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1.
Gene ; 671: 78-84, 2018 Sep 10.
Article in English | MEDLINE | ID: mdl-29860067

ABSTRACT

Natural antisense transcripts (NATs) are widely present in mammalian genomes and act as pivotal regulator molecules to control gene expression. However, studies on the NATs of pigs are relatively rare. Here, we identified a novel antisense transcript, designated PLA2G16-AS, transcribed from the phospholipase A2 group XVI locus (PLA2G16) in the porcine genome, which is a well-known regulatory molecule of fat deposition. PLA2G16-AS and PLA2G16 were dominantly expressed in porcine adipose tissue, and were differentially expressed between Tibetan pigs and Rongchang pigs. In addition, PLA2G16-AS has a weak sequence conservation among different vertebrates. PLA2G16-AS was also shown to form an RNA-RNA duplex with PLA2G16, and to regulate PLA2G16 expression at the mRNA level. Moreover, the overexpression of PLA2G16-AS increased the stability of PLA2G16 mRNA in porcine cells. We envision that our findings of a NAT for a regulatory gene associated with lipolysis might further our understanding of the molecular regulation of fat deposition.


Subject(s)
Adipose Tissue/metabolism , Phospholipases A2, Calcium-Independent/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/chemistry , Animals , Cell Line , Evolution, Molecular , Gene Expression Regulation , Organ Specificity , Phospholipases A2, Calcium-Independent/chemistry , RNA Stability , RNA, Long Noncoding/metabolism , Species Specificity , Sus scrofa , Tissue Distribution
2.
J Am Chem Soc ; 140(9): 3285-3291, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29342349

ABSTRACT

We demonstrate that lipidomics coupled with molecular dynamics reveal unique phospholipase A2 specificity toward membrane phospholipid substrates. We discovered unexpected headgroup and acyl-chain specificity for three major human phospholipases A2. The differences between each enzyme's specificity, coupled with molecular dynamics-based structural and binding studies, revealed unique binding sites and interfacial surface binding moieties for each enzyme that explain the observed specificity at a hitherto inaccessible structural level. Surprisingly, we discovered that a unique hydrophobic binding site for the cleaved fatty acid dominates each enzyme's specificity rather than its catalytic residues and polar headgroup binding site. Molecular dynamics simulations revealed the optimal phospholipid binding mode leading to a detailed understanding of the preference of cytosolic phospholipase A2 for cleavage of proinflammatory arachidonic acid, calcium-independent phospholipase A2, which is involved in membrane remodeling for cleavage of linoleic acid and for antibacterial secreted phospholipase A2 favoring linoleic acid, saturated fatty acids, and phosphatidylglycerol.


Subject(s)
Phospholipases A2, Calcium-Independent/metabolism , Phospholipases A2, Cytosolic/metabolism , Phospholipases A2, Secretory/metabolism , Phospholipids/metabolism , Binding Sites , Catalytic Domain , Humans , Hydrolysis , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Cytosolic/chemistry , Phospholipases A2, Secretory/chemistry , Phospholipids/chemistry , Substrate Specificity
3.
Biochem Biophys Res Commun ; 491(2): 257-264, 2017 09 16.
Article in English | MEDLINE | ID: mdl-28743497

ABSTRACT

Ras proteins are small GTPases that serve as master moderators of a large number of signaling pathways involved in various cellular processes. Activating mutations in Ras are found in about one-third of cancers. H-REV107, a K-Ras binding protein, plays an important role in determining K-Ras function. H-REV107 is a member of the HREV107 family of class II tumor suppressor genes and a growth inhibitory Ras target gene that suppresses cellular growth, differentiation, and apoptosis. Expression of H-REV107 was strongly reduced in about 50% of human carcinoma cell lines. However, the specific molecular mechanism by which H-REV107 inhibits Ras is still unknown. In the present study, we suggest that H-REV107 forms a strong complex with activating oncogenic mutation Q61H K-Ras from various biochemical binding assays and modeled structures. In addition, the interaction sites between K-Ras and H-REV107 were predicted based on homology modeling. Here, we found that some structure-based mutants of the K-Ras disrupted the complex formation with H-REV107. Finally, a novel molecular mechanism describing K-Ras and H-REV107 binding is suggested and insights into new K-Ras effector target drugs are provided.


