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Cyclooxygenase-1
Cyclooxygenase-1
Cyclooxygenase-1
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"COX-1" redirects here. For mitochondrial cytochrome c oxidase subunit 1 (cox1), see MT-CO1.

PTGS1
Identifiers
AliasesPTGS1, COX1, COX3, PCOX1, PES-1, PGG/HS, PGHS-1, PGHS1, PHS1, PTGHS, prostaglandin-endoperoxide synthase 1
External IDsOMIM: 176805; MGI: 97797; HomoloGene: 743; GeneCards: PTGS1; OMA:PTGS1 - orthologs
EC number1.14.99.1
Orthologs
SpeciesHumanMouse
Entrez

5742

19224

Ensembl

ENSG00000095303

ENSMUSG00000047250

UniProt

P23219

P22437

RefSeq (mRNA)

NM_008969

RefSeq (protein)

NP_032995

Location (UCSC)Chr 9: 122.37 – 122.4 MbChr 2: 36.12 – 36.14 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (HUGO PTGS1), is an enzyme that in humans is encoded by the PTGS1 gene.[5][6] In humans it is one of three cyclooxygenases. Clinically, COX-1 is notable as the target enzyme for aspirin.[7]

History

[edit]

Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from arachidonic acid. This protein was isolated more than 40 years ago and cloned in 1988.[8][9]

Gene and isozymes

[edit]

There are two isozymes of COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducible COX-2, which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevant cytokines and growth factors.[10] This gene encodes COX-1, which regulates angiogenesis in endothelial cells. COX-1 is also involved in cell signaling and maintaining tissue homeostasis. A splice variant of COX-1 termed COX-3 was identified in the central nervous system of dogs, but does not result in a functional protein in humans. Two smaller COX-1-derived proteins (the partial COX-1 proteins PCOX-1A and PCOX-1B) have also been discovered, but their precise roles are yet to be described.[11]

Function

[edit]

Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX), is the key enzyme in prostaglandin biosynthesis. It converts free arachidonic acid, released from membrane phospholipids at the sn-2 ester binding site by the enzymatic activity of phospholipase A2, to prostaglandin (PG) H2. The reaction involves both cyclooxygenase (dioxygenase) and hydroperoxidase (peroxidase) activity. The cyclooxygenase activity incorporates two oxygen molecules into arachidonic acid or alternate polyunsaturated fatty acid substrates, such as linoleic acid and eicosapentaenoic acid. Metabolism of arachidonic acid forms a labile intermediate peroxide, PGG2, which is reduced to the corresponding alcohol, PGH2, by the enzyme's hydroperoxidase activity.

While metabolizing arachidonic acid primarily to PGG2, COX-1 also converts this fatty acid to small amounts of a racemic mixture of 15-Hydroxyicosatetraenoic acids (i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE stereoisomers as well as a small amount of 11(R)-HETE.[12] The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of anti-inflammatory agents, the lipoxins.[13] In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of 12-Hydroxyheptadecatrienoic acids viz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plus Malonyldialdehyde.[14][15][16] and can be metabolized by CYP2S1 to 12-HHT[17][18] (see 12-Hydroxyheptadecatrienoic acid). These alternate metabolites of COX-1 may contribute to its activities.

COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion and reduced pepsin content.[19][20] COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.

Clinical significance

[edit]

COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. Thromboxane A2, the major product of COX-1 in platelets, induces platelet aggregation.[7][21] The inhibition of COX-1 is sufficient to explain why low dose aspirin is effective at reducing cardiac events.

