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Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2.

ABSTRACT: Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis-the conversion of arachidonic acid to prostaglandin endoperoxide H2 Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (i.e. nonsteroidal anti-inflammatory drugs and coxibs) and common fatty acids (FAs) modulate Ecat activity by binding Eallo. However, the interactions and outcomes often differ between isoforms. For example, naproxen directly and completely inhibits COX-1 by binding Ecat but indirectly and incompletely inhibits COX-2 by binding Eallo. Additionally, COX-1 is allosterically inhibited up to 50% by common FAs like palmitic acid, whereas COX-2 is allosterically activated 2-fold by palmitic acid. FA binding to Eallo also affects responses to COX inhibitors. Thus, COXs are physiologically and pharmacologically regulated by the FA tone of the milieu in which each operates-COX-1 in the endoplasmic reticulum and COX-2 in the Golgi apparatus. Cross-talk between Eallo and Ecat involves a loop in Eallo immediately downstream of Arg-120. Mutational studies suggest that allosteric modulation requires a direct interaction between the carboxyl group of allosteric effectors and Arg-120 of Eallo; however, structural studies show some allosterically active FAs positioned in COX-2 in a conformation lacking an interaction with Arg-120. Thus, many details about the biological consequences of COX allosterism and how ligand binding to Eallo modulates Ecat remain to be resolved.

SUBMITTER: Smith WL

PROVIDER: S-EPMC6364783 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2.

Smith William L WL Malkowski Michael G MG

The Journal of biological chemistry 20190201 5

Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis-the conversion of arachidonic acid to prostaglandin endoperoxide H<sub>2</sub> Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (<i>i ...[more]

PMID: 30710016

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Project description:IntroductionDrug utilization of analgesics in a private healthcare setting is useful to examine their prescribing patterns, especially the newer injectable cyclooxygenase (COX)-2 inhibitors (coxibs).ObjectivesTo evaluate the utilization of coxibs and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) indicated for postoperative orthopaedic pain control using defined daily dose (DDD) and ratio of use density to use rate (UD/UR).MethodA retrospective drug utilization review (DUR) of nonsteroidal anti-inflammatory drugs (NSAIDs) at an inpatient department of a private teaching hospital in Seremban, Malaysia was conducted. Patients' demographic characteristics, medications prescribed, clinical lab results, visual analogue scale (VAS) pain scores and length of hospital stay were documented. Orthopaedic surgeries, namely arthroscopy, reconstructive, and fracture fixation, were included. Stratified random sampling was used to select patients. Data were collected through patients' medical records. The DDD per 100 admissions and the indicator UD/UR were calculated with the World Health Organization's DDD as a benchmark. The inclusion criteria were patients undergoing orthopaedic surgery prescribed with coxibs (celecoxib capsules, etoricoxib tablets, parecoxib injections) and tNSAIDs (dexketoprofen injections, diclofenac sodium tablets). Data were analysed descriptively. This research was approved by the academic institution and the hospital research ethics committee.ResultA total of 195 records of patients who received NSAIDs were randomly selected among 1169 cases. In term of the types of orthopaedic surgery, the ratio of included records for arthroscopy:fracture fixation:reconstructive surgery was 55.4:35.9:8.7. Most of the inpatients had low rates of common comorbidities such as cardiovascular disease as supported by their baseline parameters. The majority were not prescribed with other concomitant prescriptions that could cause drug interaction (74.9%), or gastroprotective agents (77.4%). Overall, DDDs per 100 admissions for all NSAIDs were less than 100, except for parecoxib injections (389.23). The UD/UR for all NSAIDs were less than 100, except for etoricoxib tablets (105.75) and parecoxib injections (108.00).DiscussionAs per guidelines, the majority (96.9%) received other analgesics to ensure a multimodal approach was carried out to control pain. From the UD/UR results, the arthroscopy surgery was probably the most appropriate in terms of NSAID utilization.ConclusionThe prescribing pattern of NSAIDs except parecoxib was appropriate based on adverse effect and concurrent medication profile. The findings of this DUR provide insight for a low-risk patient population at a private specialized teaching hospital on the recommended use of NSAIDs for postoperative orthopaedic pain control.

Project description:The diterpene forskolin (FS) binds to, and activates, mammalian membranous adenylyl cyclase (AC) isoforms I-VIII. Diterpenes without C(1)-OH group do not activate ACs. The C(1)-OH group forms a hydrogen bond with the backbone oxygen of Val506 of the C1 catalytic subunit of AC (isoform V numbering). To better understand the mechanism of AC activation we examined the interactions of FS and eight FS analogs with purified catalytic AC subunits C1 (AC V) and C2 (AC II) by fluorescence spectroscopy, using 2',3'-O-(N-methylanthraniloyl)-guanosine 5'-triphosphate (MANT-GTP) as fluorescent reporter probe, and by enzymatic activity. FS analogs induced C1/C2 assembly as assessed by fluorescence resonance energy transfer from Trp1020 of C2 to MANT-GTP and by increased direct MANT-GTP fluorescence in the order of efficacy FS approximately 7-deacetyl-FS approximately 6-acetyl-7-deacetyl-FS approximately 9-deoxy-FS>7-deacetyl-7-(N-methylpiperazino-gamma-butyryloxy)-FS>1-deoxy-FS approximately 1,9-dideoxy-FS approximately 7-deacetyl-1-deoxy-FS approximately 7-deacetyl-1,9-dideoxy-FS. In contrast, FS analogs activated catalysis in the order of efficacy FS>7-deacety-FS approximately 6-acetyl-7-deacetyl-FS approximately 9-deoxy-FS>7-deacetyl-7-(N-methylpiperazino-gamma-butyryloxy)-FS>>1-deoxy-FS, 1,9-dideoxy-FS, 7-deacetyl-1-deoxy-FS and 7-deacetyl-1,9-dideoxy-FS (all ineffective). 1-Deoxy-FS analogs inhibited FS-stimulated catalysis by an apparently non-competitive mechanism. Our data suggest a two-step mechanism of AC activation by diterpenes. In the first step, diterpenes, regardless of their substitution pattern, promote C1/C2 assembly. In the second and yet poorly understood step, diterpenes that form a hydrogen bond between C(1)-OH and Val506 promote a conformational switch that results in activation of catalysis. The apparent non-competitive interaction of FS with 1-deoxy-FS analogs is explained by impaired ligand exchange due to strong hydrophobic interactions with C1/C2.

Dataset Information

Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2.

Publications

Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2.

Similar Datasets

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