Making Squalene

 
Squalene is the essential precursor for making cholesterol [How to Make Cholesterol]. The pathway for synthesis of squalene is complicated and it was only worked out in second half of the last century.

The initial substrate is a compound called mevalonate. It's a six carbon branched organic acid. In a later posting we'll wee how cells make mevalonate and learn how that pathway can be controlled by Lipitor® and other drugs that regulate cholesterol levels.

Mevalonate is first phosphorylated by mevalonate kinase in a reaction that requires ATP.


The product of this reaction is mevalonate-5-phosphate and it is immediately phosphorylated again to produce the disphospate derivative. The next step removes the carboxylate group, which is released as a bicarbonate ion (CO₂ dissolved in water produces bicarbonate). This decarboxylation reaction is associated with the formation of a double bond at the end of the product molecule, isopentenyyl diphosphate. This is an important step in the pathway to squalene since squalene has a lot of carbon-carbon double bonds.

The five-carbon isopentenyl group of isopentenyl diphosphate is known as an isoprenyl unit. This molecule (isopentenyl diphosphate) is the source of isoprenyl units for many other biosynthesis reactions in addition to squalene synthesis. &Beta:-carotene and the lipid vitamin A (retinol) are good example of compounds with these isoprene units [Vitamin A (retinol)]. Ubiquinone is an absolutely essential cofactor in many important biochemical reactions an it has an isoprenoid tail [Ubiquinone and the Proton Pump]. Vitamin K, which is required for blood clotting, has a derived isoprenoid tail [THEME: Blood Clotting].

The pathway from isopentenyl diphosphate to squalene is complicated but the basic strategy is quite simple. The idea is to join two five carbon (C₅) isoprene units to make the C₁₀ molecule geranyl diphosphate. Then another C₅ isoprenyl unit is added to make C₁₅ farnesyl diphosphate. Finally, two molecule of farnesyl diphosphate are joined head-to-head to make C₃₀ squalene.


The difficult part of this reaction was figuring out the mechanism so that all of the double bonds would be in the trans conformation. Most of the work was done by John Cornforth who received the Nobel Prize in 1975 [Nobel Laureate: John Cornforth].

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