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(Received for publication, February 7, 1996, and in revised form, March 28, 1996)
From Searle Research and Development, St. Louis, Missouri 63198
ABSTRACT Nonsteroidal anti-inflammatory drugs (NSAIDs)
currently available for clinical use inhibit both COX-1 and COX-2. This
suggests that clinically useful NSAIDs inhibit pro-inflammatory
prostaglandins (PGs) derived from the activity of COX-2, as well as PGs
in tissues like the stomach and kidney (via COX-1). A new class of
compounds has recently been developed (SC-58125) that have a high
degree of selectivity for the inducible form of cyxlooxygenase (COX-2)
over the constitutive form (COX-1). This unique class of compounds
exhibit a time-dependent irreversible inhibition of COX-2,
while reversibly inhibiting COX-1. The molecular basis of this
selectivity was probed by site-directed mutagenesis of the active site
of COX-2. The sequence differences in the active site were determined
by amino acid replacement of the COX-2 sequences based on the known
crystal structure of COX-1, which revealed a single amino acid
difference in the active site (valine 509 to isoleucine) and a series
of differences at the mouth of the active site. Mutants with the single
amino acid substitution in the active site and a combination of three
changes in the mouth of the active site were made in human COX-2,
expressed in insect cells and purified. The single amino acid change of
valine 509 to isoleucine confers selectivity of COX-2 inhibitors in the
class of SC-58125 and others of the same class (SC-236, NS-398), while
commonly used NSAIDs such as indomethacin showed no change in
selectivity. Substitutions of COX-1 sequences in COX-2 at the mouth of
the active site of COX-2 did not change the selectivity of SC-58125.
This indicates that the single amino acid substitution of isoleucine at
position 509 for a valine is sufficient to confer COX-2 selectivity in
this example of a diaryl-heterocycle COX inhibitor.
INTRODUCTION Prostaglandin synthase catalyzes two separate reactions; the first
being the cyclooxygenase function, which is the addition of molecular
oxygen to arachidonic acid to form the unstable
PGG2,1 and the second the
further conversion of PGG2 to the more stable
PGH2 by a peroxidase function. Hence, this
``cyclooxygenase'' (COX) enzyme performs the critical initial
reaction in the arachidonic metabolic cascade leading to the formation
of the prostaglandins, thromboxane, and prostacyclin (1).
Recently, a second form of the COX enzyme was isolated whose expression
is inducible by cytokines and growth factors (COX-2) (2, 3, 4, 5, 6). This
inducible COX-2 is linked to inflammatory cell types and tissues and is
believed to be the target enzyme for the anti-inflammatory activity of
nonsteroidal anti-inflammatory drugs (NSAIDs) (7, 8, 9, 10, 11, 12). NSAIDs currently
available for clinical use inhibit both COX-1 and COX-2 (13, 14). This
suggests that clinically useful NSAIDs inhibit pro-inflammatory PGs
derived from the activity of COX-2, as well as PGs in tissues like the
stomach and kidney (via COX-1). These homeostatic PGs are linked to
normal gastric and renal function (15). It is possible that a selective
COX-2 inhibitor may eliminate the side effects associated with COX-1
inhibition while providing anti-inflammatory COX-2 inhibition.
A new class of compounds has been described that are all selective
inhibitors of COX-2. Compounds such as NS-398, DUP-697, and SC-58125
have been key in elucidating the physiological role of the two types of
enzymes. These compounds have both in vivo and in
vitro selectivity (9, 16). Recently, the mechanism of inhibition
has been elucidated. It has been demonstrated that the selective COX-2
inhibitor NS-398 exhibits a time-dependent inactivation of
COX-2 and no time dependence versus COX-1. The mechanism of
this time dependence is unknown. Inhibitor enzyme complexes can be
separated after protein denaturation with no change in either the
inhibitor or protein (17). Thus, it is apparently a very tight binding
interaction and not a covalent one.
Sequence alignment of the two enzymes offers little insight into the
differences between the two enzymes at or around the active site.
Recently, the x-ray crystal structure of sheep seminal vesicle COX-1
has been solved (18), which gives insight into the structure of the
active site. The sequence of COX-2 can be overlaid on the structure,
and the differences can be mapped. Major sequence differences were
found in the mouth of the substrate access channel and one difference
in the active site channel.
Therefore, mutants of COX-2 were constructed and expressed to evaluate
specific residues for their contribution to the selective inhibition of
compounds.
EXPERIMENTAL PROCEDURES Materials
Arachidonic acid was purchased from Nu-Chek-Prep Inc. (Elysian,
MN); CHAPS, hemin chloride, TMPD, Tris, and heme (bovine hemin
chloride) were purchased from Sigma; all other reagents were purchased
from Fisher Scientific. NS-398
(N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide)
was provided by Dr. John Talley and Dup-697
(5-bromo-2[4-fluorophenyl]-3-[4-methylsulfonylphenyl]-thiophene)
was provided by Dr. Len Lee, both of Monsanto Corporate Research, St.
Louis.
