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From the Department of Biochemistry, Michigan State University,
East Lansing, Michigan 48824
INTRODUCTION Prostaglandin endoperoxide H synthases
(PGHSs)1 catalyze the conversion of
arachidonic acid and O2 to PGH2, the committed
step in prostanoid biosynthesis (Fig. 1) (1). Before
1991, only one PGHS had been described, the isozyme now called
PGHS-1, COX-1 (for cyclooxygenase-1) or the
constitutive enzyme. At that time Simmons and
Herschman and their colleagues discovered mRNAs whose expression
was induced in chicken and mouse fibroblasts in response to
src and tumor-promoting phorbol esters, respectively, and
which encoded proteins having 60% amino acid sequence identity with PGHS-1. Subsequent work has shown that the new protein, called PGHS-2,
COX-2 or the inducible isoform, is very similar to PGHS-1 in
structure but differs substantially from PGHS-1 with respect to its
pattern of expression and its biology. The reason for the existence of
the two PGHS isozymes is unknown. However, PGHS-1 and -2 are often
coexpressed in the same cell and may act as parts of separate
prostanoid biosynthetic systems that function somewhat independently to
channel prostanoids to the extracellular milieu and the nucleus,
respectively.
PGHS-1 and -2 are interesting in the context of both structural
biology and enzymology in that they are homodimeric,
heme-containing, glycosylated proteins with two catalytic sites.
Moreover, the enzymes have a novel mechanism for membrane attachment;
they are anchored to one leaflet of the lipid bilayer through the
hydrophobic surfaces of amphipathic helices rather than through
transmembrane motifs typical of many integral membrane proteins. The
isozymes are also important pharmacologically as targets of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) (2). For example,
aspirin acts via PGHS-1 to inhibit platelet thromboxane A2
formation and as a clinical consequence lowers the relative risk for
mortality from cardiovascular disease (3). PGHS-2 is the relevant
target of NSAIDs acting to inhibit inflammation (4, 5), fever (5), pain
(4), and probably colon cancer (6, 7, 8). NSAID therapy may even retard
the development of Alzheimer's disease (9) although it is not clear
which PGHS isozyme may be involved. In this review we compare and
contrast PGHS-1 and -2 in the context of the regulation of expression
of the two enzymes, the mechanisms of enzyme catalysis, and the
biological significance of having two PGHSs.
Regulation of PGHS-1 and PGHS-2 Expression PGHS-2 is undetectable in most mammalian tissues, but its
expression can be induced rapidly (2-6 h) in fibroblasts (10, 11, 12, 13),
endothelial cells (14), monocytes (15), and ovarian follicles (16) in
response to growth factors, tumor promoters, hormones, bacterial
endotoxin, and cytokines; in most cases the level of the protein then
decreases rapidly. The rapid induction of PGHS-2 mRNA, which can be
superinduced by cycloheximide, parallels the expression of
c-fos leading to the classification of PGHS-2 as an
immediate early gene. In fibroblasts, increased expression is due to an
increased rate of PGHS-2 gene transcription (11). In other systems,
post-transcriptional regulation contributes to the magnitude and
duration of PGHS-2 mRNA expression (17). A second notable feature
of PGHS-2 expression is that anti-inflammatory steroids
(i.e. cortisol, dexamethasone) inhibit stimulated expression of PGHS-2 mRNA and protein (18, 19, 20) via both transcriptional (11)
and post-transcriptional mechanisms (10, 17).
In contrast to PGHS-2, PGHS-1 can be detected in most tissues
although not within all cells of a tissue (1). In cultured cells
PGHS-1 is typically expressed at constant levels throughout the cell
cycle (11). Hence, PGHS-1 has become known as the
constitutive isozyme, and PGHS-2 is known as the
inducible isoform. This is actually an oversimplification
because PGHS-2 is expressed constitutively in brain (21), testes (22),
tracheal epithelia (23), and the macula densa in kidney (24), while
PGHS-1 levels change during development (25), and its expression can be
down-regulated in endothelial cells in response to acidic fibroblast
growth factor (26) and up-regulated in mast cells treated with stem
cell factor plus dexamethasone (27).
PGHS-1 and -2 are encoded by separate genes located on different
chromosomes. The gene for PGHS-1 is approximately 22 kilobase pairs and
contains 11 exons (28). Typical of developmentally regulated
"housekeeping" genes, the PGHS-1 gene lacks a TATA box. Virtually
nothing is known about the details of the regulation of PGHS-1 gene
expression.