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cyclooxygenase-1

View on Grokipedia
from Grokipedia
Cyclooxygenase-1 (COX-1), also known as G/H 1 (PTGS1), is a constitutively expressed that catalyzes the committed first two steps in the biosynthesis of prostanoids from , converting it first to the endoperoxide G2 (PGG2) via cyclooxygenation and then to H2 (PGH2) through peroxidation. This process occurs at the and , where PGH2 serves as a precursor for bioactive lipid mediators including , thromboxanes, and prostacyclins, which regulate diverse physiological functions. As a key component of the housekeeping cascade, COX-1 maintains basal prostanoid levels essential for throughout the body. Structurally, COX-1 is a homodimeric monotopic with a molecular weight of approximately 70 kDa, comprising 599 encoded by the PTGS1 gene on 9q33.2; each monomer features an N-terminal epidermal growth factor-like domain, a central membrane-binding domain with four transmembrane helices, and a C-terminal catalytic domain housing the cyclooxygenase active site (near Tyr-385) and peroxidase active site. The requires by a tyrosyl radical for and exhibits narrower substrate specificity compared to its isoform, with optimal activity under higher conditions. First identified in the early 1970s as the primary target of non-steroidal anti-inflammatory drugs (NSAIDs) through studies on aspirin inhibition, COX-1 was purified in 1976 and molecularly cloned in 1988, revealing its distinction from the inducible COX-2 isoform discovered shortly thereafter. In , COX-1-derived prostanoids play critical roles in cytoprotection of the , promotion of platelet aggregation and via A2, and regulation of renal perfusion and vascular tone; its ubiquitous, stable expression contrasts with the inflammation-inducible COX-2, making COX-1 inhibition a common cause of NSAID-associated gastrointestinal . While traditionally viewed as a "housekeeping" , emerging evidence also links COX-1 to pathological processes such as certain cancers and , underscoring its broader therapeutic relevance.

Discovery and Molecular Biology

History and Nomenclature

The enzymatic activity of cyclooxygenase-1 (COX-1), initially known as the fatty acid cyclooxygenase or prostaglandin synthase, was first isolated and characterized in the through studies on the biosynthesis of prostaglandins from . In 1964, D.A. van Dorp and colleagues demonstrated the enzymatic conversion of polyunsaturated fatty acids, such as , into prostaglandins using microsomal preparations from sheep vesicular glands, establishing the gland as a rich source for the enzyme. Bengt Samuelsson's group extended this work in 1967 by detailing the oxygenation mechanism, showing that the enzyme inserts two oxygen molecules to form a cyclic endoperoxide intermediate, prostaglandin G2 (PGG2), in a process termed cyclooxygenation. These early biochemical assays relied on radio-labeled substrates and to measure product formation, confirming the enzyme's role in the initial committed step of prostanoid synthesis. Purification efforts in the advanced the understanding of COX-1 as a membrane-bound, -dependent . In 1976, M. Hemler and W.E.M. Lands achieved significant purification from sheep vesicular gland microsomes using detergent solubilization (e.g., Tween-40), , and , yielding an preparation with approximately 200 units/mg protein activity and revealing two forms of iron ( and non-heme) in the holoenzyme. Concurrently, T. Miyamoto et al. purified the from bovine vesicular glands, separating it into solubilized fractions that retained both and activities essential for converting PGG2 to (PGH2). These methods highlighted the enzyme's instability and requirement for hematin activation, laying the groundwork for structural studies. Sheep vesicular glands remained the preferred tissue due to their high COX-1 expression and ease of extraction. The molecular cloning of the COX-1 gene, officially symbolized as PTGS1 (prostaglandin-endoperoxide synthase 1), occurred in 1988, marking a pivotal advancement. D.L. DeWitt and W.L. Smith isolated and sequenced the complementary DNA (cDNA) from sheep vesicular gland mRNA, deducing the primary structure of the 600-amino-acid protein and confirming its bifunctional nature. Independently, C. Yokoyama, T. Takai, and T. Tanabe reported the sheep sequence and cloned the human PTGS1 homolog from endothelial cells, revealing 91% amino acid identity between species. The human PTGS1 gene is located on chromosome 9q33.2, spanning about 25 kb with 11 exons. These cloning efforts used oligonucleotide probes based on partial amino acid sequences from purified protein and expression in Xenopus oocytes or COS cells to verify activity. Nomenclature for the enzyme evolved alongside these discoveries to reflect its catalytic properties and distinction from related isoforms. Initially termed "prostaglandin endoperoxide synthase" (PGES or PGHS) to emphasize its endoperoxide-forming activity, the name shifted to "" in the 1970s to underscore the unique cyclization and dioxygenation of at the . Following the 1991 of the inducible isoform (later COX-2), the constitutive form was specifically designated COX-1 to differentiate their expression patterns and roles, with PTGS1 as the approved gene symbol by the Human Genome Organization. This naming convention facilitated targeted research into isoform-specific inhibitors. The distinction from COX-2, encoded by PTGS2 on , highlights COX-1's housekeeping functions versus COX-2's inflammation-associated induction.