Molecular Modeling
Differences between hCOX-1 and hCOX-2 were identified using a
combination of multiple sequence alignment and molecular graphics.
ssvCOX-1 (19), hCOX-1 (20), and hCOX-2 (2) sequences were obtained from
the Swiss-Prot data base (21) and were aligned using the CLUSTAL W
(European Molecular Biology Laboratory, Heidelberg, Germany) package
(22). The alignment used the percentage scoring method, a gap penalty
of 3, K-tuple of 1, and a window size of 5. Differences between hCOX-1
and hCOX-2 were mapped onto the ssvCOX-1 x-ray coordinates using the
Insight II (Molecular Simulations Inc., San Diego, CA) molecular
graphics package. Residues for mutagenesis were selected based on a
visual examination of side chains both in close proximity to the
ssvCOX-1 x-ray structure of the inhibitor, flurbiprofen and along the
channel reported to be the putative path of inhibitor binding.
hCOX-2 Mutagenesis
The coding region of hCOX-2 (16) was subcloned into the plasmid
pALTER-1, and in vitro mutagenesis was performed using an
Altered Sites® II kit (Promega). One pmol of mutant primer
(5 Generation of Recombinant Baculoviruses
Plasmid DNA containing the gene of interest was prepared by
alkaline lysis of bacterial cultures and purified over a Qiagen column
as described by the manufacturer. Recombinant baculoviruses were
generated by transfecting 5 µg of plasmid DNA with 400 ng of
linearized baculovirus DNA (Pharmingen, San Diego, CA) using the
calcium phosphate procedure. Using the linearized DNA, the transfection
mixture yields 99.0% or more recombinants. A stock of the recombinant
baculoviruses was made from the transfection supernatant. Cells in a
1-liter spinner flask were grown to 0.5 × 106 cells/ml in
serum-containing medium (IPL41, tryptose phosphate, 10% fetal bovine
serum) and infected with COX recombinant baculoviruses inoculum at a
multiplicity of infection of 0.1 at 27 °C. The cells were harvested
at 4 days postinfection by centrifugation at 3,000 × g.
COX Purification from Infected Insect Cells
The purification has been described previously (16) and is
summarized here. 4-6 g of wet weight cells were homogenized in 10 volumes of 25 mM Tris-HCl, pH 8.1, 0.25 M
sucrose. After centrifugation at 10,000 × g and
resuspension in the same buffer, CHAPS detergent was added to 1%
(w/v). The supernatant was removed following a 50,000 × g
centrifugation and loaded directly onto a 5-ml anion exchange column
(Macro-Prep High Q; Bio-Rad), equilibrated with 20 mM
Tris-HCl, 0.4% CHAPS, pH 8.1. COX enzyme was eluted with a linear
gradient of increasing salt concentration to 0.3 M. The
pool was concentrated 10× with a stirred cell (Amicon, Beverly, MA)
YM-30 membrane to 1 ml and loaded onto a 25-ml Superose-12 column
(Pharmacia Biotech Inc.) equilibrated with 25 mM Tris-HCl,
150 mM NaCl, 0.4% CHAPS, pH 8.1, and eluted with the
identical buffer at a flow rate of 0.5 ml/min. Pools were aliquoted and
stored at Enzyme Assays
Half-maximal inhibition
(IC50) was determined by measuring the turnover of TMPD
used in a spectrophotometric assay. Arachidonic acid was used, as a
hydroperoxide source, along with the peroxidase substrate
N,N,N Inhibitory profiles were also assessed by
PGE2 determination. Inhibitors (0.001-100
µM) were preincubated with enzyme for 20 min in 50 mM KPO4, pH 7.5, 1 µM heme,
0.01% phenol, 0.3 mM epinephrine. Following a 10-min
incubation of arachidonic acid, PGE2 formed as a function
of the COX activity was detected by ELISA (Caymen, Ann Arbor, MI).
RESULTS COX-1 and -2 are 63% identical and 77% similar at the amino acid
level. A cursory look at the sequence alignment of human COX-1 and
COX-2 reveals that most of the major differences are in the N-terminal
and C-terminal regions. The catalytic domain (117-587) is highly
conserved, with the major residues known to be involved in catalysis or
heme binding; Arg-120, His-206, Tyr-385, His-386, and His-388 all
conserved, along with the residue which is acetylated by aspirin
(Ser-530). Differences that could be responsible for selectivity are
most likely found in the cyclooxygenase active site rather than the
peroxidase site, due to the fact that the known selective inhibitors,
as do most common NSAIDs, inhibit the cyclooxygenase activity and not
the peroxidase activity.
With the availability of the ram COX-1 structure, a better view of the
cyclooxygenase active site is now available. The residues of COX-2 were
overlaid onto the COX-1 structure. The subsequent alignment revealed a
number of amino acid differences at the mouth of the cyclooxygenase
substrate channel, where a series of amino acids on three
Significant cyclooxygenase 1 and 2 active site differences
Volume 271, Number 26,
Issue of June 28, 1996
pp. 15810-15814
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
-TGAAACCATGAT AGA- AGTTGGAG-3, Midland Certified Reagent Company,
Midland, TX) was annealed to 100 ng of single-stranded template, and
mutagenesis was performed following the manufacturer's instructions.
