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Bone (in press)
0165-6147/$ - see front matter. Published by Elsevier Ltd.
doi:10.1016/j.tips.2005.05.001
Lord of the rings the mechanism for
oxidosqualene:lanosterol cyclase becomes crystal clear
Murray W. Huff and Dawn E. Telford
Robarts Research Institute, Vascular Biology Group, Departments of Medicine and Biochemistry, The University of Western Ontario,
London, Ontario N6A 5K8, Canada
The enzyme oxidosqualene:lanosterol cyclase (OSC)
represents a novel target for the treatment of hyper-
cholesterolemia. OSC catalyzes the cyclization of the
linear 2,3-monoepoxysqualene to lanosterol, the initial
four-ringed sterol intermediate in the cholesterol bio-
synthetic pathway. OSC also catalyzes the formation
of 24(S),25-epoxycholesterol, a ligand activator of the
liver X receptor. Inhibition of OSC reduces cholesterol
biosynthesis and selectively enhances 24(S),25-epoxy-
cholesterol synthesis. Through this dual mechanism,
OSC inhibition decreases plasma levels of low-density
lipoprotein (LDL)-cholesterol and prevents cholesterol
deposition within macrophages. The recent crystalliz-
ation of OSC identies the mechanism of action for
this complex enzyme, setting the stage for the
design of OSC inhibitors with improved pharmaco-
logical properties for cholesterol lowering and treat-
ment of atherosclerosis.
Inhibition of cholesterol synthesis as a therapeutic
target for hypercholesterolemia and atherosclerosis
Since the elucidation and characterization of cholesterol
biosynthesis by Konrad Bloch and his colleagues
O50 years ago [1], who would have guessed that this
complex cascade of 25 enzymatic reactions would continue
to teach us new tricks? Probably the best-understood
enzyme involved in this pathway is hydroxymethyl-
glutaryl-coenzyme A (HMG-CoA) reductase, which is the
target of the statin class of cholesterol-lowering drugs [2]
(Figure 1). Statins have revolutionized the treatment
of hypercholesterolemia and cardiovascular disease, and
recent landmark clinical trials of statin treatments have
revealed signicant reductions in cardiovascular mortal-
ity and morbidity that are associated with lowering
cholesterol levels [3]. Statins are well tolerated, although,
theoretically, reductions in the levels of non-sterol inter-
mediates (e.g. isoprenoids and coenzyme Q) synthesized
through the second messenger branch of the cholesterol
synthesis pathway (Figure 1), could be associated with
adverse clinical events, particularly at high doses of statin
[4,5]. Furthermore, as the recommended clinical treat-
ment targets for plasma LDL-cholesterol reduction
become lower, many patients will not achieve the recom-
mended low-density lipoprotein (LDL)-cholesterol concen-
trations with current therapies [3]. This has stimulated
the search for, and development of, compounds that inhibit
cholesterol biosynthesis but act distal to the second
messenger branch pathway, thereby preserving the syn-
thesis of metabolically important non-sterol molecules.
Oxidosqualene:lanosterol cyclase catalyzes the
formation of the rst sterol in cholesterol biosynthesis
2,3-Oxidosqualene:lanosterol cyclase (OSC; EC 5.4.99.7)
is a microsomal enzyme that functions downstream of
squalene inthe cholesterol biosynthetic pathway (Figure 1).
Corresponding author: Huff, M.W. (mhuff@uwo.ca).
Update TRENDS in Pharmacological Sciences Vol.26 No.7 July 2005 335
www.sciencedirect.com
OSC catalyzes the highly selective cyclization of
2,3-monoepoxysqualene to form lanosterol, the rst sterol
to be formed in the pathway [1]. This extraordinary
reaction has been described as the most complex known
enzyme-catalyzed reaction in human biology [6]. Expres-
sion of the gene encoding OSC (LSS; GenBank Accession
no. NM_001001438), like that of several other enzymes in
this pathway, is regulated by sterol regulatory element
binding protein 2 (SREBP-2) [7]. These characteristics
make OSC an attractive and unique target for a
cholesterol-lowering drug [8,9].
