Phosphatidate phosphatase

{{Short description|Class of enzymes}} {{infobox enzyme | Name = Phosphatidate phosphatase | EC_number = 3.1.3.4 | CAS_number = 9025-77-8 | GO_code = 0008195 | image = | width = | caption = }} 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:<ref>{{Cite web|url=http://www.brenda-enzymes.org/enzyme.php?ecno=3.1.3.4|title=BRENDA - Information on EC 3.1.3.4 - phosphatidate phosphatase|website=www.brenda-enzymes.org|access-date=2017-03-01}}</ref><ref name="pmid13475370">{{cite journal |vauthors=Smith SW, Weiss SB, Kennedy EP | title = The enzymatic dephosphorylation of phosphatidic acids | journal = J. Biol. Chem. | volume = 228 | issue = 2 | pages = 915–22 |date=October 1957 | doi = 10.1016/S0021-9258(18)70670-4 | doi-access = free | pmid = 13475370 }}</ref>

:a 1,2-diacylglycerol 3-phosphate + H2O <math>\rightleftharpoons</math> 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.<ref name="auto">{{Cite journal|last1=Carman|first1=George M.|last2=Han|first2=Gil-Soo|date=2009-01-30|title=Phosphatidic Acid Phosphatase, a Key Enzyme in the Regulation of Lipid Synthesis|journal=The Journal of Biological Chemistry|volume=284|issue=5|pages=2593–2597|doi=10.1074/jbc.R800059200 |doi-access=free |issn=0021-9258|pmc=2631973|pmid=18812320}}</ref> PAP1, a cytosolic phosphatidate phosphatase found in the lung, is also Mg2+-dependent, but PAP2, a six-transmembrane-domain integral protein found in the plasma membrane, is not.<ref name=":1">{{Cite journal|last1=Carman|first1=George M.|last2=Han|first2=Gil-Soo|date=2006-12-01|title=Roles of phosphatidate phosphatase enzymes in lipid metabolism|journal=Trends in Biochemical Sciences|volume=31|issue=12|pages=694–699|doi=10.1016/j.tibs.2006.10.003|issn=0968-0004|pmc=1769311|pmid=17079146}}</ref><ref>{{Cite journal|last1=Nanjundan|first1=Meera|last2=Possmayer|first2=Fred|date=2003-01-01|title=Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase|journal=American Journal of Physiology. Lung Cellular and Molecular Physiology|volume=284|issue=1|pages=L1–23|doi=10.1152/ajplung.00029.2002|issn=1040-0605|pmid=12471011}}</ref> [[File:Phosphatidate_phosphatase_reaction.png|left|thumb|448x448px|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.<ref name=":1" /> When the phosphatase is active, diacylglycerols formed by it can go on to form any of several products, including phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and triacylglycerol.<ref>{{Cite book|last1=Martin|first1=Ashley|last2=Gomez-Muñoz|first2=Antonio|last3=Jamal|first3=Zahirali|last4=Brindley|first4=David N.|date=1991-01-01|publisher=Academic Press|editor-last=Enzymology|editor-first=BT - Methods in|volume=197|pages=553–563|doi=10.1016/0076-6879(91)97183-Y|pmid=2051944|chapter=[55] Characterization and assay of phosphatidate phosphatase|title=Phospholipases|isbn=9780121820985}}</ref> 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.<ref name=":0">{{Cite book|title=Biochemistry, 7th Edition|last=Berg|first=Jeremy|publisher=W.H. Freeman and Company|isbn=978-1429229364|location=New York|pages=766–767|date=2010-12-24}}</ref>

== 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.<ref name=":0" />

== 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'''.<ref>{{Cite web|url=http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/1/3/4.html|title=EC 3.1.3.4|website=www.chem.qmul.ac.uk|access-date=2017-03-01}}</ref> Other names in common use include: * phosphatidic acid phosphatase (PAP), * 3-sn-phosphatidate phosphohydrolase, * acid phosphatidyl phosphatase, * phosphatidic acid phosphohydrolase, * phosphatidate phosphohydrolase, and * lipid phosphate phosphohydrolase (LPP).

