Novel reversible, irreversible and fluorescent inhibitors of platelet-activating factor acetylhydrolase as mechanistic probes

Deigner, Hans Peter; Kinscherf, Ralf; Claus, Ralf A.; Fyrnys, Beatrix; Blencowe, Christopher; Hermetter, Albin

doi:10.1016/s0021-9150(99)00034-9

Cited by 6 publications

(4 citation statements)

References 42 publications

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“…The most common chemical inhibitors of plasma PAF-AH in vitro are PMSF and DFP, active in mM concentrations [179,180]. Plasma PAF-AH is also inhibited by the esterase inhibitors MAFP, its linoleoyl homolog, and 4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride (Pefabloc) [181].…”

Section: Paf-ahs Inhibitorsmentioning

confidence: 99%

Phospholipase A2 subclasses in acute respiratory distress syndrome

Kitsiouli

Nakos

Lekka

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Phospholipases A2 (PLA2) catalyse the cleavage of fatty acids esterified at the sn-2 position of glycerophospholipids. In acute lung injury-acute respiratory distress syndrome (ALI-ARDS) several distinct isoenzymes appear in lung cells and fluid. Some are capable to trigger molecular events leading to enhanced inflammation and lung damage and others have a role in lung surfactant recycling preserving lung function: Secreted forms (groups sPLA2-IIA, -V, -X) can directly hydrolyze surfactant phospholipids. Cytosolic PLA2 (cPLA2-IVA) requiring Ca2+ has a preference for arachidonate, the precursor of eicosanoids which participate in the inflammatory response in the lung. Ca(2+)-independent intracellular PLA2s (iPLA2) take part in surfactant phospholipids turnover within alveolar cells. Acidic Ca(2+)-independent PLA2 (aiPLA2), of lysosomal origin, has additionally antioxidant properties, (peroxiredoxin VI activity), and participates in the formation of dipalmitoyl-phosphatidylcholine in lung surfactant. PAF-AH degrades PAF, a potent mediator of inflammation, and oxidatively fragmented phospholipids but also leads to toxic metabolites. Therefore, the regulation of PLA2 isoforms could be a valuable approach for ARDS treatment.

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Section: Paf-ahs Inhibitorsmentioning

confidence: 99%

Phospholipase A2 subclasses in acute respiratory distress syndrome

Kitsiouli

Nakos

Lekka

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Many researchers have tailored the structure of mechanism-based probes to specifically address enzymes or certain enzyme classes of their interest. To date mechanistic probes have been designed for different enzyme classes, namely serine hydrolases [45][46][47] including serine proteases [48][49][50][51], lipases [52][53][54][55][56][57][58] and PAF-acetylhydrolases [59], cysteine proteases including caspases [60,61], papains [62][63][64][65][66][67][68] and ubiquitin-and ubiquitin-like specific proteases [69,70], threonine proteases [71][72][73], tyrosine phosphatases [74,75] and glycosidases [76][77][78][79].…”

Section: Activity-based Proteomics For Target and Drug Discoverymentioning

confidence: 99%

Activity-Based Proteomics of Lipolytic Enzymes

Birner‐Gruenberger¹,

Hermetter

2007

CDDT

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Lipases play fundamental roles in biological processes since hydrolysis of triacylglycerols and cholesteryl esters is a key event in energy homeostasis of animals. Perturbations in the metabolism and the cellular retention of lipids result in common diseases such as obesity, type 2 diabetes, and atherosclerosis. The introduction of active site-directed chemical probes for enzymatic activity profiling in complex mixtures, known as activity-based proteomics, has greatly facilitated and accelerated global analysis and functional annotation of lipolytic proteins. Here we review probe design and application for discovery and discrimination of lipolytic and esterolytic enzymes. These probes are usually detected by their fluorescent or affinity tags and their protein targets are analyzed using established proteomics techniques. Moreover, microarray technologies can be applied for higher throughput screenings of enzyme or probe specificity.

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“…Typically, irreversible inhibitors have been used as probes to understand enzyme mechanisms (Deigner et al, 1999;Rempel and Withers, 2008). In the current study, their use was expanded to quantify enzyme in vivo kinetic properties through mechanistic modeling.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition

Chang

Fonseca

et al. 2018

Mol Pharmacol

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Kynurenic acid (KYNA) plays a significant role in maintaining normal brain function, and abnormalities in KYNA levels have been associated with various central nervous system disorders. Confirmation of its causality in human diseases requires safe and effective modulation of central KYNA levels in the clinic. The kynurenine aminotransferases (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, ) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16-76 hours' half-life ()], whereas KYNA is cleared more rapidly from the brain (<1 hour ) in both rats and NHPs, 2) KAT II turnover is slower in NHPs than in rats (76 hours vs. 16 hours, respectively), and 3) the percent contribution of KAT II to KYNA formation is constant (∼80%) across rats and NHPs. Additionally, modeling results enabled establishment of in vitro-in vivo correlation for both enzyme turnover rates and drug potencies. In summary, quantitative translational analysis confirmed the feasibility of central KYNA modulation in humans. Model-based analysis, where system-specific properties and drug-specific properties are mechanistically separated from in vivo responses, enabled quantitative understanding of the KAT II-KYNA pathway, as well as assisted development of promising candidates to test KYNA hypothesis in humans.

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Novel reversible, irreversible and fluorescent inhibitors of platelet-activating factor acetylhydrolase as mechanistic probes

Cited by 6 publications

References 42 publications

Phospholipase A2 subclasses in acute respiratory distress syndrome

Phospholipase A2 subclasses in acute respiratory distress syndrome

Activity-Based Proteomics of Lipolytic Enzymes

Quantitative Translational Analysis of Brain Kynurenic Acid Modulation via Irreversible Kynurenine Aminotransferase II Inhibition

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