Crystallization of human OSC reveals its complex
mechanism of action
In higher organisms, the synthesis of the steroid scaffold
is catalyzed exclusively by OSC. In a highly selective
cyclization reaction, OSC catalyzes the formation of
lanosterol from the linear substrate 2,3-monoepoxysqual-
ene [1]. The mechanisms that underlie this complex
cyclization cascade have been elucidated during the past
50 years using specic inhibitors, site-directed muta-
genesis experiments and homology modeling largely
based on the bacterial enzyme squalene hopene cyclase
TRENDS in Pharmacological Sciences
Squalene
epoxidase
Cholesterol synthesis
pathway
Alternative oxysterol
synthesis pathway
Statins
2,3-Monoepoxysqualene 2,3;22,23-Diepoxysqualene
24(S),25-Epoxylanosterol
24(S),25-Epoxycholesterol
Lanosterol
Cholesterol
(d) (e)
(c)
(f)
Squalene
Mevalonic acid
HMG-CoA
Acetyl-CoA
Second messenger pathway
(isoprenoids, coenzyme Q,
FPP, GPP, dolichol)
(b)
HMG-CoA reductase (a)
2,3-Oxidosqualene:lanosterol
cyclase inhibitor
2,3-Oxidosqualene:lanosterol
cyclase
LXRE Gene ?
ABCA1, ABCG1
ABCG5, ABCG8
SREBF1
FASN
LXR
RXR
Figure 1. The cholesterol biosynthetic pathway and alternative pathway for oxysterol synthesis. The complex process of cholesterol synthesis involves O25 steps and only
those relevant to this revieware highlighted here. Acetyl-CoAis initially converted to isoprene units, which subsequently condense to forma linear molecule with 30 carbons
(squalene) that cyclizes to form lanosterol, the initial four-ring structure formed in the synthesis of cholesterol. A rate-limiting, regulated enzyme that functions early in the
pathway is hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (a), which converts HMG-CoA to mevalonic acid. The statin class of drugs are competitive inhibitors of
HMG-CoA reductase. Downstream of mevalonic acid is the isoprenoid branch pathway or second messenger pathway (b) in which metabolically important molecules,
including isoprenoids, coenzyme Q, farnesylpyrophosphate (FPP), geranylgeranylpyrophosphate (GPP) and dolichol, are synthesized. Another rate-limiting, regulated
enzyme of the cholesterol biosynthetic pathway is 2,3-oxidosqualene:lanosterol cyclase (OSC) (c), which functions distal to the second messenger pathway branch-point.
OSC catalyzes the conversion of 2,3-monoepoxysqualene (MOS) to the initial four-ringed steroid formed, namely lanosterol (d). Alternatively, MOS is converted to 2,3;22,23-
diepoxysqualene (DOS) by squalene epoxidase, which is the initial step of the alternate oxysterol synthesis pathway. OSC catalyzes the conversion of DOS to 24(S),25-
epoxylanosterol (e), which is ultimately converted to 24(S),25-epoxycholesterol (red triangles). OSC has a higher afnity for DOS compared with MOS. Through this
competition, partial inhibition of OSC (f) increases the conversion of MOS to DOS, and the conversion of DOS via OSC to 24(S),25-epoxylanosterol and subsequently to
24(S),25-epoxycholesterol. 24(S),25-Epoxycholesterol is a potent activator of the nuclear hormone receptor liver X receptor (LXR). LXR heterodimerizes with the retinoid
X receptor (RXR) and regulates genes involved in the metabolism of cholesterol and fatty acids, including the ATP-binding cassette transporters [ABCA1, ABCG1, ABCG5,
ABCG8 and sterol regulatory element binding protein 1c (SREBF1)]. In contrast to synthetic LXR agonists, activation of LXR by 24(S),25-epoxycholesterol does not appear to
affect the expression of the gene encoding fatty acid synthase (FASN). Adapted from [15].
Update TRENDS in Pharmacological Sciences Vol.26 No.7 July 2005 336
www.sciencedirect.com
(SHC) [10,11]. However, the molecular topology of the
mammalian enzymatic reaction remained unresolved. In
2004, Thoma and colleagues provided unique insights into
this complex cyclization reaction by reporting two crystal
structures of human OSC: one crystallized in the presence
of the product lanosterol and the other crystallized in the
presence of a specic inhibitor of OSC [12]. Now, for the
rst time, a clear picture has emerged of the complex
mechanism whereby this enzyme achieves the initial
synthesis of the four-ringed structure of the steroid
nucleus (Figure 2).
OSC is monomeric in the crystal and consists of a large
active-site cavity centered between two (a/a) barrel
domains that are connected by loops and three smaller
b-structures [12]. The catalytic mechanism for the
polycyclization reaction involves adoption of a pre-
organized conformation by 2,3-monoepoxysqualene, fol-
lowed by protonation of the epoxide ring. A cascade is
triggered, resulting in a series of ring-forming reactions.