One-half of the final mutagenesis reaction was used to transform
competent BMH 71-18 mutS cells (Clontech, Palo Alto, CA) which were
grown overnight in LB broth without ampicillin. Plasmid DNA was
isolated from 50-ml cultures using a Qiagen kit (Qiagen, Chatsworth,
CA). 10 ng of mutant plasmid was used to transform competent DH10B
cells (Life Technologies, Inc., Gaithersburg, MD). Plasmid DNA was
isolated from ampicillin-resistant colonies and screened for the
presence of the desired mutation by sequencing with a
Prism® Cycle Sequencing Kit and 373 DNA Sequencer (Applied
Biosystems, Foster City, CA). Human COX-2 inserts containing the
desired mutation with no secondary misincorporations were isolated with
Qiaex resin (Qiagen, Studio City, CA) and subcloned into baculovirus
transfer vector pVL 1393 for expression in SF-9 insect cells.
80 °C for further use.
N-tetramethyl-p-phenylenediamine
(TMPD) as a cosubstrate (10). Inhibitors were incubated for 1 min with
purified enzyme in 1 µM heme, 0.1 M Tris-HCl,
pH 8.1. The reaction was started by addition of 100 µM
arachidonic acid, 170 µM TMPD and measured by a change in
absorbance at 611 nm. Either the initial rate (linear for approximately
10 s) was measured or time points at 1 and 5 min were taken.
Time-dependent inactivation curves were made by incubating
10 µM inhibitor with enzyme for 5 s to 2 min.
-helixes
surrounding the mouth of the channel that have residue changes at
approximately every turn in the helix (3 amino acids) and are all on
the solvent side of the substrate channel (Table I). The
first helix contains two changes; threonine 89 to valine 74 and leucine
92 to isoleucine 77. The helix directly on the opposite side of the
channel contains three consecutive changes: leucine 112 to isoleucine
98, leucine 115 to tyrosine 101, and valine 119 to serine 105. A third
helix located between the previous two contains one change:
phenylalanine 357 to leucine 343. The first three changes (89, 92, 112)
are rather benign, with nonpolar residues being exchanged for nonpolar
residues of about the same size. More significant changes occur at
position 115, where a nonpolar leucine is replaced by an uncharged
polar tyrosine; 119 where a nonpolar valine is replaced by an uncharged
polar serine; and 357 where a nonpolar leucine is replaced by the much
larger nonpolar phenylalanine. One difference is observed at the
cyclooxygenase active site, where the isoleucine at position 523 in
COX-1 is a valine in COX-2.
Substrate channel entrance
Upper channel
COX-1
89
92
112
115
119
357
523
Sheep-1
Inpa
Lnp
Lnp
Lnp
Vnp
Lnp
Inp
Human-1
Tucp
Lnp
Lnp
Lnp
Vnp
Lnp
Inp
COX-2
74
77
98
101
105
343
509
Human-2
Vnp
Inp
Inp
Yucp
Sucp
Fnp
Vnp
a
Subscripts np = nonpolar and ucp = uncharged
polar.
ABSTRACTA model of sheep COX-1 indicating the relative position of the
differing residues and other residues of importance is shown
graphically in Fig. 1. The substrate channel is oriented
from top to bottom with heme at the top and residues 112, 115, and 119 at the bottom. A little further up the channel, but slightly below the
catalytic site and NSAID binding pocket sits leucine 357, which is a
phenylalanine in COX-2. Residues crucial for catalysis (Tyr-385,
Arg-120) are found in close contact with flurbiprofen, which is
presumed to be bound in the same space as substrate. Serine 530, which
is acetylated by aspirin, is shown next to flurbiprofen. The only amino
acid difference in the catalytic site, isoleucine 523, is found on the
opposite side.
Fig. 1. View of the ovine COX active site (1). The heme group is shown at the top of the figure. The inhibitor, flurbiprofen, is rendered as a shaded Corey-Pauling-Koltun. Several residues have been annotated. Annotated residues are rendered as ball and stick. Arg-120, Ser-530, and Tyr-385 (ovine COX numbering) are common among ssvCOX-1, hCOX-1, and hCOX-2 and are shown to orient the reader. The remaining annotated residues represent active site differences between hCOX-1 and hCOX-2, mapped onto the ssvCOX-1 structure. Using a residue numbering scheme of ssvCOX-1 (hCOX-1
hCOX-2), these changes include: Leu-112 (Leu-111 Ile-98), Leu-115
(Leu-114 Tyr-101), Val-119 (Val-118 Ser-105), Leu-357 (Leu-356
Phe-343), and Ile-523 (Ile-522 Val-509).
Two hCOX-2 mutants were constructed by introducing hCOX-1 amino acids into a selected site(s); the first combined the three significant changes near the mouth of the substrate channel, tyrosine 101 to leucine, serine 105 to leucine, and phenylalanine 343 to leucine; the second is the single amino acid change, valine 509 to Isoleucine found in the active site. Insect cell expression levels of the mutants were similar to wild type without optimization at the 1-liter level. The purification scheme described under ``Experimental Procedures'' produced approximately 4 mg of protein from 1 liter at 50% purity. All assays were done with enzyme of this purity. Vmax of both mutants appears to be close to wild type hCOX-2 expressed in insect cells (data not shown).