Gene Structure and Isozymes

The PTGS1 gene, which encodes the cyclooxygenase-1 (COX-1) enzyme, is located on the long arm of human at q33.2 and spans approximately 25 kb in length. It consists of 11 exons that are interrupted by 10 introns, with the canonical mRNA transcript (ENST00000362012) measuring about 2.8 kb. The promoter region of PTGS1 lacks a canonical or but includes multiple regulatory elements, such as binding sites for the , which contribute to its constitutive expression pattern. These structural features were first elucidated through genomic cloning efforts in the late . COX-1, the protein product of PTGS1, is a constitutively expressed isoform comprising 599 , playing a housekeeping role in synthesis across various tissues. In contrast, the related COX-2, encoded by the PTGS2 on , is inducible under inflammatory or stress conditions and consists of 604 , sharing approximately 60% identity with COX-1 but differing in regulatory responsiveness. A third variant, COX-3, arises as a splice variant of a COX-1 paralog (COX-1b) primarily in canine tissues, where it retains enzymatic activity sensitive to analgesics like acetaminophen; however, the human equivalent splice variant produces a truncated, non-functional protein lacking key catalytic domains. Genetic variation in PTGS1 includes common polymorphisms such as the C50T (rs3842787) in the proximal promoter region, which has been linked to modulated levels and potential influences on activity in response to stimuli. Other variants, like -842A>G, similarly affect transcriptional efficiency by altering binding. The PTGS1 sequence exhibits strong evolutionary conservation across mammalian , with over 90% identity in coding regions between humans and , underscoring its essential role in conserved physiological pathways.

Protein Structure and Catalytic Mechanism

Tertiary Structure and Active Sites

Cyclooxygenase-1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (PTGS1), is a homodimeric integral membrane with each approximately 70 kDa in size. The enzyme is embedded in the and membranes, where it functions as a bifunctional . The three-dimensional structure, first determined for the ovine ortholog at 3.5 Å resolution, reveals a monomeric architecture comprising three distinct domains: an N-terminal (EGF)-like domain (residues 34–72), a membrane-binding domain (residues 73–116) consisting of four amphipathic α-helices that facilitate non-covalent association with the , and a large C-terminal catalytic domain (residues 117–587) dominated by a barrel-like arrangement of 23 α-helices surrounding four antiparallel β-sheets. This catalytic domain houses both the cyclooxygenase and active sites, with the overall fold conserved across species, as confirmed by the recent 3.36 Å of COX-1. The homodimer interface is primarily mediated by interactions between the EGF-like domains and the catalytic domains of opposing monomers, ensuring stability and cooperative function. The is located near the protein surface within the catalytic domain, centered around a axially ligated by a proximal (His-388). Key residues in the distal heme pocket include His-207, which serves as the conserved distal facilitating substrate binding and reduction, and Trp-199, which participates in long-range to support the cycle. This site enables the reduction of hydroperoxides to alcohols, generating oxidized intermediates essential for . In contrast, the is a narrow, L-shaped hydrophobic channel approximately 25 long, extending from the membrane-binding domain into the catalytic core. The channel apex features Tyr-385, the catalytic residue that forms a tyrosyl radical to initiate abstraction, and Ser-530, which coordinates substrate groups and is the site of irreversible by aspirin. The channel's constriction, formed by residues like Arg-120 and Val-523, regulates access for , with the hydrophobic lining (e.g., Leu-384, Phe-518) accommodating the substrate's acyl chain. Post-translational modifications are critical for COX-1 folding, stability, and trafficking. The enzyme undergoes N-linked at three conserved sites—Asn-53, Asn-144, and Asn-410—in the mature protein, with chains contributing approximately 10 kDa to the monomer mass and aiding in endoplasmic reticulum retention and dimerization. Additionally, the EGF-like domain contains three intramolecular bonds (Cys-37–Cys-47, Cys-41–Cys-57, and Cys-69–Cys-79, using ovine numbering adjusted for ), which stabilize the compact fold and promote inter-monomer interactions. These covalent modifications occur co-translationally in the , where the oxidative environment supports formation.

