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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    • "Among the classes of proteins that have been addressed by ABPP, the serine hydrolases are a particularly large and diverse enzyme family that plays many key roles in the nervous system (Simon and Cravatt, 2010, Long and Cravatt, 2011). Serine hydrolases regulate proteolysis at the synapse to modulate neuronal plasticity (Melchor and Strickland, 2005), the post-translational modification state of key brain signaling proteins (Sontag et al., 2007, Siegel et al., 2009), and, perhaps most notably, the metabolism of a wide range of chemical messengers, including neurotransmitters (e.g., acetylcholine [Phillis, 2005], neuropeptides (e.g., a-melanocyte-stimulating hormone [Wallingford et al., 2009]), and lipid messengers (e.g., endocannabinoids; eCBs [Blankman and Cravatt , 2013]). "
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    ABSTRACT: Metabolic specialization among major brain cell types is central to nervous system function and determined in large part by the cellular distribution of enzymes. Serine hydrolases are a diverse enzyme class that plays fundamental roles in CNS metabolism and signaling. Here, we perform an activity-based proteomic analysis of primary mouse neurons, astrocytes, and microglia to furnish a global portrait of the cellular anatomy of serine hydrolases in the brain. We uncover compelling evidence for the cellular compartmentalization of key chemical transmission pathways, including the functional segregation of endocannabinoid (eCB) biosynthetic enzymes diacylglycerol lipase-alpha (DAGLα) and -beta (DAGLβ) to neurons and microglia, respectively. Disruption of DAGLβ perturbed eCB-eicosanoid crosstalk specifically in microglia and suppressed neuroinflammatory events in vivo independently of broader effects on eCB content. Mapping the cellular distribution of metabolic enzymes thus identifies pathways for regulating specialized inflammatory responses in the brain while avoiding global alterations in CNS function.
    Full-text · Article · Jan 2016 · eLife Sciences
    • "Mice lacking NAPE-PLD have decreased tissue levels of NAEs, although it is unclear whether the decrease is restricted only to saturated and monounsaturated N-acylethanolamines [24] or also includes anandamide and polyunsaturated NAEs [25]. The fact that N-acylethanolmines are not entirely absent in the knockout mice indicates that other biosynthetic pathways exist as indicated in Figure 1.1, and as discussed in Chapter 8. NAEs are hydrolyzed within the tissues by mainly two enzymes, fatty acid amide hydrolase (FAAH) [26] and N-acylethanolamine acid amidase (NAAA) Fig. 1 "
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    ABSTRACT: N-Acylethanolamine (NAE) and 2-monoacylglycerol (2-MAG) containing arachidonic acid are being called endocannabinoids since they can activate cannabinoid receptors. The same molecules containing stearic acid, palmitic acid, oleic acid, or linoleic acid cannot activate cannabinoid receptors, and are thus called non-endocannabinoid NAEs and 2-MAGs. However, these molecules do also have biological activities, e.g., via activation of the transcription factor PPARα, which mediate anti-inflammatory, antinociceptive, and anorectic effects. Furthermore, activation of the G-protein coupled receptor GPR119 in the small intestine could mediate release of the incretin hormone GLP-1. The present chapter describes the formation and degradation of these lipid molecules, as well as their pharmacology and their related drug targets.
    No preview · Chapter · Dec 2015
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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.
    Full-text · Article · Jun 2015 · Chemistry & biology
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