Subject(s)
Molecular Docking Simulation , Phospholipases A2, Calcium-Independent/chemistry , Proto-Oncogene Proteins p21(ras)/chemistry , Signal Transduction/genetics , Tumor Suppressor Proteins/chemistry , Amino Acid Sequence , Binding Sites , Cloning, Molecular , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Humans , Kinetics , Mutation , Phospholipases A2, Calcium-Independent/genetics , Phospholipases A2, Calcium-Independent/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Structural Homology, Protein , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
4.
J Biol Chem ; 290(28): 17520-34, 2015 Jul 10.
Article in English | MEDLINE | ID: mdl-26018079

ABSTRACT

Phospholipase A/acyltransferase (PLA/AT)-3 (also known as H-rev107 or AdPLA) was originally isolated as a tumor suppressor and was later shown to have phospholipase A1/A2 activity. We have also found that the overexpression of PLA/AT-3 in mammalian cells results in specific disappearance of peroxisomes. However, its molecular mechanism remained unclear. In the present study, we first established a HEK293 cell line, which stably expresses a fluorescent peroxisome marker protein (DsRed2-Peroxi) and expresses PLA/AT-3 in a tetracycline-dependent manner. The treatment with tetracycline, as expected, caused disappearance of peroxisomes within 24 h, as revealed by diffuse signals of DsRed2-Peroxi and a remarkable decrease in a peroxisomal membrane protein, PMP70. A time-dependent decrease in ether-type lipid levels was also seen. Because the activation of LC3, a marker of autophagy, was not observed, the involvement of autophagy was unlikely. Among various peroxins responsible for peroxisome biogenesis, Pex19p functions as a chaperone protein for the transportation of peroxisomal membrane proteins. Immunoprecipitation analysis showed that PLA/AT-3 binds to Pex19p through its N-terminal proline-rich and C-terminal hydrophobic domains. The protein level and enzyme activity of PLA/AT-3 were increased by its coexpression with Pex19p. Moreover, PLA/AT-3 inhibited the binding of Pex19 to peroxisomal membrane proteins, such as Pex3p and Pex11ßp. A catalytically inactive point mutant of PLA/AT-3 could bind to Pex19p but did not inhibit the chaperone activity of Pex19p. Altogether, these results suggest a novel regulatory mechanism for peroxisome biogenesis through the interaction between Pex19p and PLA/AT-3.


Subject(s)
Membrane Proteins/metabolism , Peroxisomes/metabolism , Phospholipases A2, Calcium-Independent/metabolism , Tumor Suppressor Proteins/metabolism , Animals , COS Cells , Chlorocebus aethiops , Down-Regulation , HEK293 Cells , Humans , Lipoproteins/chemistry , Lipoproteins/genetics , Lipoproteins/metabolism , Membrane Proteins/chemistry , Membrane Proteins/genetics , Models, Biological , Peroxins , Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Calcium-Independent/genetics , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/genetics
5.
FEBS Lett ; 589(11): 1179-86, 2015 May 08.
Article in English | MEDLINE | ID: mdl-25871522

ABSTRACT

H-REV107-like family proteins TIG3 and H-REV107 are class II tumor suppressors. Here we report that the C-terminal domains (CTDs) of TIG3 and H-REV107 can induce HeLa cell death independently. The N-terminal domain (NTD) of TIG3 enhances the cell death inducing ability of CTD, while NTD of H-REV107 plays an inhibitory role. The solution structure of TIG3 NTD is very similar to that of H-REV107 in overall fold. However, the CTD binding regions on NTD are different between TIG3 and H-REV107, which may explain their functional difference. As a result, the flexible main loop of H-REV107, but not that of TIG3, is critical for its NTD to modulate its CTD in inducing cell death.