Enzymatic Reaction Pathway

Cyclooxygenase-1 (COX-1), also known as prostaglandin endoperoxide H synthase-1 (PGHS-1), catalyzes the committed step in prostanoid biosynthesis by converting arachidonic acid to prostaglandin H2 (PGH2) via two linked enzymatic activities: a bis-oxygenase (cyclooxygenase) reaction and a peroxidase reaction. The overall transformation incorporates two molecules of oxygen into arachidonic acid (C20_{20}H32_{32}O2_2) to yield PGH2 (C20_{20}H32_{32}O4_4), with the equation arachidonic acid + 2 O2_2 → PGG2_2 for the cyclooxygenase step, followed by PGG2_2 + 2 e−^- + 2 H+^+ → PGH2_2 for the peroxidase step. The activity initiates catalysis at the hydrophobic , where a tyrosyl radical at residue Tyr-385 abstracts the pro-S from (C-13) of , generating a delocalized pentadienyl radical intermediate. This radical subsequently adds molecular oxygen at C-11 to form a peroxyl radical, which cyclizes via formation of a C-8 to C-12 endoperoxide bond, transferring the radical to C-8; a second cyclization then establishes the five-membered ring, followed by oxygenation at C-15 to produce the endoperoxide intermediate PGG2, with concomitant regeneration of the Tyr-385 radical to allow multiple turnovers. The peroxidase activity occurs at a distinct heme-containing site and reduces the 15-hydroperoxyl group of PGG2 to an alcohol, yielding PGH2. This involves the heme iron cycling through oxidation states: Compound I (a ferryl-oxo π-cation radical) abstracts an from PGG2 to form Compound II (ferryl-oxo species), which accepts a second to complete the reduction, thereby linking the two activities by regenerating the Tyr-385 radical essential for the step. Kinetically, COX-1 displays a Michaelis constant (Km) of approximately 5 μM for , reflecting efficient substrate binding under physiological conditions. However, the enzyme undergoes suicide inactivation after about 100 catalytic turnovers, primarily due to self-oxidation and covalent modification of residues during the radical-mediated process.