Using the selective COX-2 inhibitor SC-58125, both wild type hCOX-2 and
the triple mutant demonstrated similar inhibition profiles
(IC50 = 1 µM). The single V509I mutation
increased the IC50 to >100 µM, which looks
like COX-1 at >100 µM (Fig. 2). The assay
protocol influences the selectivity of the compound for hCOX-2 and the
mutants. Wild type hCOX-2 has an IC50 of 1-2
µM with the assay run as an initial rate or as an end
point assay at 1 min read time or 5 min read time. The V509I mutant,
however, exhibited a much different behavior. At the initial
velocities, there is only a slight right shift in the IC50
curve (to 4 µM). At 1 min, the curve is further shifted
to >100 µM and, finally, at 5 min, there is no hint of
inhibition at 100 µM, looking completely like COX-1 (Fig.
3).
Fig. 2. Inhibition curves of the selective COX-2 inhibitor SC-58125 versus hCOX-1, hCOX-2, and the mutants of hCOX-2: V509I and the triple mutant Y101L,S105V,F343L. The selective COX-2 inhibitor SC-58125 was incubated with 4 µg of either hCOX-2 (open squares), hCOX-1 (circles), triple mutant of hCOX-2 (triangles), or V509I hCOX-2 mutant (closed squares) for 1 min. Initial rate of the peroxidase reaction was measured.
Fig. 3. Inhibition curves, with variable assay time of the selective COX-2 inhibitor SC-58125. A, hCOX-2; B, the hCOX-2 mutant V509I. 1-min preincubation of inhibitor and enzyme. Assays were performed using peroxidase substrate TMPD and arachidonate. Initial velocity (squares) at A611 is measured among A611 readings at 1 min (triangles) and 5 min (circles).
Time dependent inhibition of COX-2 selective inhibitors was measured
for hCOX-2 and the V509I hCOX-2 mutant. Inhibition of wild type enzyme
by 10 µM SC-58125 is time-dependent and is
complete by 1 min, with a half-maximal inhibition at 20 s (Fig.
4A). The mutant exhibits
time-dependent behavior, as evidenced by a logarithmic
decay in activity over time, only there is a distinct decrease in the
rate at which the enzyme is inhibited over time, with only 20%
inhibition at 2 min. DUP-697 at 0.5 µM shows a very
similar profile with half-maximal inhibition at 5 s and maximal
inhibition of 20% at 2 min (Fig. 4B). NS-398 at 10 µM exhibited half-maximal inhibition at 10 s
with with wild type that increased to 40 s with the mutant (Fig.
4C).
Fig. 4. Time-dependent inactivation of hCOX-2 and the mutant V509I hCOX-2 by SC-58125, DUP-697, and NS-398. 4 µg of either hCOX-2 (squares) or the mutant V509I hCOX-2 (triangles) preincubated from 5 s to 2 min with inhibitor before addition of the peroxidase substrate TMPD and arachidonate. A611 was measured at 1 min. Data were fit to a logarithmic least squares curve at a correlation of >0.95.
Half-maximal inhibition profiles were determined by the prostaglandin ELISA assay, which favors compounds with a time-dependent component, for a wide range of selective COX-2 inhibitors and known NSAIDs (Table II). All selective COX-2 inhibitors tested (SC-58125, SC-236, DUP-697, and NS-398) demonstrated hCOX-1-like activities with the mutant enzyme. The other commonly used NSAIDs, indomethacin, diclofenac, mephanamate, and flurbiprofen, showed no change in selectivity with the mutant. The only compound that did not follow the trend, Naproxen, had no inhibitory effect with the mutant compared to COX-1 and-2.
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1 mgDISCUSSION
With the identification of a second COX isoform, numerous groups have embarked on efforts to identify selective inhibitors of COX-2. Prior to their discovery, the ability to identify selective inhibitors of COX-2 was not obvious as the enzymes utilize the same substrate and have a high degree of sequence homology. Nonetheless, we and others have reported the identification of selective inhibitors of COX-2 (16, 23). The mechanism of inhibition of COX-2 has been described as ``time-dependent,'' involving a tight binding component, while these compounds are reversible inhibitors of COX-1. (17). This time-dependent component is the apparent basis for selectivity of this new class of COX-2 inhibitors, since these compounds are reversible inhibitors of COX-1. To further understand the molecular basis of this differential inhibition, a series of mutants was evaluated. We observed that a single amino acid change in COX-2 confers a COX-1 inhibitory profile for these COX-2 selective inhibitors. Specifically, the data suggest that the mechanism for selectivity is intimately associated with the removal of a single methyl group at position 523. Therefore, the time-dependent step could possibly be inhibited by the presence of an additional methyl group in the substrate channel.
How do these subtle differences in the active site translate to two functionally distinct enzymes? Recombinant COX-1 and -2 demonstrate a similar Km and Vmax for their common substrate, arachidonic acid (23). Both enzymes appear to reside on the luminal side of the endoplasmic reticulum (24). Likewise, their catalytic roles appear to be the same. Therefore, the major differences between these isoenzymes may be a function of the regulatory mechanisms by which the two enzymes are expressed. For instance, COX-2 expression is induced in discrete cell population response to an inflammatory stimulus, while COX-1 is expressed constitutively in most tissue (9). Recently, it has been suggested that COX-1 and -2 have different requirements for hydroperoxide activation and that the hydroperoxide environment in the cell may influence the regulation of the enzyme activity (25), a mechanism that is distinct from that of all known NSAIDs and COX-2 selective inhibitors.
