420
chapter 19
Lipids II: Phospholipids, Glycosphingolipids, and Cholesterol
pyrophosphates not only for sterol synthesis but also for
the nonsterol isoprene compounds dolichol, CoQ, heme A,
isopentenyl-tRNA and farnesylated proteins.
Condensation of Isoprenyl Pyrophosphate to
Form Squalene
IPPP, a nucleophile (by virtue of its terminal vinyl group),
and DMAPP, an electrophile, undergo condensation with
elimination of pyrophosphate to yield geranyl pyrophos-
phate (an electrophile), which condenses with a molecule
of IPPP to yield a farnesyl pyrophosphate and pyrophos-
phate. These reactions are probably catalyzed by the
same cytosolic enzyme complex. Two molecules of far-
nesyl pyrophosphate and then condense head-to-head to
form squalene by action of microsomal squalene synthase
(Figure 19-14).
The farnesyl pyrophosphate generated in this pathway
is also used in the farnesylation of proteins. The far-
nesyl group is attached to a protein via the thioether
H — o — ®
— o — ©
C H
C — C H ,
H ,c
3,3-Dim ethylallyl pyrophosphate
(D M A P P )
PP~^
C H ,— O — ®
— O — <£)
C H ,
I
C = C H ,
H,C
3-lsopentenyl pyrophosphate
(IP P P )
Prenyl
transferase
F IG U R E 1 9-14
Synthesis of squalene from isomeric pentenyl pyrophosphates.
linkage involving a cysteine residue found in the C termi-
nus. Several proteins that are modified by farnesyl groups
have been identified, e.g., growth-regulating
ms
proteins
(Chapter 26) and nuclear envelope proteins. Proteins at-
tached to a geranyl-geranyl group (a 20-C isoprene unit)
have also been identified. The modification of proteins
by these lipid moieties increases their hydrophobicity and
may be required for these proteins to interact with other
hydrophobic proteins and for proper anchoring in the cell
membrane. The importance of farnesylation of proteins is
exemplified by blockage of cell growth when mevalonate
synthesis is inhibited.
Conversion of Squalene to Lanosterol
This step comprises cyclization of squalene to lanosterol
(the first sterol to be formed) and conversion of lanosterol
to cholesterol. The cyclization begins with conversion of
squalene to squalene-
2
,3-epoxide by a microsomal mixed-
function oxidase that requires O
2
, NADPH, and FAD
(Figure 19-15). Cyclization of squalene-2,3-epoxide to
lanosterol occurs by a series of concerted
1
,
2
-methyl group
S q u alen e
Q,, NADPH + r fC -J S qualene
m on oxygen ase
HjO NADP+*— ' (sq u alen e ep oxid ase),
F IG U R E 19-15
Cyclization of squalene to lanosterol. Supernatant protein factor (SPF), a
cytosolic protein, promotes both stages of the cyclization.