Biological Functions and Regulation

Prostaglandin Biosynthesis and Cellular Roles

Cyclooxygenase-1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 (PTGS1), catalyzes the conversion of to (PGH2), the central precursor in the biosynthesis of various prostanoids. This reaction occurs following the release of from membrane phospholipids by (PLA2), integrating COX-1 into the broader signaling network. PGH2 is then rapidly metabolized by downstream terminal synthases to produce bioactive prostaglandins, including (PGE2) via microsomal prostaglandin E synthase-1 (mPGES-1) or other PGE synthases, (PGD2) via prostaglandin D synthases, prostaglandin F2α (PGF2α) via PGF synthase, (PGI2) via prostacyclin synthase, and (TXA2) via thromboxane A synthase. These transformations occur in a cell- and tissue-specific manner, reflecting COX-1's constitutive expression and its role in basal prostanoid production for housekeeping functions. In cellular contexts, COX-1-derived PGE2 plays a critical role in maintaining gastric mucosal integrity by promoting and secretion, enhancing epithelial , and modulating blood flow to prevent damage from luminal acids. Similarly, TXA2 synthesized via the COX-1 pathway in platelets induces shape change, aggregation, and , facilitating and formation. In the , COX-1-mediated TXA2 production contributes to the regulation of renal blood flow through vasoconstrictive effects on glomerular arterioles, balancing the vasodilatory actions of other prostanoids like PGE2 and PGI2 to maintain glomerular under basal conditions. The basal activity of COX-1 ensures steady-state production of these prostanoids, supporting essential cellular such as cytoprotection and vascular tone without the need for external stimuli, distinguishing it from inducible pathways. This constitutive coupling with PLA2 and downstream synthases underscores COX-1's integration into the network, where disruptions can impair immediate cellular signaling and physiological balance.

Expression Patterns and Regulatory Mechanisms

Cyclooxygenase-1 (COX-1), encoded by the PTGS1 gene, displays ubiquitous basal expression in most mammalian tissues, reflecting its role as a that supports constitutive production for physiological maintenance. High levels of COX-1 are particularly noted in the , where it contributes to mucosal protection; in the , aiding renal blood flow and salt balance; and in platelets, facilitating synthesis for . This steady-state pattern contrasts sharply with (COX-2), which exhibits minimal basal expression but undergoes rapid transcriptional induction in response to proinflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, enabling acute inflammatory responses. Unlike COX-2, COX-1 maintains consistent mRNA and protein levels due to their inherent stability, without prominent reliance on destabilizing elements like AU-rich sequences in the 3' . Transcriptional regulation of COX-1 expression is primarily governed by features, including a TATA-less promoter with high and multiple Sp1 binding sites that drive basal activity and responsiveness to stimuli. For instance, the Sp1 sites at positions -610, -111, and -89 are critical for phorbol 12-myristate 13-acetate (PMA)-induced upregulation in megakaryocytic cells, while an AP-1 site in intron 8 cooperates with the -111 Sp1 site to enhance transcription during . Additional inducers include in endothelial cells, in , and in vascular tissues, underscoring tissue-specific modulation without the broad cytokine-driven surges seen in COX-2. In certain inflammatory contexts, such as tobacco carcinogen exposure in macrophages, activation can contribute to COX-1 induction, though this is less dominant than for COX-2. Glucocorticoids exert cell-type-dependent effects on COX-1 transcription via the , often repressing expression to fine-tune levels. In fetal endothelial cells, dexamethasone reduces COX-1 mRNA by up to 50% and protein by 44% within 48 hours, leading to decreased synthesis, an effect reversed by glucocorticoid receptor antagonists like . Conversely, in cardiomyocytes and cells, glucocorticoids can elevate COX-1 levels, highlighting contextual variability in regulatory outcomes. Post-transcriptional mechanisms are limited, with COX-1 mRNA stability ensuring sustained expression, though specific interactions, such as with miR-146a, show no significant impact on COX-1 unlike their prominent role in destabilizing COX-2 transcripts. -mediated feedback, while well-documented for COX-2, lacks clear evidence of direct inhibitory control over COX-1 levels, maintaining its constitutive profile.

