Phosphatidate phosphatase

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Phosphatidate phosphatase
Identifiers
EC no. 3.1.3.4
CAS no. 9025-77-8
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
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The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol: [1] [2]

Contents

a 1,2-diacylglycerol 3-phosphate + H2O a 1,2-diacyl-sn-glycerol + phosphate

The reverse conversion is catalyzed by the enzyme diacylglycerol kinase, which replaces the hydroxyl group on diacylgylcerol with a phosphate from ATP, generating ADP in the process.

In yeast, the forward direction is Mg2+-dependent, while the reverse process is Ca2+-dependent. [3] PAP1, a cytosolic phosphatidate phosphatase found in the lung, is also -dependent, but PAP2, a six-transmembrane-domain integral protein found in the plasma membrane, is not. [4] [5]

Reactants and products of the reaction catalyzed by the enzyme phosphatidate phosphatase, and thus also those of the reverse reaction, which is catalyzed by the enzyme diacylglycerol kinase. Phosphatidate phosphatase reaction.png
Reactants and products of the reaction catalyzed by the enzyme phosphatidate phosphatase, and thus also those of the reverse reaction, which is catalyzed by the enzyme diacylglycerol kinase.

Role in the regulation of lipid flux

Phosphatidate phosphatase regulates lipid metabolism in several ways. In short, it is a key player in controlling the overall flux of triacylglycerols to phospholipids and vice versa, also exerting control through the generation and degradation of lipid-signaling molecules related to phosphatidate. [4] When the phosphatase is active, diacylglycerols formed by it can go on to form any of several products, including phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and triacylglycerol. [6] Phospholipids can be formed from diacylglycerol through reaction with activated alcohols, and triacylglycerols can be formed from diacylglycerols through reaction with fatty acyl CoA molecules. When phosphatidate phosphatase is inactive, diacylglycerol kinase catalyzes the reverse conversion, allowing phosphatidate to accumulate as it brings down diacylglycerol levels. Phosphatidate can then be converted into an activated form, CDP-diacylglycerol by liberation of a pyrophosphate from a CTP molecule, or into cardiolipin. This is a principal precursor used by the body in phospholipid synthesis. Furthermore, because both phosphatidate and diacylglycerol function as secondary messengers, phosphatidate phosphatase is able to exert extensive and intricate control of lipid metabolism far beyond its local effect on phopshatidate and diacylglycerol concentrations and the resulting effect on the direction of lipid flux as outlined above. [7]

Enzyme regulation

Phosphatidate phosphatase is up-regulated by CDP-diacylglycerol, phosphatidylinositol (formed from reaction of CDP-diacylglycerol with inositol), and cardiolipin. It is down-regulated by sphingosine and dihydrosphingosine. This makes sense in the context of the discussion above. Namely, a build up of products that are formed from phosphatidate serves to up-regulate the phosphatase, the enzyme that consumes phosphatidate, thereby acting as a signal that phosphatidate is in abundance and causing its consumption. At the same time, a build up of products that are formed from DAG serves to down regulate the enzyme that forms diacylglycerol, thereby acting as a signal that this is in abundance and its production should be slowed. [7]

Classification

PAP belongs to the family of enzymes known as hydrolases, and more specifically to the hydrolases that act on phosphoric monoester bonds. This enzyme participates in 4 metabolic pathways: glycerolipid, glycerophospholipid, ether lipid, and sphingolipid metabolism.

Nomenclature

The systematic name is diacylglycerol-3-phosphate phosphohydrolase. [8] Other names in common use include:

Types

There are several different genes that code for phosphatidate phosphatases. They fall into one of two types (type I and type II), depending on their cellular localization and substrate specificity. [9]

Type I

Type I phosphatidate phosphatases are soluble enzymes that can associate to membranes. They are found mainly in the cytosol and the nucleus. Encoded for by a group of genes named Lipin, they are substrate specific only to phosphatidate. There are speculated to be involved in the de novo synthesis of glycerolipids.

