SECTION 19.3
Cholesterol
419
CH
3
CH,
M evalonate
“O O C — C H — C — C H — CH,OH ■^
nas< ^ » O O C — C H — C — C H — C H — O — ®
I
ATP
ADP
I
OH
OH
M evalonate
5-P hosphom evalonate
A T P -
'
CH3
ADP—-'p
^OOC—CH—
C— CH — CH— O— ® — O— ® -
Phosphom evatonate
kinase
M evalonate-
ATP
5-pyrophospho-
decartx>xylase ''•»ADP
OH
5-Pyrophosphom evalonate
V,
ÇHa
"O O C— c h — ç — c h — c h —
o—®—o—®
O—®
3-Phospho-5-pyrophospho-
m evalonate (unstable intermediate)
H3C
H.C
; c =
c h — C H — O — ® — o — ®
3,3-Dimethylallyl
pyrophosphate
(DMAPP) ».
Isom erase
H,G
H,C
:c—CH—ch—o—® —o—®
3-lsopentenyl pyro-
. phosphate (IPPP)
^
Isop ren yr
pyrophosphates
F IG U R E 1 9 -1 3
Synthesis of isoprenoid units from mevalonate.
Despite inhibition of HMG-CoA reductase by statins,
cells compensate by increasing enzyme expression several
fold. However, the total body cholesterol is reduced by
20-40% due to increased expression of LDL-receptors
after statin administration; this enhances LDL (the ma-
jor cholesterol carrying lipoprotein) clearance from serum
with a net reduction of serum cholesterol (Chapter 20).
Individuals who lack functional LDL-receptors (homozy-
gous familial hypercholesterolemia, Chapter 20) do not
benefit from statin therapy. However, statin therapy is
useful in the treatment of heterozygous familial hy-
percholesterolemia. Since HMG-CoA reductase plays
a pivotal role in the synthesis of many products vi-
tal for cellular metabolism, inhibitors of the enzyme
may have toxic effects. Monitoring of liver and mus-
cle function may be necessary to detect any toxicity
of statin drug therapy. A decreased risk of bone frac-
tures with statin therapy has been observed in subjects
age 50 years or older, who are being treated for hyper-
cholesterolemia. The mechanism of action of statins in
bone metabolism may involve inhibition of prenylation
of
signaling
proteins
of
osteoclast
cell
membrane
(Chapter 37).
Conversion of Mevalonate to
Isoprenyl Pyrophosphate
Isoprenyl pyrophosphates are synthesized by successive
phosphorylation of mevalonate with ATP to yield the
5-monophosphate, 5-pyrophosphate, and 5-pyrophospho-
3-monophospho derivatives. This last compound is very
unstable and loses the 3-phosphate and the carboxyl group
to yield isopentenyl pyrophosphate (IPPP), which is iso-
merized to 3,3-dimethylallyl pyrophosphate (DMAPP).
These reactions, catalyzed by cytosolic enzymes, are
shown in Figure 19-13.
Patients with severe forms of inherited mevalonate
kinase deficiencies exhibit mevalonic aciduria, failure to
thrive, developmental delay, anemia, hepatosplenomegaly,
gastroenteropathy, and dysmorphic features during neona-
tal development. These clinical manifestations under-
score the importance of the formation of isoprenyl