Currently, our understanding of COX-2 structure has been deduced from the known COX-1 crystal structure. Given the high degree of homology between the two enzymes, replacement of the COX-2 residues with those predicted from COX-1 may provide a model of a COX-2 active site. Confirmation of the crystal structure of COX-2 will provide the final evidence as to the exact placement of valine 509 in the active site and the relationship of specific inhibitors in the active site of the enzyme.
FOOTNOTES
To whom correspondence should be addressed: Monsanto/Searle,
700 Chesterfield Parkway N, AA2I, Chesterfield, MO
63198. Tel.: 314-537-6243; Fax: 314-537-7005; E-mail:
JKGIER{at}CCMAIL.MONSANTO.COM.
1 The abbreviations used are: PG, prostaglandin; COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drugs; ssv, sheep seminal vesicle; h, human; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate; TMPD, N,N,N
N-tetramethyl-p-phenylenediamine;
KPO4, potassium phosphate buffer; ELISA, enzyme-linked
immunosorbent assay.
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 E. F. Ekman, G. Ruoff, K. Kuehl, L. Ralph, P. Hormbrey, J. Fiechtner, and M. F. Berger The COX-2 Specific Inhibitor Valdecoxib Versus Tramadol in Acute Ankle Sprain: A Multicenter Randomized, Controlled Trial Am. J. Sports Med., June 1, 2006; 34(6): 945 - 955. [Abstract] [Full Text] [PDF]
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 K. P. Choe, J. Havird, R. Rose, K. Hyndman, P. Piermarini, and D. H. Evans COX2 in a euryhaline teleost, Fundulus heteroclitus: primary sequence, distribution, localization, and potential function in gills during salinity acclimation J. Exp. Biol., May 1, 2006; 209(9): 1696 - 1708. [Abstract] [Full Text] [PDF]
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 H. Wang, J. L. Garvin, J. R. Falck, Y. Ren, S. S. Sankey, and O. A. Carretero Glomerular Cytochrome P-450 and Cyclooxygenase Metabolites Regulate Efferent Arteriole Resistance Hypertension, November 1, 2005; 46(5): 1175 - 1179. [Abstract] [Full Text] [PDF]
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 C. A. Rouzer and L. J. Marnett Glycerylprostaglandin Synthesis by Resident Peritoneal Macrophages in Response to a Zymosan Stimulus J. Biol. Chem., July 22, 2005; 280(29): 26690 - 26700. [Abstract] [Full Text] [PDF]
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 J. K. Gierse, Y. Zhang, W. F. Hood, M. C. Walker, J. S. Trigg, T. J. Maziasz, C. M. Koboldt, J. L. Muhammad, B. S. Zweifel, J. L. Masferrer, et al. Valdecoxib: Assessment of Cyclooxygenase-2 Potency and Selectivity J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1206 - 1212. [Abstract] [Full Text] [PDF]
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A. F. Rowley, C. L. Vogan, G. W. Taylor, and A. S. Clare Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems J. Exp. Biol., January 1, 2005; 208(1): 3 - 14. [Abstract] [Full Text] [PDF]
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 D. R. Bauman, S. I. Rudnick, L. M. Szewczuk, Y. Jin, S. Gopishetty, and T. M. Penning Development of Nonsteroidal Anti-Inflammatory Drug Analogs and Steroid Carboxylates Selective for Human Aldo-Keto Reductase Isoforms: Potential Antineoplastic Agents That Work Independently of Cyclooxygenase Isozymes Mol. Pharmacol., January 1, 2005; 67(1): 60 - 68. [Abstract] [Full Text] [PDF]
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M. R. Heitmeier, C. B. Kelly, N. J. Ensor, K. A. Gibson, K. G. Mullis, J. A. Corbett, and T. J. Maziasz Role of Cyclooxygenase-2 in Cytokine-induced {beta}-Cell Dysfunction and Damage by Isolated Rat and Human Islets J. Biol. Chem., December 17, 2004; 279(51): 53145 - 53151. [Abstract] [Full Text] [PDF]
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 S M Day, J C Lockhart, W R Ferrell, and J S McLean Divergent roles of nitrergic and prostanoid pathways in chronic joint inflammation Ann Rheum Dis, December 1, 2004; 63(12): 1564 - 1570. [Abstract] [Full Text] [PDF]
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C. A. Rouzer, P. J. Kingsley, H. Wang, H. Zhang, J. D. Morrow, S. K. Dey, and L. J. Marnett Cyclooxygenase-1-dependent Prostaglandin Synthesis Modulates Tumor Necrosis Factor-{alpha} Secretion in Lipopolysaccharide-challenged Murine Resident Peritoneal Macrophages J. Biol. Chem., August 13, 2004; 279(33): 34256 - 34268. [Abstract] [Full Text] [PDF]
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 C. G. Egan, J. C. Lockhart, and W. R. Ferrell Pathophysiology of vascular dysfunction in a rat model of chronic joint inflammation J. Physiol., June 1, 2004; 557(2): 635 - 643. [Abstract] [Full Text] [PDF]
