Cholesterol: chemistry and biosynthesis
Cholesterol:
Cholesterol is a waxy, fat-like substance that’s found in all the cells in our body. It is an organic
compound that belongs to the steroids family and it is a type of lipid. In humans, all steroid
hormones are derived from cholesterol. About 90% of cholesterol in the body is synthesized in
the liver from acetate while 10% comes from the food we eat. Cholesterol is transported in the
body in the form of high density lipoprotein (HDL) also term as “good cholesterol” and low
density lipoprotein (LDL) also referred to as “bad cholesterol”. Cholesterol is also found to
associate with plasma membrane where it contributes to membrane fluidity. Therefore, synthesis
and uptake of cholesterol in target cells is highly regulated. Below is the structure of cholesterol
Structure of cholesterol
Types of cholesterol
• high density lipoprotein (HDL
• low density lipoprotein (LDL)
High density lipoprotein (HDL
The level of HDL cholesterol should be above 40 mg/dL. HDL brings down the level of
cholesterol in the blood by transporting cholesterol back to the liver, which helps prevent the
cholesterol from being deposited in arteries. So, having higher levels of HDL cholesterol reduces
the risk of heart attack and heart disease.
Low-density Lipoprotein (LDL)
The majority of the cholesterol in the body is LDL. An increase in the quantity of LDL in the
blood leads to an increase in the risk of heart attack or stroke as LDL builds up in the walls of the
blood vessels, causing them to narrow and stiffen, thus blocking blood flow. The level of LDL
cholesterol should be less than 100 mg/dL
Biosynthesis of cholesterol
Cholesterol, like long-chain fatty acids, is made from acetyl-CoA. But the assembly plan of
cholesterol is quite different from that of long-chain fatty acids. Synthesis takes place in four
stages: 1: condensation of three acetate units to form a six-carbon intermediate, mevalonate; 2:
conversion of mevalonate to activated isoprene units; 3: polymerization of six 5-carbon isoprene
units to form the 30-carbon linear squalene; and 4: cyclization of squalene to form the four rings
of the steroid nucleus, with a further series of changes (oxidations, removal or migration of
methyl groups) to produce cholesterol.
Biosynthetic pathway:
Reaction steps
The steps of this process include:
• Thiolase catalyzes the joining of 2 acetyl-coenzyme A (CoA; precursor) molecules →
acetoacetyl-CoA
• 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) synthase adds another acetyl-CoA → βhydroxy-β-methylglutaryl-CoA (HMG-CoA)
• HMG-CoA reductase → mevalonate:
Critical role in cholesterol synthesis
Only regulated enzyme step in the process (feedback inhibition by cholesterol)
Target for cholesterol-lowering medications (statins)
• Mevalonate → isoprenoid precursors (by decarboxylating mevalonate):
Isopentenyl pyrophosphate (IPP)
Dimethylallyl pyrophosphate (DMAPP)
• IPP and DMAPP are combined → geranyl pyrophosphate (geranyl-PP)
• Another IPP is added → farnesyl pyrophosphate (farnesyl-PP)
• 2 farnesyl-PP molecules are joined → squalene
• Squalene is modified → lanosterol (Note: Acetyl-CoA is the exclusive building block up
•
to this point.)
Lanosterol → cholesterol
19 steps
Functions of cholesterol
• Cholesterol is a major precursor for the synthesis of various steroid hormones and also
adrenal gland hormones like cortisol and aldosterone, vitamin D in the calcium
metabolism and sex hormone such as progesterone, estrogen and testosterone.
• It also plays an important role in immune system and brain synapses.
• Cholesterol is a component of bile salt and is oxidized by the liver into a variety of bile
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acids. It also helps the digestive system to absorb fat soluble vitamins A,D,E and K
About 30% of animal cell membranes are made of cholesterol. Therefore, it is necessary
for building and maintaining of the membrane
Cholesterol changes the fluid of the membrane, which may impact the internal cell
environment. It also promotes transportation inside the cell
Overview of Cholesterol Biosynthesis