Each of the 3 Lipin proteins found in mammals—Lipin1, Lipin2, and Lipin3—has unique tissue expression motifs and distinct physiological functions. [10]

Regulation

Regulation of mammalian Lipin PAP enzymes occurs at the transcriptional level. For example, Lipin1 is induced by glucocorticoids during adipocyte differentiation as well as in cells that are experiencing proliferation of the endoplasmic reticulum (ER). Lipin2, on the other hand, is repressed during adipocyte differentiation. [3]

Lipin is phosphorylated in response to insulin in skeletal muscle and adipocytes, linking the physiologic action of insulin to fat cell differentiation. Lipin phosphorylation is inhibited by treatment with rapamycin, suggesting that mTOR controls signal transduction feeding into lipin and may partially explain dyslipidemia resulting from rapamycin therapy. [11]

Type II

Type II phosphatidate phosphatases are transmembrane enzymes found mainly in the plasma membrane. They can dephosphorylate other substrates besides phosphatidate, and therefore are also known as lipid phosphate phosphatases. Their main role is in lipid signaling and in phospholipid head-group remodeling.

One example of a type II phosphatidate phosphatase is PgpB (PDBe: 5jwy). [12] [13] PgpB is one of three integral membrane phosphatases in Escherichia coli that catalyzes the dephosphorylation of phosphatidylglycerol phosphate (PGP) to PG (phosphatidylglycerol). [14] The other two are PgpA and PgpC. While all three catalyze the reaction from PGP to PG, their amino acid sequences are dissimilar and it is predicted that their active sites open to different sides of the cytoplasmic membrane. PG accounts for approximately 20% of the total membrane lipid composition in the inner membrane of bacteria. PgpB is competitively inhibited by phosphatidylethanolamine (PE), a phospholipid formed from DAG. This is therefore an example of negative feedback regulation. The enzyme active site contains a catalytic triad Asp-211, His-207, and His-163 that establishes a charge relay system. However, this catalytic triad is essential for the dephosphorylation of lysophosphatidic acid, phosphatidic acid, and sphingosine-1-phosphate, but is not essential in its entirety for the enzyme's native substrate, phosphatidylglycerol phosphate; His-207 alone is sufficient to hydrolyze PGP. [14]

Dephosphorylation of phosphatidylglycerol phosphate (PGP) to form PG (phosphatidylglycerol). This reaction is catalyzed by PgpB, a bacterial integral membrane lipid phosphate phosphatase. PgpB Reaction.png
Dephosphorylation of phosphatidylglycerol phosphate (PGP) to form PG (phosphatidylglycerol). This reaction is catalyzed by PgpB, a bacterial integral membrane lipid phosphate phosphatase.

In the cartoon depiction of PgpB below, one can see its six transmembrane alpha helices, which are here shown horizontally. Of the three PGP phosphatases discussed above, PgpB is the only to have multiple transmembrane alpha helices. [14]

PgpB (PDBe: 5jwy) cartoon with ribbons. Made in MacPyMOL. PgpB structure.png
PgpB (PDBe: 5jwy) cartoon with ribbons. Made in MacPyMOL.

Genes

Human genes that encode phosphatidate phosphatases include:

Pathology

Lipin-1 deficiency in mice results in lipodystrophy, insulin resistance, and neuropathy. In humans, variations in Lipin-1 expression levels can result in insulin sensitivity, hypertension, and risk for metabolic syndrome. Serious mutations in Lipin-2 lead to an inflammatory disorder in humans. [10]

Related Research Articles

<span class="mw-page-title-main">Phospholipid</span> Class of lipids

Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Glycerophospholipid</span> Class of lipids

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea.