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C. Schneider, W. E. Boeglin, and A. R. Brash Identification of Two Cyclooxygenase Active Site Residues, Leucine 384 and Glycine 526, That Control Carbon Ring Cyclization in Prostaglandin Biosynthesis J. Biol. Chem., February 6, 2004; 279(6): 4404 - 4414. [Abstract] [Full Text] [PDF]
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W. F. Hood, J. K. Gierse, P. C. Isakson, J. R. Kiefer, R. G. Kurumbail, K. Seibert, and J. B. Monahan Characterization of Celecoxib and Valdecoxib Binding to Cyclooxygenase Mol. Pharmacol., April 1, 2003; 63(4): 870 - 877. [Abstract] [Full Text] [PDF]
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M. M. Hardy, E. A. G. Blomme, A. Lisowski, K. S. Chinn, A. Jones, J. M. Harmon, A. Opsahl, R. L. Ornberg, and C. S. Tripp Selective Cyclooxygenase-2 Inhibition Does Not Alter Keratinocyte Wound Responses in the Mouse Epidermis after Abrasion J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 959 - 967. [Abstract] [Full Text] [PDF]
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 R. C. Hubbard, T. M. Naumann, L. Traylor, and S. Dhadda Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia Br. J. Anaesth., February 1, 2003; 90(2): 166 - 172. [Abstract] [Full Text] [PDF]
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 T. Yang, S. J. Forrest, N. Stine, Y. Endo, A. Pasumarthy, H. Castrop, S. Aller, J. N. Forrest Jr., J. Schnermann, and J. Briggs Cyclooxygenase cloning in dogfish shark, Squalus acanthias, and its role in rectal gland Cl secretion Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R631 - R637. [Abstract] [Full Text] [PDF]
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 W. Bensen, A. Weaver, L. Espinoza, W. W. Zhao, W. Riley, B. Paperiello, and D. P. Recker Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen Rheumatology, September 1, 2002; 41(9): 1008 - 1016. [Abstract] [Full Text] [PDF]
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 T. Grosser, S. Yusuff, E. Cheskis, M. A. Pack, and G. A. FitzGerald Developmental expression of functional cyclooxygenases in zebrafish PNAS, June 11, 2002; 99(12): 8418 - 8423. [Abstract] [Full Text] [PDF]
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C. G Egan, J. C Lockhart, W. R Ferrell, S. M Day, and J. S McLean Pathophysiological basis of acute inflammatory hyperaemia in the rat knee: roles of cyclo-oxygenase-1 and -2 J. Physiol., March 1, 2002; 539(2): 579 - 587. [Abstract] [Full Text] [PDF]
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 H. Harizi, M. Juzan, V. Pitard, J.-F. Moreau, and N. Gualde Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions J. Immunol., March 1, 2002; 168(5): 2255 - 2263. [Abstract] [Full Text] [PDF]
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C. Schneider, W. E. Boeglin, J. J. Prusakiewicz, S. W. Rowlinson, L. J. Marnett, N. Samel, and A. R. Brash Control of Prostaglandin Stereochemistry at the 15-Carbon by Cyclooxygenases-1 and -2. A CRITICAL ROLE FOR SERINE 530 AND VALINE 349 J. Biol. Chem., January 4, 2002; 277(1): 478 - 485. [Abstract] [Full Text]
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 T. G. Burnakis, M. Fleming, M. A. Konstam, L. A. Demopoulos, K. D. Grant, E. J. Haldey, M. Pappagallo, M. Minic, P. L. McGeer, E. G. McGeer, et al. Cardiovascular Events and COX-2 Inhibitors JAMA, December 12, 2001; 286(22): 2808 - 2813. [Full Text] [PDF]
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E. Fritsche, S. J. Baek, L. M. King, D. C. Zeldin, T. E. Eling, and D. A. Bell Functional Characterization of Cyclooxygenase-2 Polymorphisms J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 468 - 476. [Abstract] [Full Text] [PDF]
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A. H. Klimp, H. Hollema, C. Kempinga, A. G. J. van der Zee, E. G. E. de Vries, and T. Daemen Expression of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in Human Ovarian Tumors and Tumor-associated Macrophages Cancer Res., October 1, 2001; 61(19): 7305 - 7309. [Abstract] [Full Text] [PDF]
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Y. Devaux, C. Seguin, S. Grosjean, N. de Talance, V. Camaeti, A. Burlet, F. Zannad, C. Meistelman, P.-M. Mertes, and D. Longrois Lipopolysaccharide-Induced Increase of Prostaglandin E2 Is Mediated by Inducible Nitric Oxide Synthase Activation of the Constitutive Cyclooxygenase and Induction of Membrane-Associated Prostaglandin E Synthase J. Immunol., October 1, 2001; 167(7): 3962 - 3971. [Abstract] [Full Text] [PDF]
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 T. L. Yaksh, D. M. Dirig, C. M. Conway, C. Svensson, Z. D. Luo, and P. C. Isakson The Acute Antihyperalgesic Action of Nonsteroidal, Anti-Inflammatory Drugs and Release of Spinal Prostaglandin E2 Is Mediated by the Inhibition of Constitutive Spinal Cyclooxygenase-2 (COX-2) but not COX-1 J. Neurosci., August 15, 2001; 21(16): 5847 - 5853. [Abstract] [Full Text] [PDF]
