Phospholipase D1 (PLD1) is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that in humans is encoded by the ''PLD1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, though analogues are found in plants, fungi, prokaryotes, and even viruses.

History

The possibility of PLD1 was first mentioned in 1947 by authors Hanahan and Chaikoff at Berkeley when describing a carrot enzyme that could " plit

choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but re ...

from

phospholipids 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 (usually a glycerol molecule). Marine phospholipids typ ...

." PLD was first derived in mammals in 1975 by Saito and Kanfer, who noted its activity in rats. PLD was first cloned from

HeLa HeLa (; also Hela or hela) is an immortalized cell line used in scientific research. It is the oldest and most commonly used human cell line. The line is derived from cervical cancer cells taken on February 8, 1951, named after Henrietta La ...

cell

cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...

in 1995, while mammalian PLD1 was first cloned from a rat in 1997.

Function

Site_of_hydrolysis_on_phosphatidylcholine_by_PLD1

Phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soyb ...

(PC)-specific phospholipases D (PLDs) catalyze the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of PC to produce

phosphatidic acid 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 ac ...

(PA) and choline. A range of

agonists An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...

acting through

G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

and

receptor tyrosine kinases Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...

stimulate this hydrolysis. PC-specific PLD activity has been implicated in numerous cellular pathways, including

membrane trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory ...

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

, platelet coagulation,

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

, and the creation of cytoplasmic lipid droplets.

Membrane trafficking

PLD1 has been shown to associate at the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

, late

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...

, early endosome, and the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...

. There is evidence that PA is able to assist in negative membrane curvature due to its head group being smaller than in many other lipids. One experiment with PLD1 knockout showed a significant reduction in the number of exocytotic fusion events, implying a strong role in exocytosis.

Signal transduction

PLD1 may play a role in some cells in the

endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...

of signaling receptors or

exocytosis Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...

of signaling molecules. For example, one experiment in

B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

showed that limiting PLD1 led to significantly reduced endocytosis of the B cell receptor. Another experiment showed that knocking out PLD1 may hinder the ability of mice to secrete

catecholamines A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a substi ...

, molecules that are essential for vesicular communication across the body.

Structure

Mammalian PLD1 has several domains for activators, inhibitors, and catalysis, which it shares with PLD2. Domains for both activation and inhibition are referred to as the phox homology (PX) and pleckstrin homology (PH) domains. The catalytic domain consists of two HKD regions, so named for three of the amino acids that are key in catalysis. These domains are conserved across many organisms. There are two splice variants of the protein, PLD1a and PLD1b, but they do not seem to localize any differently.

Applications

Alzheimer's Disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

: PA, which is produced in part by PLD1, seems to be involved in the movement of β-amyloid, which could precede amyloidogenesis.

Cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

: certain rat tumors with dominant negative PLD do not appear to form new colonies or tumors.

Thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...

: PLD knockout mice appear to have reduced occlusion, thus offsetting thrombosis.

Type II Diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...

: the protein PED/PEA15 is often elevated in type II diabetic patients, thus enhancing PLD1 activity, and in turn impairing insulin.

Interactions

Phospholipase D1 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

Alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...

, *

Amphiphysin Amphiphysin is a protein that in humans is encoded by the ''AMPH'' gene. Function This gene encodes a protein associated with the cytoplasmic surface of synaptic vesicles. A subset of patients with stiff person syndrome who were also affected ...

, *

BIN1 Myc box-dependent-interacting protein 1, also known as Bridging Integrator-1 and Amphiphysin-2 is a protein that in humans is encoded by the ''BIN1'' gene. This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which w ...

, * CDC42, *

PEA15 Astrocytic phosphoprotein PEA-15 is a protein that in humans is encoded by the ''PEA15'' gene. PEA15 is a death effector domain (DED)-containing protein predominantly expressed in the central nervous system, particularly in astrocytes. PEA-15 pr ...

, *

Protein kinase N1 Serine/threonine-protein kinase N1 is an enzyme that in humans is encoded by the ''PKN1'' gene. Function The protein encoded by this gene belongs to the protein kinase C superfamily. This kinase is activated by Rho family of small G proteins a ...

RALA Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the ''RALA'' gene on chromosome 7. This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. RalA functions as a mole ...

, and *

RHOA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...

Inhibitors

* Calphostin-c, an inhibitor *VU-0359595: 1,700-fold selective versus phospholipase D2, IC₅₀ = 3.7nM.