Skeletal rearrangement through a series of hydride- and
methyl-group shifts and a nal deprotonation step
produces lanosterol (Figure 2). Product specicity and
stereoselectivity are achieved by the requirement for a
pre-folded conformation of the substrate, progression
of the reaction through rigidly held intermediates, and
stabilization of the intermediate carbocations, thus
preventing early truncation of the cyclization cascade.
OSC represents a potential target for the development
of novel cholesterol synthesis inhibitors [8,9]. The OSC
crystals produced by Thoma et al. revealed that the
structure of the benchmark OSC inhibitor RO0488071
(see Chemical names) in complex with human OSC was
well dened and conrmed previous uorescent experi-
ments that demonstrated competitive inhibitor binding
and a 1:1 binding ratio [12]. Importantly, the OSC
structure pinpoints the fact that inhibitor design based
on the previously dened structure of bacterial SHC [12]
results in inaccurate predictions for the conformation of
OSC inhibitors. Direct hydrogen bonding occurs between
the amino group of RO0488071 and the catalytic Asp455
residue within OSC but does not occur between the amino
group of RO0488071 and SHC. Furthermore, the active-
site cavity in OSC is smaller than in SHC. Therefore,
solving the OSC co-crystal structure provides a signicant
breakthrough for the development of highly selective OSC
inhibitors with enhanced physiochemical properties.
Why is OSC such an attractive target for inhibition of
cholesterol synthesis?
OSC occupies a unique position in the cholesterol bio-
synthetic pathway. OSC not only catalyzes the conversion
of 2,3-monoepoxysqualene to lanosterol but also catalyzes
the cyclization of 2,3;22,23-diepoxysqualene to 24(S),25-
epoxylanosterol, which is subsequently transformed into
24(S),25-epoxycholesterol in the alternative oxysterol
synthesis pathway [13] (Figure 1). Synthesis of 24(S),25-
epoxycholesterol is favored over cholesterol synthesis
under conditions of partial OSC inhibition because
2,3;22,23-diepoxysqualene has a lower K
m
for OSC than
does 2,3-monoepoxysqualene [14]. 24(S),25-Epoxycholes-
terol is one of the most potent naturally occurring ligand
activators of the liver X receptor (LXR) [15]. LXR
HO
+
B-ring
10
H
HO
H
+
C-ring
15
O
Enz
BH
Above molecular plane
Below molecular plane
HO
+
A-ring
6
O
6
3
10
15
19 23
HO
H
H
H
+
20
D-ring
9
8
17
HO
H
H
H
Lanosterol
MOS
Figure 2. 2,3-Oxidosqualene:lanosterol cyclase catalyzes the cyclization of 2,3-monoepoxysqualene (MOS) to lanosterol. The catalytic mechanism for the four cyclization
reactions involves several steps. Initially, the MOS becomes organized into a chair-boat-chair orientation (red outline). The epoxide ring becomes protonated, thereby
initiating a cascade of ring-forming reactions. Rearrangement of the skeletal structure of this intermediate is achieved through a series of 1,2-hydride- and 1,2-methyl-group
shifts. A nal deprotonation step leads to the formation of lanosterol. The putative conformations after closure of the A-ring, B-ring and C-rings (using the MOS cation
numbering) and rearrangement of the molecular skeleton of the protosterol cation (using lanosterol numbering) resulting in D-ring closure through 1,2-shifts of hydride and
methyl groups are depicted. Reproduced, with permission, from [12].
Update TRENDS in Pharmacological Sciences Vol.26 No.7 July 2005 337
www.sciencedirect.com
activationbyother oxysterols and/or synthetic non-steroidal
LXR activators enhances the expression of several genes
that are important in the regulation of cellular lipid
metabolism. These include the ATP-binding cassette genes
ABCA1, ABCG1, ABCG5 and ABCG8 (GenBank Accession
nos NM_005502, NM_207629, NM_022436 and
NM_022437, respectively), all of which are involved in
the cellular efux of cholesterol and/or plant sterols, in
addition to the genes encoding SREBP-1c (SREBF1;
NM_004176), fatty acid synthase (FASN; NM_004104.4)
andlipoproteinlipase (LPL; NM_000237) (reviewedin[16]).
A clearer picture of how these complex regulatory mechan-
isms interact to achieve therapeutic benet in response to
inhibition of OSC is now beginning to emerge.
Administration of a prototypic OSC inhibitor,
RO0488071, to hamsters, squirrel monkeys and Gottingen
minipigs decreased the levels of plasma LDL-cholesterol by
3035% relative to untreated control animals [17]. In
hamsters, RO0488071 decreased plasma levels of triglycer-
ides and LDL-cholesterol but did not increase the activities
of HMG-CoAreductase, squalene synthase or OSCitself, an
effect attributed to OSC inhibitor-induced increased levels
of oxysterols that repress SREBP-2-responsive genes [17].