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 K. Hufnagl, W. Parzefall, B. Marian, M. Kafer, K. Bukowska, R. Schulte-Hermann, and B. Grasl-Kraupp Role of transforming growth factor {alpha} and prostaglandins in preferential growth of preneoplastic rat hepatocytes Carcinogenesis, August 1, 2001; 22(8): 1247 - 1256. [Abstract] [Full Text] [PDF]
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D. A. Rudnick, D. H. Perlmutter, and L. J. Muglia Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration PNAS, July 5, 2001; (2001) 151217998. [Abstract] [Full Text] [PDF]
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D. Riendeau, M. D. Percival, C. Brideau, S. Charleson, D. Dubé, D. Ethier, J.-P. Falgueyret, R. W. Friesen, R. Gordon, G. Greig, et al. Etoricoxib (MK-0663): Preclinical Profile and Comparison with Other Agents That Selectively Inhibit Cyclooxygenase-2 J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 558 - 566. [Abstract] [Full Text]
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 L M Jackson, K C Wu, Y R Mahida, D Jenkins, and C J Hawkey Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa Gut, December 1, 2000; 47(6): 762 - 770. [Abstract] [Full Text] [PDF]
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E. Castaño, R. Bartrons, and J. Gil Inhibition of Cyclooxygenase-2 Decreases DNA Synthesis Induced by Platelet-Derived Growth Factor in Swiss 3T3 Fibroblasts J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 509 - 513. [Abstract] [Full Text]
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 E. H. Awtry and J. Loscalzo Aspirin Circulation, March 14, 2000; 101(10): 1206 - 1218. [Full Text] [PDF]
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S. W. Rowlinson, B. C. Crews, D. C. Goodwin, C. Schneider, J. K. Gierse, and L. J. Marnett Spatial Requirements for 15-(R)-Hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic Acid Synthesis within the Cyclooxygenase Active Site of Murine COX-2. WHY ACETYLATED COX-1 DOES NOT SYNTHESIZE 15-(R)-HETE J. Biol. Chem., February 25, 2000; 275(9): 6586 - 6591. [Abstract] [Full Text] [PDF]
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A. S. Kalgutkar, B. C. Crews, S. W. Rowlinson, A. B. Marnett, K. R. Kozak, R. P. Remmel, and L. J. Marnett Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors PNAS, January 18, 2000; 97(2): 925 - 930. [Abstract] [Full Text] [PDF]
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C. Bandeira-Melo, M. F. Serra, B. L. Diaz, R. S. B. Cordeiro, P. M. R. Silva, H. L. Lenzi, Y. S. Bakhle, C. N. Serhan, and M. A. Martins Cyclooxygenase-2-Derived Prostaglandin E2 and Lipoxin A4 Accelerate Resolution of Allergic Edema in Angiostrongylus costaricensis-Infected Rats: Relationship with Concurrent Eosinophilia J. Immunol., January 15, 2000; 164(2): 1029 - 1036. [Abstract] [Full Text] [PDF]
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P. O. T. Tran, C. E. Gleason, V. Poitout, and R. P. Robertson Prostaglandin E2 Mediates Inhibition of Insulin Secretion by Interleukin-1beta J. Biol. Chem., October 29, 1999; 274(44): 31245 - 31248. [Abstract] [Full Text] [PDF]
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L. J. Marnett, S. W. Rowlinson, D. C. Goodwin, A. S. Kalgutkar, and C. A. Lanzo Arachidonic Acid Oxygenation by COX-1 and COX-2. MECHANISMS OF CATALYSIS AND INHIBITION J. Biol. Chem., August 13, 1999; 274(33): 22903 - 22906. [Full Text] [PDF]
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S. W. Rowlinson, B. C. Crews, C. A. Lanzo, and L. J. Marnett The Binding of Arachidonic Acid in the Cyclooxygenase Active Site of Mouse Prostaglandin Endoperoxide Synthase-2 (COX-2). A PUTATIVE L-SHAPED BINDING CONFORMATION UTILIZING THE TOP CHANNEL REGION J. Biol. Chem., August 13, 1999; 274(33): 23305 - 23310. [Abstract] [Full Text] [PDF]
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C. J. Rieke, A. M. Mulichak, R. M. Garavito, and W. L. Smith The Role of Arginine 120 of Human Prostaglandin Endoperoxide H Synthase-2 in the Interaction with Fatty Acid Substrates and Inhibitors J. Biol. Chem., June 11, 1999; 274(24): 17109 - 17114. [Abstract] [Full Text] [PDF]
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K. Varvas, I. Jarving, R. Koljak, K. Valmsen, A. R. Brash, and N. Samel Evidence of a Cyclooxygenase-related Prostaglandin Synthesis in Coral. THE ALLENE OXIDE PATHWAY IS NOT INVOLVED IN PROSTAGLANDIN BIOSYNTHESIS J. Biol. Chem., April 9, 1999; 274(15): 9923 - 9929. [Abstract] [Full Text] [PDF]
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D. L. DeWitt Cox-2-Selective Inhibitors: The New Super Aspirins Mol. Pharmacol., April 1, 1999; 55(4): 625 - 631. [Full Text]
