HRASLS3

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Adipose Phospholipase A2
ADPLA protein structure.jpg
Crystallographic structure of Adipose Phospholipase A2 (AdPLA)
Identifiers
EC no. 3.1.1.4
CAS no. 9001-84-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

Group XVI phospholipase A2 also commonly known as adipocyte phospholipase A2 (AdPLA) is an enzyme that in humans is encoded by the PLA2G16 gene. [1] [2] [3] This enzyme has also been identified as PLA2G16, HRASLS3, HREV107, HREV107-3, MGC118754 or H-REV107-1 from studies on class II tumor suppression but not on its enzymatic properties. [4] AdPLA is encoded by a 1.3 kilobase AdPLA messenger RNA and is an 18 kDa protein. It belongs to a superfamily of phospholipase A2 (PLA2) enzymes and is found primarily in adipose tissue. AdPLA regulates adipocyte lipolysis and release of fatty acids through a G-protein coupled pathway involving prostaglandin and EP3. It has also been reported to play a crucial role in the development of obesity in mouse models. [5]

Contents

Enzyme characteristics

AdPLA has been characterized in Group XVI as a separate subgroup of the PLA2 family for its distinct properties from other known PLA2s. It bears similarity to its PLA2 family in phospholipase activity and calcium dependence. Unlike other PLA2 enzymes, AdPLA is expressed predominantly in adipose tissue at higher levels than in the rest of the body, more so in white adipose tissue (WAT) than brown adipose tissue (BAT). Its primary enzymatic function is to catalyze the preferential hydrolysis of phosphatidylcholines at the sn-2 position, generating free fatty acids.

AdPLA active site with labeled His-23 and Cys-113 residues are responsible for AdPLA catalysis. ADPLA protein active site.jpg
AdPLA active site with labeled His-23 and Cys-113 residues are responsible for AdPLA catalysis.

AdPLA contains a membrane-spanning domain on the C-terminus, which localizes intracellularly for phospholipase activity in proximity to cyclooxygenase 1 (COX-1). His-23 and Cys-113 residues have been shown to be essential in AdPLA activity, which differs from the known His/Asp catalytic dyad or Ser/His/Asp catalytic triad of other PLA2 enzymes. Gln-129 and Asn-112 have also been shown to be necessary in catalysis but their role is not known. [2]

AdPLA activity is calcium and pH dependent. Calcium binds to AdPLA and forms a positively charged oxyanion hole to stabilize a negatively charged transition state, similar to other PLA2 active sites. Whereas asparagine binds to calcium in other PLA2 enzymes, [6] the residue that participates in the creation of oxyanion hole in AdPLA has not yet been verified. Optimum AdPLA activity occurs in relatively basic conditions, between pH 7 and 9, to facilitate formation of a histidine-water complex and subsequent fatty acid hydrolysis. [2]

Function

PLAAT3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PLAAT3 , AdPLA, H-REV107-1, HRASLS3, HREV107, HREV107-1, HREV107-3, HRSL3, phospholipase A2 group XVI, H-REV107, PLAAT-3, PLA2G16, phospholipase A and acyltransferase 3
External IDs OMIM: 613867 MGI: 2179715 HomoloGene: 5136 GeneCards: PLAAT3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001128203
NM_007069

NM_139269
NM_001362425

RefSeq (protein)

NP_001121675
NP_009000

NP_644675
NP_001349354

Location (UCSC) Chr 11: 63.57 – 63.62 Mb Chr 19: 7.53 – 7.57 Mb
PubMed search [9] [10]
Wikidata
View/Edit Human View/Edit Mouse

Studies on AdPLA have shown lipolysis regulation following a G-protein coupled pathway in WAT. [5] WAT is responsible for releasing fatty acids from stored triacylglycerol as energy sources for other tissues which is regulated predominately by AdPLA over other phospholipase A2 enzymes. Lipolysis is inversely related to AdPLA activity. AdPLA catalyzes the rate-limiting step, production of arachidonic acid, for the production of prostaglandins, specifically prostaglandin E2 (PGE2). PGE2 enters the signaling pathway binding to G protein-coupled receptor (EP3) which inhibits adenylyl cyclase. Inhibition of adenylyl cyclase decreases the conversion of cyclic AMP (cAMP) from ATP. Lower levels of cAMP decrease the activity of protein kinase A to phosphorylate, thereby activating, hormone-sensitive lipase. [11] The opposite effect can be reached with inactivated AdPLA, decreasing PGE2 concentration and EP3 activity, leading to an increase in cAMP and lipase activity. This mechanism was postulated on the basis that the predominant signaling protein and receptor present in WAT are PGE2 and EP3. These results were based on a mouse model and although they are mammalian cells, it has not been shown to apply to human cells.