== 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.<ref name="pmid17079146">{{cite journal |vauthors=Carman GM, Han GS | title = Roles of phosphatidate phosphatase enzymes in lipid metabolism | journal = Trends Biochem. Sci. | volume = 31 | issue = 12 | pages = 694–9 |date=December 2006 | pmid = 17079146 | pmc = 1769311 | doi = 10.1016/j.tibs.2006.10.003 }}</ref>

=== {{anchor|Lipin-20160208}} 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.<ref name="auto1">{{Cite journal|last1=Reue|first1=Karen|last2=Brindley|first2=David N.|date=2008-12-01|title=Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism|journal=Journal of Lipid Research|language=en|volume=49|issue=12|pages=2493–2503|doi=10.1194/jlr.R800019-JLR200 |doi-access=free |issn=0022-2275|pmc=2582367|pmid=18791037}}</ref>

==== 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.<ref name="auto"/>

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.<ref>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</ref>

=== 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 phosphatase<nowiki/>s. 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).<ref>{{Cite web|url=http://www.ebi.ac.uk/pdbe/entry/pdb/5jwy|title=PDB 5jwy structure summary ‹ Protein Data Bank in Europe (PDBe) ‹ EMBL-EBI|last=Europe|first=Protein Data Bank in|website=www.ebi.ac.uk|language=en|access-date=2017-03-02}}</ref><ref>{{Cite journal|last1=Dillon|first1=Deirdre A.|last2=Wu|first2=Wen-I.|last3=Riedel|first3=Bettina|last4=Wissing|first4=Josef B.|last5=Dowhan|first5=William|last6=Carman|first6=George M.|date=1996-11-29|title=The Escherichia coli pgpB Gene Encodes for a Diacylglycerol Pyrophosphate Phosphatase Activity|journal=Journal of Biological Chemistry|language=en|volume=271|issue=48|pages=30548–30553|doi=10.1074/jbc.271.48.30548|pmid=8940025|issn=0021-9258|doi-access=free}}</ref> PgpB is one of three integral membrane phosphatases in ''Escherichia coli'' that catalyzes the dephosphorylation of phosphatidylglycerol phosphate (PGP) to PG (phosphatidylglycerol).<ref name="auto2">{{Cite journal|last1=Tong|first1=Shuilong|last2=Lin|first2=Yibin|last3=Lu|first3=Shuo|last4=Wang|first4=Meitian|last5=Bogdanov|first5=Mikhail|last6=Zheng|first6=Lei|date=2016-08-26|title=Structural Insight into Substrate Selection and Catalysis of Lipid Phosphate Phosphatase PgpB in the Cell Membrane|journal=The Journal of Biological Chemistry|volume=291|issue=35|pages=18342–18352|doi=10.1074/jbc.M116.737874 |doi-access=free |issn=1083-351X|pmc=5000081|pmid=27405756}}</ref> 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.<ref name="auto2"/> thumb|578x578px|Dephosphorylation of phosphatidylglycerol phosphate (PGP) to form PG (phosphatidylglycerol). This reaction is catalyzed by PgpB, a bacterial integral membrane lipid phosphate phosphatase.|centerIn 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.<ref name="auto2"/>center|thumb|582x582px|PgpB (PDBe: 5jwy) cartoon with ribbons. Made in MacPyMOL.

== Genes ==

Human genes that encode phosphatidate phosphatases include: * PPAP2A (LPP1) – phosphatidic acid phosphatase type 2A * PPAP2B (LPP3) – phosphatidic acid phosphatase type 2B * PPAP2C (LPP2) – phosphatidic acid phosphatase type 2C * PPAPDC1A (PPC1A) – phosphatidic acid phosphatase type 2 domain containing 1A * PPAPDC1B (PPC1B) – phosphatidic acid phosphatase type 2 domain containing 1B * PPAPDC2 – phosphatidic acid phosphatase type 2 domain containing 2 * PPAPDC3 – phosphatidic acid phosphatase type 2 domain containing 3 * LPPR2 – lipid phosphate phosphatase-related protein type 2 * LPIN1 – lipin 1<ref name="pmid16467296">{{cite journal |vauthors=Han GS, Wu WI, Carman GM | title = The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme | journal = J. Biol. Chem. | volume = 281 | issue = 14 | pages = 9210–8 |date=April 2006 | pmid = 16467296 | pmc = 1424669 | doi = 10.1074/jbc.M600425200 |doi-access=free }}</ref><ref name="pmid17158099">{{cite journal |vauthors=Donkor J, Sariahmetoglu M, Dewald J, Brindley DN, Reue K | title = Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns | journal = J. Biol. Chem. | volume = 282 | issue = 6 | pages = 3450–7 |date=February 2007 | pmid = 17158099 | doi = 10.1074/jbc.M610745200 | doi-access = free }}</ref> * LPIN2 – lipin 2<ref name="pmid17158099"/> * LPIN3 – lipin 3<ref name="pmid17158099"/>

== 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.<ref name="auto1"/>

==References== {{reflist}}

Category:EC 3.1.3 Category:Enzymes of unknown structure