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B. F. McAdam, F. Catella-Lawson, I. A. Mardini, S. Kapoor, J. A. Lawson, and G. A. FitzGerald Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2 PNAS, January 5, 1999; 96(1): 272 - 277. [Abstract] [Full Text] [PDF]
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 M. M. Taketo Cyclooxygenase-2 Inhibitors in Tumorigenesis (Part I) J Natl Cancer Inst, October 21, 1998; 90(20): 1529 - 1536. [Abstract] [PDF]
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D. M. Dirig, P. C. Isakson, and T. L. Yaksh Effect of COX-1 and COX-2 Inhibition on Induction and Maintenance of Carrageenan-Evoked Thermal Hyperalgesia in Rats J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1031 - 1038. [Abstract] [Full Text]
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 A. S. Kalgutkar, B. C. Crews, S. W. Rowlinson, C. Garner, K. Seibert, and L. J. Marnett Aspirin-like Molecules that Covalently Inactivate Cyclooxygenase-2 Science, May 22, 1998; 280(5367): 1268 - 1270. [Abstract] [Full Text]
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G. Xiao, W. Chen, and R. J. Kulmacz Comparison of Structural Stabilities of Prostaglandin H Synthase-1 and -2 J. Biol. Chem., March 20, 1998; 273(12): 6801 - 6811. [Abstract] [Full Text] [PDF]
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O.-Y. So, L. E. Scarafia, A. Y. Mak, O. H. Callan, and D. C. Swinney The Dynamics of Prostaglandin H Synthases. STUDIES WITH PROSTAGLANDIN H SYNTHASE 2 Y355F UNMASK MECHANISMS OF TIME-DEPENDENT INHIBITION AND ALLOSTERIC ACTIVATION J. Biol. Chem., March 6, 1998; 273(10): 5801 - 5807. [Abstract] [Full Text] [PDF]
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J. A. Williams and E. Shacter Regulation of Macrophage Cytokine Production by Prostaglandin E2. DISTINCT ROLES OF CYCLOOXYGENASE-1 AND -2 J. Biol. Chem., October 10, 1997; 272(41): 25693 - 25699. [Abstract] [Full Text] [PDF]
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E. Wong, C. Bayly, H. L. Waterman, D. Riendeau, and J. A. Mancini Conversion of Prostaglandin G/H Synthase-1 into an Enzyme Sensitive to PGHS-2-selective Inhibitors by a Double His513 right-arrow Arg and Ile523 right-arrow Val Mutation J. Biol. Chem., April 4, 1997; 272(14): 9280 - 9286. [Abstract] [Full Text] [PDF]
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P. C. Chulada and R. Langenbach Differential Inhibition of Murine Prostaglandin Synthase-1 and -2 by Nonsteroidal Anti-Inflammatory Drugs Using Exogenous and Endogenous Sources of Arachidonic Acid J. Pharmacol. Exp. Ther., February 1, 1997; 280(2): 606 - 613. [Abstract] [Full Text]
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W. L. Smith, R. M. Garavito, and D. L. DeWitt Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2 J. Biol. Chem., December 27, 1996; 271(52): 33157 - 33160. [Full Text] [PDF]
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K. R. Kozak, S. W. Rowlinson, and L. J. Marnett Oxygenation of the Endocannabinoid, 2-Arachidonylglycerol, to Glyceryl Prostaglandins by Cyclooxygenase-2 J. Biol. Chem., October 20, 2000; 275(43): 33744 - 33749. [Abstract] [Full Text] [PDF]
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E. D. Thuresson, K. M. Lakkides, C. J. Rieke, Y. Sun, B. A. Wingerd, R. Micielli, A. M. Mulichak, M. G. Malkowski, R. M. Garavito, and W. L. Smith Prostaglandin Endoperoxide H Synthase-1. THE FUNCTIONS OF CYCLOOXYGENASE ACTIVE SITE RESIDUES IN THE BINDING, POSITIONING, AND OXYGENATION OF ARACHIDONIC ACID J. Biol. Chem., March 23, 2001; 276(13): 10347 - 10357. [Abstract] [Full Text] [PDF]
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R. Koljak, I. Jarving, R. Kurg, W. E. Boeglin, K. Varvas, K. Valmsen, M. Ustav, A. R. Brash, and N. Samel The Basis of Prostaglandin Synthesis in Coral. MOLECULAR CLONING AND EXPRESSION OF A CYCLOOXYGENASE FROM THE ARCTIC SOFT CORAL GERSEMIA FRUTICOSA J. Biol. Chem., March 2, 2001; 276(10): 7033 - 7040. [Abstract] [Full Text] [PDF]
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K. R. Kozak, J. J. Prusakiewicz, S. W. Rowlinson, C. Schneider, and L. J. Marnett Amino Acid Determinants in Cyclooxygenase-2 Oxygenation of the Endocannabinoid 2-Arachidonylglycerol J. Biol. Chem., August 3, 2001; 276(32): 30072 - 30077. [Abstract] [Full Text] [PDF]
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D. A. Rudnick, D. H. Perlmutter, and L. J. Muglia Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration PNAS, July 17, 2001; 98(15): 8885 - 8890. [Abstract] [Full Text] [PDF]
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C. G. Egan, J. C. Lockhart, W. R. Ferrell, S. M. Day, and J. S. McLean Pathophysiological basis of acute inflammatory hyperaemia in the rat knee: roles of cyclo-oxygenase-1 and -2 J. Physiol., January 25, 2002; (2002) 200101347. [Abstract] [PDF]
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