Cholesterol Synthesis
Thomas Dayspring, MD, FACP
Clinical Assistant Professor of Medicine
University of Medicine and Dentistry of New Jersey,
New Jersey Medical School
Diplomate of the American Board of Clinical Lipidology
Certified Menopause Practitioner: North American Menopause Society
North Jersey Institute of Menopausal Lipidology
Wayne, New Jersey
St Joseph’s Regional Medical Center Paterson, NJ
Joseph’s
1964 Nobel Prize Physiology & Medicine
Cholesterol Synthesis Pathway
Feodor Lynen
Konrad Bloch
A sterol with 27 carbon molecules with
an -OH group at the # 3 position
Hydrocarbon tail
22 24
21 26
25
20 23
18
CH3
12 17 27
11 13 16
19
C27H45OH
CH3 14 15
1 9
2 10 8
3 5 7 4 Hydrocarbon Rings
OH 4
6 3 Hydroxy cholesterol
Sterols are waxy insoluble substances or lipids synthesized from acetyl
coenzyme A (CoA). They are steroid-based alcohols having a hydrocarbon
(aliphatic) side chain of 8–10 carbons at the 17 position and a hydroxyl group
(-OH) at the 3 position (making it an alcohol). Because of the hydrophilicity at
the -OH end and hydrophobicity at the hydrocarbon side chain, sterols can be
incorporated into the lipid bilayers of the cytoplasmic membrane.
Four Stages of 1
Cholesterol
Biosynthesis
2
The liver is responsible for about 15%
of cholesterol synthesis and the
remainder is extrahepatic. 3
Cholesterol synthesis is a four-step
process starting from its precursor
acetate: CH3-COO−
4
Cholesterol Synthesis: Stage 1
Thiolase is an oxidant
enzyme (removes
electrons)
In the first step, two molecules of acetyl-CoA
upon the action of thiolase reversibly forms
acetoacetyl-CoA
Cholesterol Synthesis: Stage 1
Acetyl-CoA condenses with
acetoacetyl-Co upon the action of
cytosolic hydroxymethylglutaryl
(HMG) synthase and becomes
HMG-CoA.
Cholesterol Synthesis: Stage 1
HMG-CoA
β-hydroxy-β-methylglutaryl-CoA
The catalytic action (rate-limiting state)
of HMG-CoA reductase, an integral part
of the smooth endoplasmic reticulum,
irreversibly forms mevalonate (a five-
carbon intermediate) with NADPH
serving as the reductant. HMG-CoA
reductase transcription is tightly
regulated by a membrane-bound
transcription factor designated as sterol
regulatory element-binding protein-2
(SREBP-2)
Different from mitochondrial HMG-CoA
which plays a role in ketosis
Cholesterol Synthesis: Stage 2
5 Carbon units
5 Carbon units
In the second step, mevalonate is phosphorylated from ATP to isoprene units or
isoprenoids, namely isopentyl pyrophosphate, which can isomerize or interconvert to
dimethylallyl pyrophosphate
Cholesterol +
Synthesis:
Stage 3
10 carbon intermediate
Isoprenoids react with each
other to form geranyl
pyrophosphate.
+
Condensation with another
15 carbon intermediate
isopentyl-PP yields farnesyl
pyrophosphate.
Squalene synthase catalyzes +
the condensation of two
molecules of farnesyl-PP with
reduction by NADPH to make
squalene.
30 carbon intermediate
Squalene
Cholesterol
Synthesis:
Stage 4 A series of reactions -
oxidation, cyclization, and
loss of three methyl groups -
results in conversion of
squalene to cholesterol.
The fourth step
involves
conversion of
the linear
squalene
molecule to the
four-ringed
steroid
nucleus.
Lathosterol
27carbon molecule
Cholesterol
Cholesterol Synthesis
Acetate Acetoacetyl-CoA
HMG synthase
Dimethylallyl-PP
HMGCoA
HMG CoA reductase isomerization
Mevalonate Isopentyl-pyrophosphate
condensation
Farnesyl-pyrophosphate
Squalene
Squalene synthase Isoprenoids
Lanosterol Cholesterol
4 ringed structure
19-20 reactions including
Desmosterol, Lathosterol
Dayspring T in Chap 14 Davidson, Toth, Maki Therapeutic Lipidology 2008
Natural Products Derived from Activated Isoprene Units
Isoprene units or Isoprenoids are a class of
largely hydrophobic or nonpolar compounds
related by being constructed biosynthetically
from five-carbon units.