<span class="mw-page-title-main">Glucose 6-phosphatase</span> Enzyme

The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:

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

Lipid signaling, broadly defined, refers to any biological cell 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.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Diacylglycerol kinase</span> Class of enzymes

Diacylglycerol kinase is a family of enzymes that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), utilizing ATP as a source of the phosphate. In non-stimulated cells, DGK activity is low, allowing DAG to be used for glycerophospholipid biosynthesis, but on receptor activation of the phosphoinositide pathway, DGK activity increases, driving the conversion of DAG to PA. As both lipids are thought to function as bioactive lipid signaling molecules with distinct cellular targets, DGK therefore occupies an important position, effectively serving as a switch by terminating the signalling of one lipid while simultaneously activating signalling by another.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

sn-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of two stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of bacterial and eukaryotic glycerophospholipids. From a historical reason, it is also known as L-glycerol 3-phosphate, D-glycerol 1-phosphate, L-α-glycerophosphoric acid.

<span class="mw-page-title-main">Phosphatidylglycerol</span> Lipid

Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion channels.

The enzyme phosphatidylglycerophosphatase (EC 3.1.3.27) catalyzes the following reaction:

Phosphatidate cytidylyltransferase (CDS) is the enzyme that catalyzes the synthesis of CDP-diacylglycerol from cytidine triphosphate and phosphatidate.

<span class="mw-page-title-main">PPAP2A</span> Protein-coding gene in the species Homo sapiens

Lipid phosphate phosphohydrolase 1 also known as phosphatidic acid phosphatase 2a is an enzyme that in humans is encoded by the PPAP2A gene.

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

Lipid phosphate phosphohydrolase 2 is an enzyme that in humans is encoded by the PPAP2C gene.

<span class="mw-page-title-main">LPIN1</span> Protein-coding gene in the species Homo sapiens

Lipin-1 is a protein that in humans is encoded by the LPIN1 gene.

<span class="mw-page-title-main">PPAP2B</span> Protein-coding gene in the species Homo sapiens

Lipid phosphate phosphohydrolase 3 (LPP3), also known as phospholipid phosphatase 3 (PLPP3) and phosphatidic acid phosphatase type 2B, is an enzyme that in humans is encoded by the PPAP2B gene on chromosome 1. It is ubiquitously expressed in many tissues and cell types. LPP3 is a cell-surface glycoprotein that hydrolyzes extracellular lysophosphatidic acid (LPA) and short-chain phosphatidic acid. Its function allows it to regulate vascular and embryonic development by inhibiting LPA signaling, which is associated with a wide range of human diseases, including cardiovascular disease and cancer, as well as developmental defects. The PPAP2B gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">CDS2</span> Protein-coding gene in the species Homo sapiens

Phosphatidate cytidylyltransferase 2 is an enzyme that in humans is encoded by the CDS2 gene.

<span class="mw-page-title-main">CDS1 (gene)</span> Protein-coding gene in the species Homo sapiens

Phosphatidate cytidylyltransferase 1 is an enzyme that in humans is encoded by the CDS1 gene.

<span class="mw-page-title-main">Diglyceride</span> Type of fat derived from glycerol and two fatty acids

A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are natural components of food fats, though minor in comparison to triglycerides. DAGs can act as surfactants and are commonly used as emulsifiers in processed foods. DAG-enriched oil has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat; with total annual sales of approximately USD 200 million in Japan since its introduction in the late 1990s till 2009.

Diacylglycerol diphosphate phosphatase (EC 3.1.3.81, DGPP phosphatase, DGPP phosphohydrolase, DPP1, DPPL1, DPPL2, PAP2, pyrophosphate phosphatase) is an enzyme with systematic name 1,2-diacyl-sn-glycerol 3-phosphate phosphohydrolase. This enzyme catalyses the following chemical reaction