Coenzyme Q10 was unaffected in heart and liver [17]. Thus,
OSCinhibitors appear to lower serum- and LDL-cholesterol
effectively in small-animal models in which the animals are
fed diets high in both fat and cholesterol.
Inhibition of OSC decreases LDL-cholesterol through a
dual mechanism of action
Recently, Telford et al. explored the mechanism whereby
OSCinhibitors modulate the kinetics of apolipoprotein(apo)
TRENDS in Pharmacological Sciences
Intestine
Cholesterol
LDL
Hepatocyte
VLDL
Blood
vessel
ABCG5, ABCG8
Dietary
cholesterol
Blood vessel
NPC1L1
Cholesterol (C) and
plant sterols (PS)
C
+
PS
CE C
24(S),25-EC
CE
droplets
24(S),25-EC
apoAI
HDL2,3
ABCG1
ABCA1
(a)
(b)
(i)
(f)
(c)
(d)
ABCG5, ABCG8
(k)
(h)
LDL
receptor-
mediated
uptake
(j)
(l)
(d)
(f)
24(S),25-EC OSC
Synthesis
HMG-CoA reductase
(g)
VLDL
secretion
Chylo-
microns
ABCG5, ABCG8
(e)
Biliary cholesterol
Enterocyte Intestinal lumen Lymph
OSC
OSC
LDL-apoB
VLDL-
apoB
Macrophage
LXR
LXR
LXR
Figure 3. Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC) by the OSC inhibitor RO0717625 reduces plasma concentrations of apolipoprotein B (apoB)-containing
lipoproteins and blocks macrophage foam cell formation through a dual mechanism of action. In a large-animal model of human lipoprotein metabolism, OSC inhibition
(red X) leads to inhibition of hepatic cholesterol biosynthesis (a) in addition to enhanced synthesis of 24(S),25-epoxycholesterol (EC) (b). 24(S),25-Epoxycholesterol
potentiates the decrease in the hepatic concentration of cholesterol through upregulation of the liver Xreceptor (LXR)-responsive genes that encode the ATP-binding cassette
transporters ABCG5 and ABCG8 in both liver (c) and intestine (d). Hepatic expression of ABCG5 and ABCG8 increases the secretion of cholesterol from liver into bile (e).
Cholesterol and plant sterols are absorbed from the intestine by the sterol transporter Niemann-Pick C1-like 1 (NPC1L1). Both sterols can be re-excreted into the intestine by
ABCG5 and ABCG8. Thus, enhanced expression of ABCG5 and ABCG8 limits net cholesterol absorption (f) and therefore reduces the amount of cholesterol reaching the liver
via chylomicrons (intestinal apoB-containing lipoproteins). The primary mechanism for a reduction in plasma levels of apoB is a substantial decrease in VLDL-apoB
production (g) and enhanced LDL receptor-mediated LDL-apoB clearance (h), both of which are linked to the reduction in hepatic cholesterol levels. In macrophages, OSC
inhibitor-induced synthesis of 24(S),25-epoxycholesterol (i) inhibits cholesterol ester (CE) deposition (j) through upregulation of ABCA1 and ABCG1 (k), resulting in enhanced
cholesterol efux to apoA1 or high-density lipoproteins (HDL2 and HDL3), respectively (l). Thus, OSC inhibition represents a potential treatment of hypercholesterolemia and
atherosclerosis via a dual mechanism of action.
Update TRENDS in Pharmacological Sciences Vol.26 No.7 July 2005 338
www.sciencedirect.com
B metabolism in a large-animal model in which animals
were fed a physiologically relevant diet [18]. The kinetics of
plasma apoB, the structural apoprotein component of very
low-density lipoprotein (VLDL) and LDL, were examined in
miniature pigs following administration of RO0717625, a
recently developed OSC inhibitor. Compared with control
animals, inhibition of OSC signicantly decreased
LDL-apoB concentrations as a result of a large increase in
its clearance from plasma, and VLDL-apoB secretion into
plasma was signicantly reduced. Furthermore, hepatic
concentrations of cholesterol were decreased, and were
associated with increased mRNA levels of hepatic LDL
receptors and HMG-CoAreductase. Expression of the LXR-
responsive genes ABCG5 and ABCG8 were enhanced in
both liver and intestine. Liver triglyceride concentrations
were unaffected, which indicates that neither fatty acid
synthesis nor triglyceride synthesis was altered by OSC
inhibition. Therefore, OSCinhibition can reduce the levels
of LDL-cholesterol as a consequence of a reduction of the
concentration of hepatic cholesterol; this occurs through
a dual mechanism of action: decreased cholesterol
synthesis and increased synthesis of 24(S),25-epoxy-
cholesterol (Figure 3).
