The serine hydrolase (SH) superfamily consists of >200 enzymes in humans characterized by the presence of an active site serine that is used for the hydrolysis of substrates. The membership of this enzyme class is near-equally split between serine proteases (trypsin/chymotrypsin/subtilisin enzymes) and ‘metabolic’ SHs that cleave ester, amide, or thioester bonds in small molecules, peptides, or proteins.1 The serine proteases have been the subject of several books and reviews.2–5 This article will instead focus on the metabolic SHs (Fig. 1).



Fig. 1

Dendrogram showing the primary sequence alignment of the human mammalian metabolic SHs, where alignment was generated by anchoring sequences at the site of their catalytic Ser residues.



The nucleophilicity of the active site serine of metabolic SHs arises from its participation in a catalytic dyad (e.g. Ser-Lys or Ser-Asp) or triad (e.g. Ser-His-Asp or Ser-Ser-Lys).6,7 The SH catalytic mechanism proceeds by formation of an acyl-enzyme intermediate at the active site serine, followed by water-induced saponification of the product, and regeneration of the free serine residue for entry into the next reaction cycle (Fig. 2).8,9 Owing to the enhanced reactivity of the active site serine, the functional state of most SHs can be assessed using active-site directed affinity labels such as fluorophosphonates (FPs, Fig. 2).1,10



Fig. 2

(A) Mechanism of SH catalysis. (B) Mechanism of SH labeling by the active site-directed activity-based probe fluorophosphonate-biotin (FP-biotin). (C) Three dimensional structure of MGLL, a SH with a canonical α/β-hydrolase fold.



The serine nucleophile of metabolic SHs is generally, though not exclusively embedded within a GXSXG motif and a majority these enzymes adopt an α/β hydrolase fold that consists of a central β-sheet surrounded by α-helicies (Fig. 2).11 This superfamily also encompasses other smaller subsets of structurally distinct enzymes such as the phospholipase A2s, the amidase signature enzymes, and the dipeptidylpeptidases.12,13 Metabolic SHs have been shown to participate in virtually all (patho)physiological processes in mammals, including neurotransmission,14 metabolism,15 pain sensation,16 inflammation,17 oxidative stress,18 cancer,19 and bacterial infection.20

Many excellent reviews have described the structure and function of individual SHs.15,19,21–23 Here, we attempt to provide a comprehensive summary that captures our state of knowledge about mammalian metabolic SHs in their entirety, including those enzymes that remain mostly or completely uncharacterized. Particular emphasis will be placed on relating the biochemistry and enzymology of individual SHs to the physiological substrates and products that they regulate in living systems, and how SHs, through the regulation of specific metabolic pathways impact health and disease. If selective and efficacious inhibitors are available for a particular SH, we will also include a discussion of their use. The majority of this review will be organized by substrate class. Later, we will discuss SHs for which putative endogenous substrates have not been identified, as well as emerging chemoproteomic and metabolomic methods aimed at assigning functions to these enzymes. For the sake of consistency, we have elected to refer to SHs by their proper gene names throughout this review (rather than their common name or abbreviation), but have also attempted to include other aliases if possible.

/pdf/the-metabolic-serine-hydrolases-and-their-functions-in-2ga83q4zha.pdf

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

Therapeutic Targeting of Angiogenesis Molecular Pathways in Angiogenesis-Dependent Diseases

Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family.

Biological roles of lysophosphatidic acid signaling through its production by autotaxin

Calcium in the Golgi apparatus

Purified recombinant mouse endostatin protein has been reported to regress established murine solid tumors by inhibiting the proliferation of endothelial cells. To develop a clinical gene therapy strategy with endostatin, we cloned the cDNA of human endostatin by RT-PCR from human placenta. A 150-bp sequence encoding the IgG leader peptide was fused in frame to the 5′ end of the endostatin cDNA and recombinant adenoviruses, AdENDO-YFP and AdENDO, carrying endostatin gene expression cassettes were rescued. AdENDO-YFP infects cultured mammalian cells at high efficiency and expresses a biologically active human endostatin in secreted form at high levels both in vitro and in vivo. When delivered in vivo, a strain-specific expression pattern was observed, with the highest and longest endostatin expression in 129/J mice. After systemic delivery of 2 × 109 PFU of AdENDO-YFP into 129/J mice, human endostatin expression was achieved at a mean value of 1.34 ± 0.42 μg/ml of serum (n = 6) and inhibition of lung metas...

Adenovirus-mediated human endostatin gene delivery demonstrates strain-specific antitumor activity and acute dose-dependent toxicity in mice.

Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.

/pdf/identification-of-a-novel-lipase-gene-mutated-in-lpd-mice-pae3kll1q3.pdf

Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans

The spatial distributions of Cr, Ni, Cu, Zn, As, Cd and Pb (potentially toxic elements, PTEs) in sediments and intrinsic influence factors from the Wuliangsuhai wetland of the Hetao Irrigation District, China were studied in this work. The results showed that excluding Zn, the total contents of other PTEs were higher than the background values, of which As (39.26 mg·kg−1) and Cd (0.44 mg·kg−1) were six-fold and seven-fold higher, respectively. Especially, the high levels of Cd (70.17%), Pb (66.53%), and Zn (57.20%) in the non-residual fraction showed high bioavailability and mobility. It indicated that PTEs can enter the food chain more easily and produce much toxicity. Based on Igeo, ICF, and MRI, the contamination of As was the most serious in the middle areas (MDP) of the wetland, and its risk was up to moderately strong. Cd and Pb posed moderate and considerate risk, respectively. Furthermore, 29.50% and 55.54% risk contribution ratio of As and Cd, respectively, showed that they were the dominant contaminants. In addition, the positive correlation between sand, OM, and total contents and chemical fractions of PTEs by using PCM, RDA, and DHCA indicated that physicochemical properties could significantly influence the spatial distributions of PTEs. The work was useful for assessing the level of pollution in the study area and acquiring information for future and possible monitoring and remediation activities.

/pdf/spatial-distributions-and-intrinsic-influence-analysis-of-cr-gv3pr7h6.pdf

Spatial Distributions and Intrinsic Influence Analysis of Cr, Ni, Cu, Zn, As, Cd and Pb in Sediments from the Wuliangsuhai Wetland, China

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Adenovirus-mediated human endostatin gene delivery demonstrates strain-specific antitumor activity and acute dose-dependent toxicity in mice.

Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans

Spatial Distributions and Intrinsic Influence Analysis of Cr, Ni, Cu, Zn, As, Cd and Pb in Sediments from the Wuliangsuhai Wetland, China