The PGHS-2 gene is 8 kilobase pairs in length and contains 10 exons (18). PGHS-2 expression can be induced through multiple signaling
pathways involving protein kinases A and C, tyrosine kinases, bacterial
endotoxin (lipopolysaccharide), and src. Several relevant
enhancer sequences have been identified in the PGHS-2 gene promoter. In
bovine endothelial cells, a CEBP Mechanisms of Enzyme Catalysis PGHSs catalyze both a cyclooxygenase (bis-oxygenase)
reaction in which arachidonate is converted to PGG2 and a
peroxidase reaction in which PGG2 undergoes a two-electron
reduction to PGH2 (Figs. 1 and 2). PGHS-1
and -2 have similar cyclooxygenase turnover numbers (~3500 mol of
arachidonate/min/mol of dimer (33, 34)), and the Km
values for arachidonate (~5 µM (34, 35)) and
O2 (~5 µM
(36))2 are about the same for both
isozymes. Furthermore, the key residues involved in catalysis are
conserved between the isozymes, and the crystal structures of the two
isozymes are essentially superimposable (Figs. 3 and
4). There are some subtle differences in peroxide requirements (37, 38, 39) and fatty acid substrate specificities (40), but
in the overall context of catalytic mechanisms, these proteins appear
to be essentially the same.
The cyclooxygenase reaction begins with the rate-limiting abstraction
of the (13S)-hydrogen from arachidonate to yield an arachidonyl radical (Figs. 1 and 2B (41)). This is followed by sequential oxygen additions at C-11 and C-15 to yield
PGG2. Finally, the peroxidase activity reduces the
15-hydroperoxide group of PGG2 to an alcohol yielding
PGH2. NSAIDs compete directly with arachidonate for binding
to the cyclooxygenase site and inhibit cyclooxygenase activity but have
little effect on peroxidase activity (42, 43). Thus, the cyclooxygenase
and peroxidase sites are physically and functionally separate.
A combination of classical protein chemistry (1), UV-visible (44,
45) and epr spectroscopy (46, 47, 48, 49), and x-ray crystallography (50) has
established that the active sites of PGHS are configured as shown in
Fig. 2A for ovine PGHS-1 (1). The cyclooxygenase active site
is a channel that is lined with hydrophobic residues and protrudes
toward the center of the major globular domain of the enzyme (50).
The branched chain mechanism describing the interplay of the
cyclooxygenase and peroxidase activities is shown in Fig. 2B (45, 51). The cyclooxygenase reaction has an absolute requirement for a
hydroperoxide (33). Initially either an alkyl peroxide or peroxynitrite
derived from the condensation of nitric oxide and superoxide (39)
oxidizes the heme group at the peroxidase active site. The oxidized
heme group then oxidizes a neighboring Tyr-385 located in the
cyclooxygenase active site (46, 50, 52). The resulting tyrosyl radical
abstracts the (13S)-hydrogen from arachidonate.
Arg-120 is another key active site residue (Figs. 2A and 3).
It serves as the counterion for the carboxylate groups of arachidonate and common NSAIDs (50, 53, 54). Tyr-355 lies on the opposite side of
the channel from Arg-120 and governs the stereospecificity of PGHSs
toward NSAIDs (50, 53).
Serine 530 is the site of acetylation of ovine PGHS-1 by aspirin (Figs.
2A and 3 (55)). X-ray crystallographic analysis of the
aspirin-acetylated enzyme (55) and studies of mutant proteins in which
Ser-530 has been substituted with other residues (56) have established
that when serine 530 is acetylated by aspirin the acetyl group
protrudes into the cyclooxygenase active site and interferes with
arachidonate binding (Fig. 3). Covalent modifications of PGHSs by
aspirin cause permanent inactivation of the enzymes. The ability of
aspirin to modify PGHS-1 is the basis for the unique, long lived effect
of aspirin on platelet activity because circulating platelets, unlike
most cells, do not synthesize new PGHS-1.
Aspirin represents a pharmacological extreme in that it causes covalent
modification and irreversible inhibition of PGHSs (56, 57). At the
other extreme are agents such as ibuprofen, which behave as typical
reversible competitive inhibitors (35, 43). Importantly, there are a
number of NSAIDs including indomethacin, flurbiprofen, and
meclofenamate, which exhibit an intermediate form of inhibitory
behavior and which are known as time-dependent, reversible
inhibitors (1, 35, 43, 58). Binding of these drugs to PGHSs yields an
initial EI complex typical of a reversible competitive
inhibitor, but this EI complex slowly (in seconds to
minutes) rearranges to an EI* complex from which the drug
dissociates very slowly (minutes to hours) (1, 58).