Inhibition of OSC has the potential to attenuate
atherogenesis
Inhibitors of OSC have the potential to suppress athero-
genesis directly at the arterial wall through attenuation
of macrophage foam cell formation. Recently, Rowe et al.
reported that partial inhibition of OSC by RO0714565
signicantly inhibited cholesterol ester deposition induced
by atherogenic lipoproteins in cultured macrophages [15].
RO0714565 inhibited cholesterol synthesis and increased
24(S),25-epoxycholesterol synthesis, resulting in LXR acti-
vation. This resulted in substantial upregulation of ABCA1
and ABCG1 expression, which led to enhanced macrophage
cholesterol efux (Figure 3). In contrast to the synthetic,
non-steroidal LXR activator TO901317, the OSC inhibitor
had no effect on fatty acid or triglyceride synthesis, and
blocked the formation of the active nuclear formof SREBP-
1c. This concept was conrmed recently by Wong et al. [19].
These studies highlight a new mechanism for the dual
regulation of LXR- and SREBP-responsive genes, an
approach that inhibits foam cell formation without a
detrimental effect on triglyceride synthesis or its accumu-
lation within the macrophage.
Perspectives
The impact of OSCinhibition on lipoprotein metabolismin
humans remains to be elucidated. Nevertheless, the novel
data provided by Thoma et al. [12] pave the way for the
development of new, highly specic inhibitors of this
enzyme, designed to optimally increase the synthesis of
24(S),25-epoxycholesterol. It might be possible to design
OSC inhibitors that selectively attenuate the afnity of
OSC for 2,3-monoepoxysqualene, resulting in inhibition of
cholesterol synthesis, but have little or no effect on the
afnity of OSC for 2,3;22,23-diepoxysqualene as a
substrate. Such a strategy would favor 24(S),25-
epoxycholesterol synthesis, thereby facilitating LXR
activation at a wider range of inhibitor concentrations
than that observed with currently available prototype
OSC inhibitors. In a recent editorial, Bjorkhem and
Diczfalusy refer to 24(S),25-epoxycholesterol as a
potential friend and suggest that attempts to increase
levels of this compound might represent a new
strategy for the prevention of atherosclerosis [20].
Therefore, the discovery of new and specic inhibitors
of OSC could provide the required tools to explore this
novel therapeutic approach.
Acknowledgements
Research in our laboratory was supported by grants from the Heart and
Stroke Foundation of Ontario (T-5603) and the Canadian Institutes for
Health Research (MT-8014). We thank Robert A. Hegele for helpful
discussions.
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Chemical names
RO0488071: [4
0
-(6-allyl-methyl-amino-hexyloxy)-2
0
-uor-phenyl]-
(4-bromo-phenyl)-methanone fumarate
RO0714565: trans-N-(4-{5-[ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-
cyclohexyl)-N-methyl-4-triuoromethyl-benzenesulfonamide
fumarate
TO901317: N-(2,2,2-triuoro-ethyl)-N-[4-(2,2,2-triuoro-1-hydroxy-1-
triuoromethyl-ethyl)-phenyl]-benzenesulfonamide
Update TRENDS in Pharmacological Sciences Vol.26 No.7 July 2005 339
www.sciencedirect.com
16 Ory, D.S. (2004) Nuclear receptor signaling in the control of
cholesterol homeostasis: have the orphans found a home? Circ. Res.
95, 660670
17 Morand, O.H. et al. (1997) Ro 48-8071, a new 2,3-oxidosqualene:
lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters,
squirrel monkeys, and minipigs: comparison to simvastatin. J. Lipid
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18 Telford, D.E. et al. (2004) A novel inhibitor of oxidosqualene cyclase
decreases VLDL and LDL apoB 100 through decreased VLDL pro-
duction and enhanced LDL catabolism. XV International Symposium
on Drugs Affecting Lipid Metabolism Abstract,10
19 Wong, J. et al. (2004) Statins inhibit synthesis of an oxysterol
ligand for the liver x receptor in human macrophages with
consequences for cholesterol ux. Arterioscler. Throm. Vasc. Biol. 24,
23652371
20 Bjorkhem, I. and Diczfalusy, U. (2004) 24(S),25-epoxycholesterol a
potential friend. Arterioscler. Thromb. Vasc. Biol. 24, 22092210
0165-6147/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tips.2005.05.004
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