The biosynthesis of cholesterol may be divided into five steps:

(1) Synthesis of Mevalonate from acetyl-CoA.

(2) Formation of Isoprenoid units from Mevalonate by loss of CO₂.

(3) Condensation of six isoprenoid units forms Squalene.

(4) The cyclization of Squalene gives rise to the parent steroid, Lanosterol.

(5)Formation of cholesterol from lanosterol.

Always remember the formula

2+2= 4

4+2= 6

6-1=5

5+5=10

10+5=15

2×15=30

30-3=27

Details- (See the figure-1 and 2)

i) 2+2= 4

• Initially, two molecules of acetyl-CoA (2+2) condense to form Acetoacetyl-CoA (4) catalyzed by cytosolic thiolase.

ii) 4+2=6

• Acetoacetyl-CoA condenses with a further molecule of acetyl-CoA (4+2) catalyzed by HMG-CoA synthase to form HMG-CoA that is reduced to Mevalonate (6) by NADPH catalyzed by HMG-CoA reductase (figure-1).

Figure-1- Reaction catalyzed by HMF Co A reductase. Statins inhibit HMG Co-A reductase by competitive inhibition and by bile acid, cholesterol, and Mevalonate by feedback inhibition

Significance

• The synthesis of Mevalonate is the committed step in cholesterol formation.
• The enzyme catalyzing this irreversible step, 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis,
• It is the site of action of the most effective class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors (statins).

iii) 6-1=5

• Decarboxylation (6-1 =5) yields Isopentenyl pyrophosphate (5), and activated isoprene unit that is a key building block for many important biomolecules (figure-2).

iv) 5+5=10

• Isopentenyl pyrophosphate Three by a shift of the double bond to form dimethylallyl pyrophosphate that condenses with another molecule of Isopentenyl pyrophosphate (5+5 =10) to form the ten-carbon intermediate Geranyl pyrophosphate (10).

v) 10+5=15

A further condensation with Isopentenyl pyrophosphate forms Farnesyl pyrophosphate (15). 

v) 2×15=30

Two molecules of Farnesyl pyrophosphate (15+15) condense at the pyrophosphate end to form Squalene (30)

vi) 30-3=27

• Squalene can fold into a structure that closely resembles the steroid nucleus
• Before ring closure occurs, Squalene is converted to Squalene 2, 3-epoxide by a mixed-function oxidase in the endoplasmic reticulum, Squalene peroxidase.
• The methyl group on C₁₄ is transferred to C₁₃, and that on C₈ to C₁₄ as Cyclization occurs, catalyzed by oxidosqualene: lanosterol cyclase (figure-2).

The newly formed cyclized structure is Lanosterol.

• The formation of cholesterol from lanosterol takes place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus and side chain.
• Three carbon atoms are lost.
• The double bond at C₈–C₉ is subsequently moved to C₅–C₆ in two steps, forming Desmosterol.
• Finally, the double bond of the side chain is reduced, producing cholesterol.

Figure-2- Steps of cholesterol biosynthesis

As regards other options

Isopentenyl pyrophosphate (IPP) – is formed from Mevalonate- PP

Geranyl pyrophosphate (C10) is formed by condensation of Isopentenyl pyrophosphate and Dimethyl allyl pyrophosphate

Farnesyl pyrophosphate (C15) is produced by condensation of Geranyl pyrophosphate and IPP

Cholesterol- is the end product of this pathway.

Further reading