The Metabolic Serine Hydrolases and Their Functions in Mammalian Physiology and Disease

The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Chemical Reviews (Impact Factor: 46.57). 06/2011; 111(10):6022-63. DOI: 10.1021/cr200075y
Source: PubMed


The largest category of substrates for metabolic SHs is small molecules, which include neutral fatty acyl esters, acyl thioesters phospholipids, lipid amides, and other ester metabolites. The distribution of TGs and recycling of lipoprotein remnants occurs by the action of LPL, LIPC, LCAT, and LIPA. Lumenally oriented LPL and LIPC hydrolyze TGs and cholesteryl esters from chylomicrometer and VLDL particles to generate free fatty acids that can be absorbed and used by tissues. Multiple studies of deficiency in PNLIP have been reported, though none have conclusively demonstrated the extent of the contribution of PNLIP to dietary TG absorption. The available data from both humans and rodents support a role for LIPA in the hydrolysis of cholesteryl esters and TG from internalized LDL particles. While the pancreatic function in these mice is normal, there is an overall decrease in food intake, fat weight, and total weight, and pair feeding studies show that reduced adiposity is due to the reduced caloric intake.

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    • "Serine hydrolases (SHs) represent one of the largest and most diverse enzyme classes in nature, and perform myriad biochemical functions in physiology and disease (Long and Cravatt, 2011). SHs use a conserved mechanism involving a base-activated serine nucleophile to hydrolyze amide, ester, and thioester bonds in biomolecules; however, these enzymes also display markedly different structures and folds, distribute across virtually all subcellular compartments in the cell, and accept an expansive array of small-and macro-molecule substrates. "
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    ABSTRACT: Serine hydrolase inhibitors, which facilitate enzyme function assignment and are used to treat a range of human disorders, often act by an irreversible mechanism that involves covalent modification of the serine hydrolase catalytic nucleophile. The portion of mammalian serine hydrolases for which selective inhibitors have been developed, however, remains small. Here, we show that N-hydroxyhydantoin (NHH) carbamates are a versatile class of irreversible serine hydrolase inhibitors that can be modified on both the staying (carbamylating) and leaving (NHH) groups to optimize potency and selectivity. Synthesis of a small library of NHH carbamates and screening by competitive activity-based protein profiling furnished selective, in vivo-active inhibitors and tailored activity-based probes for multiple mammalian serine hydrolases, including palmitoyl protein thioesterase 1, mutations of which cause the human disease infantile neuronal ceroid lipofuscinosis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Chemistry & biology 06/2015; 22(7). DOI:10.1016/j.chembiol.2015.05.018 · 6.65 Impact Factor
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    ABSTRACT: Serine hydrolases perform crucial roles in many biological processes, and several of these enzymes are targets of approved drugs for indications such as type 2 diabetes, Alzheimer's disease and infectious diseases. Despite this, most of the human serine hydrolases (of which there are more than 200) remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds that are under clinical investigation and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation.
    Nature Reviews Drug Discovery 11/2011; 11(1):52-68. DOI:10.1038/nrd3620 · 41.91 Impact Factor
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    ABSTRACT: We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
    Bioorganic & medicinal chemistry letters 12/2011; 22(2):901-6. DOI:10.1016/j.bmcl.2011.12.032 · 2.42 Impact Factor
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