All currently available NSAIDs inhibit both PGHS-1 and -2 and compete
with arachidonate for binding to the cyclooxygenase active site (1).
These compounds are effective anti-inflammatory agents, but they are
also all quite ulcerogenic (2). Many pharmaceutical firms have
developed new cyclooxygenase inhibitors that selectively inhibit
PGHS-2. These efforts were initially driven by two notions, which
subsequently proved to be correct: (a) that PGHS-2 is the relevant enzyme in inflammation (4) and (b) that PGHS-1 but not PGHS-2 is present in the stomach (59). Indeed, PGHS-2 inhibitors have been reported to be anti-inflammatory and analgesic and to lack
gastrointestinal toxicity (4, 5).
All of the PGHS-2-selective agents are
time-dependent, reversible inhibitors of PGHS-2 (60, 61, 62).
Included in this group of agents are DuP697 (62), SC52125 (60),
L-745-337 (5), NS398 (63), and meloxicam (2). Curiously, these agents
are all relatively poor inhibitors of PGHS-1, and this is probably due
to the one amino acid difference between PGHS-1 and -2 within the
hydrophobic cyclooxygenase channel. PGHS-2 has a valine at position
509, while the corresponding amino acid in PGHS-1 is an isoleucine.
V509I PGHS-2 behaves somewhat like PGHS-1 in being relatively
unresponsive to time-dependent inhibition by most PGHS-2 inhibitors (60, 61).
A final notable feature of cyclooxygenase catalysis is suicide
inactivation. Addition of arachidonic acid to preparations of PGHSs
results in a rapid but transient burst in O2 consumption as
PGG2 is formed (33). The rapid fall in oxygenase activity is not due to product inhibition but results from a mechanism-based inactivation of the enzyme (64). On average every cyclooxygenase molecule consumes approximately 400 arachidonate molecules before becoming suicide-inactivated (33). Little is known about the chemical
changes that occur during suicide inactivation; an arachidonate metabolite is incorporated into the protein during catalysis but at a
substantially slower rate than that of suicide inactivation (65).
Suicide inactivation probably involves an intramolecular cross-linking
reaction that results from an untoward reaction of a radical
intermediate such as Intermediate II (Fig. 2B).
Tyrosyl Radicals Three types of PGHS tyrosyl radical signals have been detected,
but no clear relationships have been established between these signals
and either enzyme catalysis or suicide inactivation. A broad doublet
tyrosyl radical is formed rapidly when oPGHS-1 is incubated aerobically
with a hydroperoxide or with arachidonate (46, 47, 48, 66), and the peak in
doublet signal formation coincides temporally with peak cyclooxygenase
activity (48). A broad singlet radical signal appears subsequent to the
doublet and is present even after the enzyme is suicide-inactivated.
Finally, a broad singlet signal, which is apparently a composite of the broad doublet and narrow singlet signals, occurs when PGHS-1 is incubated with excess substrate or when the enzyme is inactivated by
preincubation with indomethacin and then incubated with a hydroperoxide (47, 48, 66, 67). Although the rate of formation of the doublet signal
is consistent with its being involved in cyclooxygenase catalysis (48),
it is not really clear that this signal represents the expected Tyr-385
radical (Fig. 2B). For instance, a Y385F mutant of oPGHS-1,
which lacks cyclooxygenase activity, can still form a tyrosyl radical
(49). Moreover, an H386A oPGHS-1, which retains 35% of the
cyclooxygenase activity of the native enzyme (1), does not form a
detectable tyrosyl radical.2 The fact that H386A oPGHS-1
fails to undergo suicide inactivation and other findings (47, 48)
raised the possibility that singlet tyrosyl radical signals are
associated with suicide inactivation. However, this concept is
inconsistent with our recent studies of an H372A mutant of human
PGHS-2, a mutant analogous to H386A oPGHS-1.2 Like H386A
PGHS-1, the H372A PGHS-2 mutant fails to form a tyrosyl radical upon
incubation with hydroperoxides, but H372A PGHS-2 does undergo suicide
inactivation.