Subject(s)
Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Calcium-Independent/metabolism , Receptors, Retinoic Acid/chemistry , Receptors, Retinoic Acid/metabolism , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/metabolism , Cell Death/genetics , HeLa Cells , Humans , Phospholipases A2, Calcium-Independent/genetics , Protein Structure, Secondary , Protein Structure, Tertiary , Receptors, Retinoic Acid/genetics , Structure-Activity Relationship , Tumor Suppressor Proteins/genetics
6.
Biochem J ; 461(3): 509-20, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24854345

ABSTRACT

Lysosomes act as terminal degradation organelles to hydrolyse macromolecules derived from both the extracellular space and the cytoplasm. In Caenorhabditis elegans fasting induces the lysosomal compartment to expand. However, the molecular and cellular mechanisms for this stress response remain largely unclear. In the present study, we find that short-term fasting leads to increased accumulation of polar lipids in lysosomes. The fasting response is co-ordinately regulated by EGL-4, the C. elegans PKG (protein kinase G) orthologue, and nuclear hormone receptor NHR-49. Further results demonstrate that EGL-4 acts in sensory neurons to enhance lysosomal lipid accumulation through inhibiting the DAF-3/SMAD pathway, whereas NHR-49 acts in intestine to inhibit lipids accumulation via activation of IPLA-2 (intracellular membrane-associated calcium-independent phospholipase A2) in cytoplasm and other hydrolases in lysosomes. Remarkably, the lysosomal lipid accumulation is independent of autophagy and RAB-7-mediated endocytosis. Taken together, our results reveal a new mechanism for lysosomal lipid metabolism during the stress response, which may provide new clues for investigations of lysosome function in energy homoeostasis.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Cyclic GMP-Dependent Protein Kinases/metabolism , Lipid Metabolism , Lysosomes/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction , Stress, Physiological , Animals , Animals, Genetically Modified , Caenorhabditis elegans/enzymology , Caenorhabditis elegans/genetics , Caenorhabditis elegans/ultrastructure , Caenorhabditis elegans Proteins/agonists , Caenorhabditis elegans Proteins/antagonists & inhibitors , Caenorhabditis elegans Proteins/genetics , Cyclic GMP-Dependent Protein Kinases/genetics , Enzyme Activation , Fasting/adverse effects , Hydrolases/chemistry , Hydrolases/genetics , Hydrolases/metabolism , Kinetics , Lysosomes/ultrastructure , Mutation , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Calcium-Independent/genetics , Phospholipases A2, Calcium-Independent/metabolism , RNA Interference , Receptors, Cytoplasmic and Nuclear/genetics , Sensory Receptor Cells/enzymology , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/ultrastructure , Smad Proteins/antagonists & inhibitors , Smad Proteins/genetics , Smad Proteins/metabolism , Up-Regulation
7.
Biochemistry ; 52(24): 4250-63, 2013 Jun 18.
Article in English | MEDLINE | ID: mdl-23701211

ABSTRACT

The multifaceted roles of calcium-independent phospholipase A2ß (iPLA2ß) in numerous cellular processes have been extensively examined through utilization of the iPLA2-selective inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL). Herein, we employed accurate mass/high resolution mass spectrometry to demonstrate that the active site serine (S465) and C651 of iPLA2ß are covalently cross-linked during incubations with BEL demonstrating their close spatial proximity. This cross-link results in macroscopic alterations in enzyme molecular geometry evidenced by anomalous migration of the cross-linked enzyme by SDS-PAGE. Molecular models of iPLA2ß constructed from the crystal structure of iPLA2α (patatin) indicate that the distance between S465 and C651 is approximately 10 Å within the active site of iPLA2ß. Kinetic analysis of the formation of the 75 kDa iPLA2ß-BEL species with the (R) and (S) enantiomers of BEL demonstrated that the reaction of (S)-BEL with iPLA2ß was more rapid than for (R)-BEL paralleling the enantioselectivity for the inhibition of catalysis by each inhibitor with iPLA2ß. Moreover, we demonstrate that the previously identified selective acylation of iPLA2ß by oleoyl-CoA occurs at C651 thereby indicating the importance of active site architecture for acylation of this enzyme. Collectively, these results identify C651 as a highly reactive nucleophilic residue within the active site of iPLA2ß which is thioesterified by BEL, acylated by oleoyl-CoA, and located in close spatial proximity to the catalytic serine thereby providing important chemical insights on the mechanisms through which BEL inhibits iPLA2ß and the topology of the active site.