Physiological and Pathophysiological Roles

Homeostatic Functions in Tissues

Cyclooxygenase-1 (COX-1) plays a pivotal role in maintaining gastrointestinal mucosal integrity through the constitutive production of prostaglandins, particularly prostaglandin E2 (PGE2), which stimulates the secretion of mucus and bicarbonate by epithelial cells. This cytoprotective mechanism helps neutralize gastric acid and forms a physical barrier against luminal irritants, thereby preventing erosion and ulceration of the gastric mucosa. Studies in COX-1-deficient models demonstrate increased susceptibility to gastric injury, underscoring the enzyme's essential function in basal mucosal defense. Additionally, COX-1-derived PGE2 and prostacyclin (PGI2) regulate mucosal blood flow, ensuring nutrient delivery and rapid removal of acid, which further supports tissue homeostasis in the stomach and intestines. In the cardiovascular system, COX-1 is constitutively expressed in platelets, where it catalyzes the conversion of to (PGH2), which is then transformed into (TXA2) by thromboxane synthase. TXA2 promotes platelet activation, shape change, and aggregation by binding to thromboxane-prostanoid (TP) receptors, facilitating primary and clot formation at sites of vascular injury. This process is amplified through autocrine and , with TXA2 also inducing to reduce blood loss. Complementing this, COX-1 in endothelial cells produces PGI2, which counterbalances TXA2 by promoting and inhibiting platelet aggregation, thereby maintaining vascular tone and preventing excessive under normal conditions. COX-1 contributes to renal primarily by supporting (GFR) through the production of vasodilatory prostaglandins, such as PGI2, in mesangial and endothelial cells of the . This is particularly crucial in states of reduced renal , where COX-1-derived prostanoids counteract vasoconstrictive influences to preserve blood flow and filtration. In COX-1 deficiency, enhanced occurs, indicating a role in modulating sodium , likely via indirect effects on tubular function and . Beyond the , COX-1 supports by generating basal levels of prostaglandins that influence and activity, maintaining bone turnover balance in response to mechanical and humoral signals. In female reproduction, COX-1 regulates maturation and lifespan; its inhibition delays the transition from primary to secondary follicles, thereby prolonging the postnatal and supporting reproductive longevity.

Involvement in Diseases and Disorders

Cyclooxygenase-1 (COX-1) plays a significant role in chronic inflammatory conditions by contributing to the sustained production of proinflammatory in affected tissues. In models of , such as the K/BxN serum-transfer , COX-1 predominates over COX-2 in generating proinflammatory prostanoids, with COX-1-deficient mice exhibiting full resistance to disease development and reduced joint inflammation. This suggests that COX-1-mediated synthesis, including potential contributions to (PGE2) levels in synovial tissues, sustains inflammatory responses in autoimmune . Similarly, in , COX-1 is constitutively expressed in both normal colonic epithelium and tumor tissues, where it catalyzes the production of , a implicated in early and tumor initiation. Expression levels of COX-1 vary in advanced colorectal tumors (Dukes' C stage), indicating its potential involvement in disease progression through ongoing -mediated signaling that supports tumor growth. In cardiovascular diseases, COX-1-derived (TXA2) from activated platelets enhances platelet aggregation and , promoting and contributing to the of . Elevated TXA2 activity is associated with increased risk of thrombotic events, including plaque instability and vessel occlusion in atherosclerotic lesions. Genetic polymorphisms in the COX-1 gene have been linked to altered vascular outcomes, with certain variants associated with a higher incidence of and other cardiovascular events in at-risk populations. Beyond these, dysregulation of COX-1 activity is implicated in other disorders, particularly through disruptions in its homeostatic prostaglandin production. Over-inhibition of COX-1 impairs gastric mucosal defense by reducing protective , leading to increased susceptibility to gastroduodenal ulcers via diminished and secretion. In neurodegenerative diseases like Alzheimer's, COX-1 contributes to neuroinflammatory responses triggered by beta-amyloid, where its deficiency reduces microglial activation, , and neuronal damage, suggesting that excessive COX-1 activity exacerbates pathology potentially through loss of balanced .