References

  1. ↑ "BRENDA - Information on EC 3.1.3.4 - phosphatidate phosphatase". www.brenda-enzymes.org. Retrieved 2017-03-01.
  2. ↑ Smith SW, Weiss SB, Kennedy EP (October 1957). "The enzymatic dephosphorylation of phosphatidic acids". J. Biol. Chem. 228 (2): 915–22. PMID   13475370.
  3. 1 2 Carman, George M.; Han, Gil-Soo (2009-01-30). "Phosphatidic Acid Phosphatase, a Key Enzyme in the Regulation of Lipid Synthesis". The Journal of Biological Chemistry. 284 (5): 2593–2597. doi: 10.1074/jbc.R800059200 . ISSN   0021-9258. PMC   2631973 . PMID   18812320.
  4. 1 2 Carman, George M.; Han, Gil-Soo (2006-12-01). "Roles of phosphatidate phosphatase enzymes in lipid metabolism". Trends in Biochemical Sciences. 31 (12): 694–699. doi:10.1016/j.tibs.2006.10.003. ISSN   0968-0004. PMC   1769311 . PMID   17079146.
  5. ↑ Nanjundan, Meera; Possmayer, Fred (2003-01-01). "Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase". American Journal of Physiology. Lung Cellular and Molecular Physiology. 284 (1): L1–23. doi:10.1152/ajplung.00029.2002. ISSN   1040-0605. PMID   12471011.
  6. ↑ Martin, Ashley; Gomez-Muñoz, Antonio; Jamal, Zahirali; Brindley, David N. (1991-01-01). "[55] Characterization and assay of phosphatidate phosphatase". In Enzymology, BT - Methods in (ed.). Phospholipases. Phospholipases. Vol. 197. Academic Press. pp. 553–563. doi:10.1016/0076-6879(91)97183-Y. ISBN   9780121820985. PMID   2051944.
  7. 1 2 Berg, Jeremy (2010-12-24). Biochemistry, 7th Edition. New York: W.H. Freeman and Company. pp. 766–767. ISBN   978-1429229364.
  8. ↑ "EC 3.1.3.4". www.chem.qmul.ac.uk. Retrieved 2017-03-01.
  9. ↑ Carman GM, Han GS (December 2006). "Roles of phosphatidate phosphatase enzymes in lipid metabolism". Trends Biochem. Sci. 31 (12): 694–9. doi:10.1016/j.tibs.2006.10.003. PMC   1769311 . PMID   17079146.
  10. 1 2 Reue, Karen; Brindley, David N. (2008-12-01). "Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism". Journal of Lipid Research. 49 (12): 2493–2503. doi: 10.1194/jlr.R800019-JLR200 . ISSN   0022-2275. PMC   2582367 . PMID   18791037.
  11. ↑ Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin Todd A. Huffman, Isabelle Mothe-Satney, John C. Lawrence Proceedings of the National Academy of Sciences Jan 2002, 99 (2) 1047-1052
  12. ↑ Europe, Protein Data Bank in. "PDB 5jwy structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI". www.ebi.ac.uk. Retrieved 2017-03-02.
  13. ↑ Dillon, Deirdre A.; Wu, Wen-I.; Riedel, Bettina; Wissing, Josef B.; Dowhan, William; Carman, George M. (1996-11-29). "The Escherichia coli pgpB Gene Encodes for a Diacylglycerol Pyrophosphate Phosphatase Activity". Journal of Biological Chemistry. 271 (48): 30548–30553. doi: 10.1074/jbc.271.48.30548 . ISSN   0021-9258. PMID   8940025.
  14. 1 2 3 Tong, Shuilong; Lin, Yibin; Lu, Shuo; Wang, Meitian; Bogdanov, Mikhail; Zheng, Lei (2016-08-26). "Structural Insight into Substrate Selection and Catalysis of Lipid Phosphate Phosphatase PgpB in the Cell Membrane". The Journal of Biological Chemistry. 291 (35): 18342–18352. doi: 10.1074/jbc.M116.737874 . ISSN   1083-351X. PMC   5000081 . PMID   27405756.
  15. ↑ Han GS, Wu WI, Carman GM (April 2006). "The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme". J. Biol. Chem. 281 (14): 9210–8. doi: 10.1074/jbc.M600425200 . PMC   1424669 . PMID   16467296.
  16. 1 2 3 Donkor J, Sariahmetoglu M, Dewald J, Brindley DN, Reue K (February 2007). "Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns". J. Biol. Chem. 282 (6): 3450–7. doi: 10.1074/jbc.M610745200 . PMID   17158099.
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