Subject(s)
Cysteine/chemistry , Phospholipases A2, Calcium-Independent/antagonists & inhibitors , Animals , Catalysis , Catalytic Domain , Crystallography, X-Ray , Drug Design , Hydrolysis , Insecta , Lipids/chemistry , Mass Spectrometry , Models, Chemical , Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Calcium-Independent/genetics , Serine/chemistry , Spectrophotometry
8.
Dis Model Mech ; 6(2): 404-13, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22996643

ABSTRACT

Mutations in patatin-like phospholipase domain containing 6 (PNPLA6), also known as neuropathy target esterase (NTE) or SPG39, cause hereditary spastic paraplegia (HSP). Although studies on animal models, including mice and Drosophila, have extended our understanding of PNPLA6, its roles in neural development and in HSP are not clearly understood. Here, we describe the generation of a vertebrate model of PNPLA6 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio). Pnpla6 knockdown resulted in developmental abnormalities and motor neuron defects, including axon truncation and branching. The phenotypes in pnpla6 knockdown morphants were rescued by the introduction of wild-type, but not mutant, human PNPLA6 mRNA. Our results also revealed the involvement of BMP signaling in pnpla6 knockdown phenotypes. Taken together, these results demonstrate an important role of PNPLA6 in motor neuron development and implicate overexpression of BMP signaling as a possible mechanism underlying the developmental defects in pnpla6 morphants.


Subject(s)
Gene Knockdown Techniques , Motor Neurons/enzymology , Motor Neurons/pathology , Phospholipases A2, Calcium-Independent/metabolism , Phospholipases/metabolism , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Amino Acid Sequence , Animals , Axons/metabolism , Axons/pathology , Bone Morphogenetic Proteins/metabolism , Cells, Cultured , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/enzymology , Embryo, Nonmammalian/pathology , Humans , Interneurons/drug effects , Interneurons/metabolism , Interneurons/pathology , Mice , Molecular Sequence Data , Morpholinos/pharmacology , Motor Neurons/drug effects , Mutant Proteins/genetics , Mutant Proteins/metabolism , Phenotype , Phospholipases/chemistry , Phospholipases A2, Calcium-Independent/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/pathology , Signal Transduction/drug effects , Up-Regulation/drug effects , Zebrafish/embryology , Zebrafish Proteins/chemistry
9.
J Biol Chem ; 287(46): 38824-34, 2012 Nov 09.
Article in English | MEDLINE | ID: mdl-23007400

ABSTRACT

Phospholipase A(2) activity plays key roles in generating lipid second messengers and regulates membrane topology through the generation of asymmetric lysophospholipids. In particular, the Group VIA phospholipase A(2) (GVIA-iPLA(2)) subfamily of enzymes functions independently of calcium within the cytoplasm of cells and has been implicated in numerous cellular processes, including proliferation, apoptosis, and membrane transport steps. However, mechanisms underlying the spatial and temporal regulation of these enzymes have remained mostly unexplored. Here, we examine the subset of Caenorhabditis elegans lipases that harbor a consensus motif common to members of the GVIA-iPLA(2) subfamily. Based on sequence homology, we identify IPLA-1 as the closest C. elegans homolog of human GVIA-iPLA(2) enzymes and use a combination of liposome interaction studies to demonstrate a role for acidic phospholipids in regulating GVIA-iPLA(2) function. Our studies indicate that IPLA-1 binds directly to multiple acidic phospholipids, including phosphatidylserine, phosphatidylglycerol, cardiolipin, phosphatidic acid, and phosphorylated derivatives of phosphatidylinositol. Moreover, the presence of these acidic lipids dramatically elevates the specific activity of IPLA-1 in vitro. We also found that the addition of ATP and ADP promote oligomerization of IPLA-1, which probably underlies the stimulatory effect of nucleotides on its activity. We propose that membrane composition and the presence of nucleotides play key roles in recruiting and modulating GVIA-iPLA(2) activity in cells.


Subject(s)
Nucleotides/chemistry , Phospholipases A2, Calcium-Independent/metabolism , Phospholipids/chemistry , Animals , Caenorhabditis elegans , Calorimetry/methods , Cell Membrane/metabolism , Dimerization , Escherichia coli/metabolism , Gene Expression Regulation , Genome , Group VI Phospholipases A2/metabolism , Humans , Lipid Metabolism , Liposomes/chemistry , Liposomes/metabolism , Mutation , Phospholipases/metabolism , Phospholipases A2, Calcium-Independent/chemistry , Phospholipids/metabolism , Protein Binding
10.
J Biol Chem ; 287(42): 35260-35274, 2012 Oct 12.
Article in English | MEDLINE | ID: mdl-22923616