Clinical and Therapeutic Aspects

Inhibition by Drugs and NSAIDs

Cyclooxygenase-1 (COX-1) is inhibited by various nonsteroidal anti-inflammatory drugs (NSAIDs) through mechanisms that target its , where binds as the substrate. Aspirin exerts irreversible inhibition by acetylating Serine-530 (Ser-530) within the COX-1 , preventing substrate access and permanently inactivating the until new protein synthesis occurs. This covalent modification relies on the group of aspirin facilitating intramolecular , with Tyrosine-385 playing a key role in the process. In contrast, ibuprofen acts as a reversible, competitive inhibitor by binding to the site in the COX-1 , thereby blocking substrate oxygenation without covalent alteration. NSAIDs are classified based on their selectivity for COX-1 versus COX-2, with many exhibiting non-selective inhibition that affects both isoforms. Non-selective NSAIDs, such as indomethacin and naproxen, potently inhibit COX-1 with low micromolar values, for example, indomethacin at approximately 1.3 μM and naproxen at 0.6 μM, contributing to broad effects but also increased risk of adverse outcomes. Aspirin also falls into this category, with an for COX-1 around 2-5 μM, reflecting its strong but irreversible potency against the . Some NSAIDs show preferential selectivity for COX-1 over COX-2, such as , which has an of about 9.4 μM for COX-1 compared to 600 μM for COX-2, indicating over 60-fold preference for COX-1 inhibition. Inhibition of COX-1 by these drugs leads to reduced prostaglandin synthesis, resulting in notable side effects. The loss of COX-1-derived prostaglandins in the impairs protective mechanisms like and , increasing the risk of and ulceration, particularly with chronic use of non-selective NSAIDs. Conversely, COX-1 inhibition in platelets blocks thromboxane A2 production, providing antiplatelet effects that prolong and offer cardioprotective benefits, as seen with low-dose aspirin therapy.

Therapeutic Targeting and Recent Advances

Efforts to develop COX-1-sparing drugs, primarily through selective COX-2 inhibitors such as celecoxib, have aimed to minimize gastrointestinal toxicity associated with non-selective NSAIDs that inhibit COX-1 in the . These agents reduce the risk of ulcers and bleeding by preserving COX-1-mediated production essential for mucosal protection, as demonstrated in clinical studies showing lower incidence of upper events compared to traditional NSAIDs. Nitric oxide-releasing derivatives of aspirin, such as NCX-4016, represent an innovative approach to gastroprotection while maintaining COX-1 inhibition for antiplatelet effects. These compounds release to enhance gastric flow and production, counteracting the ulcerogenic potential of aspirin; preclinical and early indicate they prevent - and stress-induced gastric damage more effectively than conventional aspirin without compromising cardiovascular benefits. Recent advances in the have explored selective COX-1 inhibitors for cancer therapy, highlighting their role in modulating the . Studies have shown that COX-1-dependent pathways contribute to tumor growth and immune evasion, with selective inhibitors like those derived from pyrazolo[1,5-a]pyrimidine scaffolds demonstrating potent anti-proliferative effects in models by disrupting metabolism. Pharmacogenomic research on PTGS1 variants has opened avenues for precision medicine in COX-1 modulation, identifying polymorphisms that alter activity and aspirin responsiveness. For instance, variants like R53H and L237M reduce COX-1 by aspirin, leading to variable antiplatelet efficacy; for these could guide dosing in cardiovascular prevention to optimize outcomes while minimizing risks. Ongoing clinical trials and meta-analyses underscore COX-1 modulation via low-dose aspirin for cardiovascular prevention, with established meta-analyses (e.g., as of 2019, involving over 150,000 participants) indicating a modest reduction in (approximately 11-12% ) in primary prevention settings, particularly for those aged 40-59 at elevated risk, though benefits are tempered by concerns and current guidelines (as of 2025) recommend against routine use in adults aged 60 and older due to net harm from . Precision approaches incorporating PTGS1 are being integrated into trials to personalize aspirin use, aiming to enhance net clinical benefit in diverse populations.

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