Effects on obesity

Obesity has been attributed to adipocyte hypertrophy, where triacylglycerol synthesis exceeds lipolysis, resulting in elevated triacylglycerol storage. [12] Previous studies have associated obesity with endocrine factors and have led pharmacological work toward hormone regulation. [13] Studies on AdPLA deficient mice have shown that the enzyme increased lipolysis in WAT as a result of decreased lipolysis regulation. AdPLA deficiency was shown to reduce adipose tissue mass for mice in both standard and high fat diets. Adipocyte hypotrophy was attributed primarily to reduced triacylglyceride content in WAT from lipolysis, while adipocyte differentiation did not play a role in reduced adipose tissue despite the effects of prostaglandins on adipogenesis. [14] AdPLA deficiency also led to higher oxygen consumption due to the upregulation of genes involved in oxidative metabolism, increasing fatty acid oxidation. One upregulated gene in particular, uncoupling protein-1 (UCP1), has been shown to reduce diet-induced obesity. [15]

Studies on AdPLA deficient and genetically obese mice (leptin deficiency) have also shown similar effects, reduced adipose tissue mass and increased lipolysis by reduction in PGE2 and EP3 activity. Fatty acid oxidation was also found to increase to levels of wild-type mice that were deficient in non-AdPLA deficient obese mice. Body composition also showed a higher percentage of water and lean tissue mass compared to non-AdPLA deficient obese mice. [5]

AdPLA deficiency also demonstrated adverse effects, increasing ectopic triglyceride storage and insulin resistance. Liver enlargement was attributed to higher fatty acid uptake and triacylglycerol content. Insulin stimulated glucose uptake and metabolism were also blunted in AdPLA deficiency, decreasing glycolysis and glycogen synthesis. [5] Despite these side effects, AdPLA is a novel breakthrough in studying autocrine and paracrine action of AdPLA in regulating obesity and fat metabolism. These side effects have triggered new studies to be performed on reduction of AdPLA function as opposed to complete ablation. [16]

Related Research Articles

<span class="mw-page-title-main">Prostaglandin</span> Group of physiologically active lipid compounds

Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and cytokines. In obesity, adipose tissue is also implicated in the chronic release of pro-inflammatory markers known as adipokines, which are responsible for the development of metabolic syndrome, a constellation of diseases, including type 2 diabetes, cardiovascular disease and atherosclerosis. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue – more specifically brown adipose tissue – was first identified by the Swiss naturalist Conrad Gessner in 1551.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Phospholipase A2</span> Peripheral membrane protein

The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

<span class="mw-page-title-main">Perilipin-1</span>

Perilipin, also known as lipid droplet-associated protein, Perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Hormone-sensitive lipase</span> Enzyme

Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene, and catalyzes the following reaction:

<span class="mw-page-title-main">White adipose tissue</span> Fatty tissue composed of white adipocytes

White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.

Prostaglandin EP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

Prostaglandin EP<sub>3</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin EP3 receptor (53kDa), also known as EP3, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

<span class="mw-page-title-main">PLA2G6</span> Protein-coding gene in the species Homo sapiens

85 kDa calcium-independent phospholipase A2, also known as 85/88 kDa calcium-independent phospholipase A2, Group VI phospholipase A2, Intracellular membrane-associated calcium-independent phospholipase A2 beta, or Patatin-like phospholipase domain-containing protein 9 is an enzyme that in humans is encoded by the PLA2G6 gene.