ABSTRACT

Adipose phospholipase A(2) (AdPLA or Group XVI PLA(2)) plays an important role in the onset of obesity by suppressing adipose tissue lipolysis. As a consequence, AdPLA-deficient mice are resistant to obesity induced by a high fat diet or leptin deficiency. It has been proposed that AdPLA mediates its antilipolytic effects by catalyzing the release of arachidonic acid. Based on sequence homology, AdPLA is part of a small family of acyltransferases and phospholipases related to lecithin:retinol acyltransferase (LRAT). To better understand the enzymatic mechanism of AdPLA and LRAT-related proteins, we solved the crystal structure of AdPLA. Our model indicates that AdPLA bears structural similarity to proteins from the NlpC/P60 family of cysteine proteases, having its secondary structure elements configured in a circular permutation of the classic papain fold. Using both structural and biochemical evidence, we demonstrate that the enzymatic activity of AdPLA is mediated by a distinctive Cys-His-His catalytic triad and that the C-terminal transmembrane domain of AdPLA is required for the interfacial catalysis. Analysis of the enzymatic activity of AdPLA toward synthetic and natural substrates indicates that AdPLA displays PLA(1) in addition to PLA(2) activity. Thus, our results provide insight into the enzymatic mechanism and biochemical properties of AdPLA and LRAT-related proteins and lead us to propose an alternate mechanism for AdPLA in promoting adipose tissue lipolysis that is not contingent on the release of arachidonic acid and that is compatible with its combined PLA(1)/A(2) activity.


Subject(s)
Models, Molecular , Phospholipases A2, Calcium-Independent/chemistry , Tumor Suppressor Proteins/chemistry , Acyltransferases/chemistry , Acyltransferases/genetics , Acyltransferases/metabolism , Animals , Catalytic Domain , Crystallography, X-Ray , Humans , Mice , Phospholipases A2, Calcium-Independent/genetics , Phospholipases A2, Calcium-Independent/metabolism , Protein Structure, Tertiary , Structure-Activity Relationship , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
11.
J Biol Chem ; 287(28): 23790-807, 2012 Jul 06.
Article in English | MEDLINE | ID: mdl-22605381

ABSTRACT

Lecithin:retinol acyltransferase-like proteins, also referred to as HRAS-like tumor suppressors, comprise a vertebrate subfamily of papain-like or NlpC/P60 thiol proteases that function as phospholipid-metabolizing enzymes. HRAS-like tumor suppressor 3, a representative member of this group, plays a key role in regulating triglyceride accumulation and energy expenditure in adipocytes and therefore constitutes a novel pharmacological target for treatment of metabolic disorders causing obesity. Here, we delineate a catalytic mechanism common to lecithin:retinol acyltransferase-like proteins and provide evidence for their alternative robust lipid-dependent acyltransferase enzymatic activity. We also determined high resolution crystal structures of HRAS-like tumor suppressor 2 and 3 to gain insight into their active site architecture. Based on this structural analysis, two conformational states of the catalytic Cys-113 were identified that differ in reactivity and thus could define the catalytic properties of these two proteins. Finally, these structures provide a model for the topology of these enzymes and allow identification of the protein-lipid bilayer interface. This study contributes to the enzymatic and structural understanding of HRAS-like tumor suppressor enzymes.


Subject(s)
Acyltransferases/metabolism , Phospholipases A2, Calcium-Independent/metabolism , Tumor Suppressor Proteins/metabolism , Acylation , Acyltransferases/chemistry , Acyltransferases/genetics , Amino Acid Sequence , Biocatalysis , Catalytic Domain , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Cysteine/chemistry , Cysteine/genetics , Cysteine/metabolism , Electrophoresis, Polyacrylamide Gel , Enzyme Stability , Humans , Mass Spectrometry , Models, Molecular , Molecular Sequence Data , Phospholipases A2 , Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Calcium-Independent/genetics , Phospholipids/metabolism , Protein Binding , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Substrate Specificity , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/genetics
12.
Curr Med Chem ; 17(25): 2746-63, 2010.
Article in English | MEDLINE | ID: mdl-20586719