Membrane Localization and Targeting PGHS-1 and -2 are integral membrane proteins. The
interactions of the enzymes with the lipid bilayer involve a unique
membrane binding domain (MBD), which was first recognized by analysis
of the crystal structure of ovine PGHS-1 (Fig. 4). Each monomer
contains an MBD comprised of four short amphipathic helices. In oPGHS-1 the MBD involves residues 70-117. Hydrophobic residues emanating from
these helices are thought to interdigitate into only a single leaflet
of the lipid bilayer (50). Consistent with this concept labeling
experiments with
125I-3-trifluoro-3-(m-[125I]iodophenyl)diazirine
have indicated that the label becomes associated with a region of the
protein that includes the postulated MBD (68). Crystal structures of
human and murine PGHS-2 have very recently been reported by
Browner3 and Kurumbail (69) and their
colleagues. These two structures, including the MBD, are essentially
superimposable with PGHS-1.
Both PGHS-1 and -2 are bound to the lumenal surface of the ER and
contiguous outer membrane of the nuclear envelope (70). Moreover, both isozymes also appear to be present on the lumenal surface of the inner membrane of the nuclear
envelope.4 PGHS-1 and -2 are initially
targeted to the ER via a C-terminal KDEL-type (i.e.
-(P/S)TEL) of ER retention signal (71). The one obviously unique
structural feature of PGHS-2 is that it contains an 18-amino acid
cassette near its C terminus. Deletion of this cassette yields a
catalytically active enzyme but does not affect the subcellular
location of the enzyme suggesting that this cassette is not involved in
enzyme targeting.5
Biology of the Two PGHS Isoforms Work on PGHSs during the past 5 years has concentrated on learning
about the regulation of enzyme expression and the mechanisms of enzyme
catalysis largely in the context of developing PGHS-2-specific, anti-inflammatory agents. A broader biological question is why are
there two isozymes, and even more specifically, why do some cells
express both isoenzymes? We hypothesize that PGHS-1 and -2 represent at
least partially independent prostanoid biosynthetic systems (1). PGHS-1
occurs as part of an ER prostanoid biosynthetic system, which forms
prostanoids that act extracellularly as "local" hormones
functioning through cell surface, G protein-linked receptors to mediate
acute "housekeeping" responses to circulating hormones (e.g. in the regulation of renal, gastrointestinal, and
platelet functions). PGHS-2 probably has two roles. One role, involving a subpopulation of PGHS-2 colocalizing with PGHS-1 on the lumenal surface of the ER, is to augment the function of PGHS-1 (or to substitute for PGHS-1 in cells lacking this isozyme). The subpopulation of PGHS-2 present on the lumenal surface of the inner membrane of the
nuclear envelope may operate as part of a unique nuclear prostanoid
biosynthetic system that forms products that act through nucleoplasmic
or nuclear membrane targets in association with cell differentiation
and replication. There are several general observations that support
these concepts. In cells such as murine 3T3 cells, which express PGHS-1
constitutively, maximal induction of PGHS-2 causes, at most, a 2-fold
increase in the net prostanoid biosynthetic capacity of the cell (10,
11). This finding coupled with the fact that the kinetic properties and
substrate specificities of the two isozymes are very similar (35, 40)
suggests that it is unlikely that PGHS-2 is induced solely to augment
PGHS-1. Prostanoid synthesis through PGHS-1 and -2 involves different arachidonate substrate pools and is coupled to different extracellular stimuli and perhaps different phospholipase systems (72, 73). These
observations imply that the two enzymes can operate independently. By
immunostaining at both the light (74) and electron
microscopic4 levels PGHS-1 and -2 appear to be present in
the same subcellular locations. However, PGHS-2 is more concentrated on
the nuclear envelope than PGHS-1; moreover, in histochemical staining
for enzyme activity in intact cells, the staining attributable to PGHS-1 occurs primarily in the cytoplasm whereas staining attributable to PGHS-2 occurs both in the cytoplasm and over the surface of the
nucleus (74). Thus, the two activities appear to function at different
locations within the same cells. Finally, as discussed above, the
temporal patterns of isozyme expression are such that while PGHS-1 is
expressed constitutively, PGHS-2 expression is typically maximal during
early stages of cell replication or differentiation.
PGHS-1 generates products that end up outside the cell and
function via G protein-linked receptors; this is also true for the
subset of PGHS-2 molecules found in the ER (1). However, the unique
nuclear activity of PGHS-2 leads to the prediction that there are
nuclear prostanoid targets. Peroxisomal proliferator-activated receptor
FOOTNOTES REFERENCES
Volume 271, Number 52,
Issue of December 27, 1996
pp. 33157-33160
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
MINIREVIEW:
,
INTRODUCTION
Regulation of PGHS-1 and PGHS-2 Expression
Mechanisms of Enzyme Catalysis
Tyrosyl Radicals
Membrane Localization and Targeting
Biology of the Two PGHS Isoforms
FOOTNOTES
REFERENCES
Fig. 1.