<span class="mw-page-title-main">Perilipin-2</span> Protein-coding gene in the species Homo sapiens

Adipose differentiation-related protein, also known as perilipin 2, ADRP or adipophilin, is a protein which belongs from PAT family of cytoplasmic lipid droplet(CLD) binding protein. In humans it is encoded by the ADFP gene. This protein surrounds the lipid droplet along with phospholipids and are involved in assisting the storage of neutral lipids within the lipid droplets.

<span class="mw-page-title-main">Adipose triglyceride lipase</span> Mammalian protein found in Homo sapiens

Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.

<span class="mw-page-title-main">Chemerin</span> Protein-coding gene in the species Homo sapiens

Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.

Adipose tissue macrophages comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese, leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity.

Hypoxia inducible lipid droplet-associated is a protein that in humans is encoded by the HILPDA gene.

References

  1. Husmann K, Sers C, Fietze E, Mincheva A, Lichter P, Schäfer R (Oct 1998). "Transcriptional and translational downregulation of H-REV107, a class II tumour suppressor gene located on human chromosome 11q11-12". Oncogene. 17 (10): 1305–12. doi: 10.1038/sj.onc.1202060 . PMID   9771974.
  2. 1 2 3 Duncan RE, Sarkadi-Nagy E, Jaworski K, Ahmadian M, Sul HS (Sep 2008). "Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA)". J Biol Chem. 283 (37): 25428–36. doi: 10.1074/jbc.M804146200 . PMC   2533091 . PMID   18614531.
  3. "Entrez Gene: HRASLS3 HRAS-like suppressor 3".
  4. Sers C, Emmenegger U, Husmann K, Bucher K, Andres AC, Schäfer R (February 1997). "Growth-inhibitory activity and downregulation of the class II tumor-suppressor gene H-rev107 in tumor cell lines and experimental tumors". J. Cell Biol. 136 (4): 935–44. doi:10.1083/jcb.136.4.935. PMC   2132501 . PMID   9049257.
  5. 1 2 3 4 Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, Hellerstein MK, Lee HY, Samuel VT, Shulman GI, Kim KH, de Val S, Kang C, Sul HS (February 2009). "AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency". Nat. Med. 15 (2): 159–68. doi:10.1038/nm.1904. PMC   2863116 . PMID   19136964.
  6. Six DA, Dennis EA (October 2000). "The expanding superfamily of phospholipase A(2) enzymes: classification and characterization". Biochim. Biophys. Acta. 1488 (1–2): 1–19. doi:10.1016/S1388-1981(00)00105-0. PMID   11080672. S2CID   23717374.
  7. 1 2 3 GRCh38: Ensembl release 89: ENSG00000176485 - Ensembl, May 2017
  8. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000060675 - Ensembl, May 2017
  9. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  10. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  11. Richelsen B (November 1992). "Release and effects of prostaglandins in adipose tissue". Prostaglandins Leukot. Essent. Fatty Acids. 47 (3): 171–82. doi:10.1016/0952-3278(92)90235-B. PMID   1475271.
  12. Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS (July 2007). "Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue". Am. J. Physiol. Gastrointest. Liver Physiol. 293 (1): G1–4. doi:10.1152/ajpgi.00554.2006. PMC   2887286 . PMID   17218471.
  13. Adan RA, Vanderschuren LJ, la Fleur SE (April 2008). "Anti-obesity drugs and neural circuits of feeding". Trends Pharmacol. Sci. 29 (4): 208–17. doi:10.1016/j.tips.2008.01.008. PMID   18353447.
  14. Fajas L, Miard S, Briggs MR, Auwerx J (September 2003). "Selective cyclo-oxygenase-2 inhibitors impair adipocyte differentiation through inhibition of the clonal expansion phase". J. Lipid Res. 44 (9): 1652–9. doi: 10.1194/jlr.M300248-JLR200 . PMID   12837847.
  15. Kopecký J, Hodný Z, Rossmeisl M, Syrový I, Kozak LP (May 1996). "Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution". Am. J. Physiol. 270 (5 Pt 1): E768–75. doi:10.1152/ajpendo.1996.270.5.E768. PMID   8967464.
  16. News Staff. "Disabling AdPLA Enzyme Lets You Eat Anything And Never Get Obese, If..." ION Publications LLC. Retrieved 1 March 2012.

Further reading