ABSTRACT

Enzymes belonging to the PLA(2) superfamily catalyze the hydrolysis of unsaturated fatty acids from the sn-2 position of glycerol moiety of neural membrane phospholipids. The PLA(2) superfamily is classified into cytosolic PLA(2) (cPLA(2)), calcium-independent PLA(2) (iPLA(2)), plasmalogen-selective PLA(2) (PlsEtn-PLA(2)) and secretory PLA(2) (sPLA(2)). PLA(2) paralogs/splice variants/isozymes are part of a complex signal transduction network that maintains cross-talk among excitatory amino acid and dopamine receptors through the generation of second messengers. Individual paralogs, splice variants and multiple forms of PLA(2) may have unique enzymatic properties, tissue and subcellular localizations and role in various physiological and pathological situations, hence tight regulation of all PLA(2) isoforms is essential for normal brain function. Quantitative RT-PCR analyses show significantly higher relative level of expression of iPLA(2) than cPLA(2) in all regions of the rat brain. Upregulation of the cPLA(2) family is involved in degradation of neural membrane phospholipids and generation of arachidonic acid-derived lipid metabolites that have been implicated in nociception, neuroinflammation, oxidative stress and neurodegeneration. In contrast, studies using a selective iPLA(2) inhibitor, bromoenol lactone, or antisense oligonucleotide indicate that iPLA(2) is an important "housekeeping" enzyme under basal conditions, whose activity is required for the prevention of vacuous chewing movements, a rodent model for tardive dyskinesia, and deficits in the prepulse inhibition of the auditory startle reflex, a common finding in schizophrenia. These studies support the view that PLA(2) activity may not only play a crucial role in neurodegeneration but depending on the isoform, could also be essential in prevention of neuropsychiatric diseases. The findings could open new doors for understanding and treatment of neurodegenerative and neuropsychiatric diseases.


Subject(s)
Group IV Phospholipases A2/metabolism , Mental Disorders/physiopathology , Neurodegenerative Diseases/physiopathology , Phospholipases A2, Calcium-Independent/metabolism , Phospholipases A2/metabolism , Animals , Arachidonic Acids/pharmacology , Brain/physiopathology , Group IV Phospholipases A2/chemistry , Isoenzymes/metabolism , Nerve Degeneration/physiopathology , Phospholipase A2 Inhibitors , Phospholipases A2/chemistry , Phospholipases A2/pharmacology , Phospholipases A2, Calcium-Independent/chemistry , Phospholipids/metabolism , Protein Isoforms/metabolism , Rats , Second Messenger Systems/drug effects , Signal Transduction/drug effects , Swine
13.
Med Sci (Paris) ; 26(2): 177-84, 2010 Feb.
Article in French | MEDLINE | ID: mdl-20188050

ABSTRACT

Genome sequencing technologies led to tremendous breakthrough in biology uncovering numerous genes unknown so far and thus opening the field of deep investigations to understand their associated biological functions. As a matter of fact, functional genomics have been progressively replacing sequence genomics with as a main objective to yield insight into cellular physiology. Recently, an emerging group of genes coding for proteins bearing a common domain termed patatin (PNPLA domain) have been discovered. Members of this new enzymatic family displaying lipase and transacylase properties appeared to have major roles in the regulation of lipid metabolism. The aim of this review is to make an overview on the latest discoveries concerning this new family of proteins and their relationship with lipid metabolism, physiology of mammals and their potential involvement in human pathology.


Subject(s)
Carboxylic Ester Hydrolases/physiology , Catalytic Domain , Escherichia coli Proteins/physiology , Lipid Metabolism/physiology , Lipolysis/genetics , Multigene Family , Amino Acid Sequence , Animals , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/physiology , Caenorhabditis elegans Proteins/chemistry , Caenorhabditis elegans Proteins/physiology , Carboxylic Ester Hydrolases/chemistry , Carboxylic Ester Hydrolases/classification , Carboxylic Ester Hydrolases/genetics , Catalytic Domain/genetics , Conserved Sequence , Drosophila Proteins/chemistry , Drosophila Proteins/physiology , Escherichia coli Proteins/chemistry , Humans , Lipase/chemistry , Lipase/physiology , Lipid Metabolism/genetics , Mammals/metabolism , Mice , Molecular Sequence Data , Phospholipases A2, Calcium-Independent/chemistry , Phospholipases A2, Calcium-Independent/physiology , Phylogeny , Plant Proteins/chemistry , Plant Proteins/physiology , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/physiology , Sequence Alignment , Sequence Homology, Amino Acid , Species Specificity
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