Organic Chemistry

Section 26.10 Biosynthesis of Cholesterol 027

Konrad Blochand Feodor Lynen

shared the 1964 Nobel Prize in

physiology or medicine. Bloch

showed how fatty acids and

cholesterol are biosynthesized from

acetate. Lynen showed that the two-

carbon acetate unit is actually acetyl-

CoA, and he determined the structure

of coenzyme A.

Konrad Emil Bloch(1912–2000)

was born in Upper Silesia (then a

part of Germany), left Nazi Germany

for Switzerland in 1934, and came to

the United States in 1936, becoming

a U.S. citizen in 1944. He received a

Ph.D. from Columbia in 1938, taught

at the University of Chicago, and

became a professor of biochemistry

at Harvard in 1954.

Feodor Lynen (1911–1979)was

born in Germany, received a Ph.D.

under Heinrich Wieland, and married

Wieland’s daughter. He was head of

the Institute of Cell Chemistry at the

University of Munich.

26.10 Biosynthesis of Cholesterol

How is cholesterol, the precursor of all the steroid hormones, biosynthesized? The
starting material for the biosynthesis is the triterpene squalene, which must first be
converted to lanosterol. Lanosterol is converted to cholesterol in a series of 19 steps.
The first step in the conversion of squalene to lanosterol is epoxidation of the
2,3-double bond of squalene. Acid-catalyzed opening of the epoxide initiates a series
of cyclizations resulting in the protosterol cation. Elimination of a C-9 proton from the
cation initiates a series of 1,2-hydride and 1,2-methyl shifts, resulting in lanosterol.

Converting lanosterol to cholesterol requires removing three methyl groups from
lanosterol (in addition to reducing two double bonds and creating a new double bond).
Removing methyl groups from carbon atoms is not easy: Many different enzymes are re-
quired to carry out the 19 steps. So why does nature bother? Why not just use lanosterol
instead of cholesterol? Konrad Bloch answered that question when he found that mem-
branes containing lanosterol instead of cholesterol are much more permeable. Small mol-
ecules are able to pass easily through lanosterol-containing membranes. As each methyl
group is removed from lanosterol, the membrane becomes less and less permeable.

PROBLEM 25

Draw the individual 1,2-hydride and 1,2-methyl shifts responsible for conversion of the proto-

sterol cation to lanosterol. How many hydride shifts are involved? How many methyl shifts?

cholesterol

H

H

H

HO

H 3 C H

H 3 C

biosynthesis of lanosterol and cholesterol

CH 3

H

HO

H 3 C

H 3 C

CH 3

H

HO

H 3 C

H

H

H+

O

+

squalene

epoxidase

O 2

+ H+

lanosterol

squalene

protosterol cation

19 steps

squalene oxide

CH 3