Prostanoid biosynthetic pathway. In
response to stimulation of a target cell with a relevant cytokine,
growth factor, or circulating hormone, phospholipases are activated and
arachidonic acid is hydrolyzed from the sn-2 position of
membrane phospholipids. Most evidence suggests that this occurs through
the action of a phospholipase A2, either the cytosolic,
high molecular weight, Ca2+-dependent
cytoplasmic phospholipase A2 that becomes associated with
the cytoplasmic surface of the ER and nuclear envelope and releases
arachidonate from these membranes or the nonpancreatic, Ca2+-dependent, Type II phospholipase
A2, which is secreted and acts on phospholipids on the
extracellular surface of the plasma membrane (reviewed in Ref. 1).
Arachidonate is converted by PGHS-1 or -2 to PGH2, and then
PGH2 is isomerized to biological active prostanoid products.
[View Larger Version of this Image (23K GIF file)]
site is responsible for induction
of PGHS-2 by lipopolysaccharides and tumor-promoting phorbol ester (29)
while the same site is responsible for tumor necrosis factor
-mediated induction of PGHS-2 in MC3T3-E1 cells (30). An E-box
sequence is essential for basal and luteinizing hormone- and
gonadotrophin-releasing hormone stimulated transcription, and this
element binds the upstream stimulating transcription factor (31). A
cAMP response element mediates the effect of src on PGHS-2
expression in fibroblasts (32). It is not yet known how dexamethasone
acts to inhibit PGHS-2 gene expression.
Fig. 2.
Peroxidase and cyclooxygenase catalysis.
A, model of the cyclooxygenase and peroxidase active sites
of ovine PGHS-1. An alkyl hydroperoxide is shown bound to the heme
group at the peroxidase active site, and arachidonate is shown bound to
the cyclooxygenase active site. His-388 and His-207 are the proximal and distal heme ligands, respectively. Tyr-385 neighbors the heme group
and bound arachidonate and is likely the residue that is converted to a
tyrosyl radical and abstracts the (13S)-hydrogen from
arachidonate, thereby initiating cyclooxygenase catalysis. Ser-530 is
the site of aspirin acetylation. Arg-120 is located at the opening of
the hydrophobic fatty acid binding channel and is the counterion for
the carboxylate group of arachidonate. B, the branched chain
model for the mechanistic interplay between the cyclooxygenase and
peroxidase activities (54, 61). A two-electron oxidation of the heme
group of PGHS by a hydroperoxide yields a peroxidase spectral
Intermediate I containing an oxyferryl form of iron (Fe(IV)) and a
protoporphyrin radical cation (53, 54). The oxidized heme group in turn
oxidizes a neighboring tyrosine residue, probably Tyr-385 (60, 63) to
yield peroxidase Intermediate II having a tyrosyl radical (56) and an
oxyferryl Fe(IV) (53, 54). This protein radical is likely the species
that abstracts the (13S)-hydrogen from arachidonate.
PPIX, protoporphyrin IX; AA, arachidonic
acid.
[View Larger Version of this Image (33K GIF file)]
Fig. 3.
Crystal structure of the active site of
aspirin-acetylated ovine PGHS-1. The carboxylate group of
salicylic acid is shown interacting with Arg-120 (67).
[View Larger Version of this Image (49K GIF file)]
Fig. 4.
Crystal structure of the ovine PGHS-1 dimer
highlighting the MBDs (50).
[View Larger Version of this Image (72K GIF file)]
has been shown to be activated by PGJ2 (75).
PGJ2 metabolites also activate the unfolded protein
response element (76). We expect that other nuclear targets for other
prostanoids will be identified.
To whom correspondence should be addressed. Tel.: 517-353-8680;
Fax: 517-353-9334; E-mail: smithww{at}pilot.msu.edu.
1
The abbreviations used are: PGHS, prostaglandin
endoperoxide H synthase; oPGHS, ovine PGHS; PG, prostaglandin; NSAID,
nonsteroidal anti-inflammatory drug; MBD, membrane binding domain; ER,
endoplasmic reticulum; numbering of amino acids for PGHS-1 and -2 begins in each case with the methionine at the translation start
site.
2
L. Hsi and W. L. Smith, unpublished
results.
3
M. Browner, personal communication.
4
A. Spencer, J. Woods, I. Singer, and W. L. Smith, unpublished results.
5
D. DeWitt and W. L. Smith, unpublished
results.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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