page_title: Phospholipase D
section_title: Phosphatidic acid
hierarchical_section_title: Phospholipase D / Function / Phosphatidic acid
caption_attribution_description: English: A model of the ARF-dependent activation of phospholipase D, and a proposed scheme for vesicle endocytosis. In this model, ARF activates phospholipase D (PLD), recruiting it to the plasma membrane. Hydrolysis of phosphatidylcholine (PC) by ARF-activated PLD produces phosphatidic acid (PA). PA subsequently recruits molecules that shape the inner face of the lipid bilayer, facilitating vesicle formation. Local enrichment of acidic phospholipids help recruit adaptor proteins (AP) and coat proteins (CP) to the membrane, initiating the budding of the vesicle. Vesicle fission is ultimately mediated by dynamin, which itself is a downstream effector of PA.
context_page_description: Phospholipase D is an enzyme of the phospholipase superfamily. Phospholipases occur widely, and can be found in a wide range of organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase D’s principal substrate is phosphatidylcholine, which it hydrolyzes to produce the signal molecule phosphatidic acid, and soluble choline. Plants contain numerous genes that encode various PLD isoenzymes, with molecular weights ranging from 90-125 kDa. Mammalian cells encode two isoforms of phospholipase D: PLD1 and PLD2. Phospholipase D is an important player in many physiological processes, including membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, and cell migration. Through these processes, it has been further implicated in the pathophysiology of multiple diseases: in particular the progression of Parkinson’s and Alzheimer’s, as well as various cancers. PLD may also help set the threshold for sensitivity to anesthetia and mechanical force.
context_section_description: Many of phospholipase D’s cellular functions are mediated by its principal product, phosphatidic acid (PA). PA is a negatively charged phospholipid, whose small head group promotes membrane curvature. It is thus thought to facilitate membrane-vesicle fusion and fission in a manner analogous to clathrin-mediated endocytosis. PA may also recruit proteins that contain its corresponding binding domain, a region characterized by basic amino acid-rich regions. Additionally, PA can be converted into a number of other lipids, such as lysophosphatidic acid (lyso-PA) or diacylglycerol, signal molecules which have a multitude of effects on downstream cellular pathways.PA and its lipid derivatives are implicated in myriad processes that include intracellular vesicle trafficking, endocytosis, exocytosis, actin cytoskeleton dynamics, cell proliferation differentiation, and migration.
  Mammalian PLD directly interacts with kinases like PKC, ERK, TYK and controls the signalling indicating that PLD is activated by these kinases. As choline is very abundant in the cell, PLD activity does not significantly affect choline levels, and choline is unlikely to play any role in signalling.
  Phosphatidic acid is a signal molecule and acts to recruit SK1 to membranes. PA is extremely short lived and is rapidly hydrolysed by the enzyme phosphatidate phosphatase to form diacylglycerol (DAG). DAG may also be converted to PA by DAG kinase. Although PA and DAG are interconvertible, they do not act in the same pathways. Stimuli that activate PLD do not activate enzymes downstream of DAG and vice versa.
  It is possible that, though PA and DAG are interconvertible, separate pools of signalling and non-signalling lipids may be maintained. Studies have suggested that DAG signalling is mediated by polyunsaturated DAG while PLD derived PA is monounsaturated or saturated. Thus functional saturated/monounsaturated PA can be degraded by hydrolysing it to form non-functional saturated/monounsaturated DAG while functional polyunsaturated DAG can be degraded by converting it into non-functional polyunsaturated PA.
  A lysophospholipase D called autotaxin was recently identified as having an important role in cell-proliferation through its product,
  lysophosphatidic acid (LPA).
caption: Figure 1. A model of the ARF-dependent activation of phospholipase D, and a proposed scheme for vesicle endocytosis. In this model, ARF activates phospholipase D (PLD), recruiting it to the plasma membrane. Hydrolysis of phosphatidylcholine (PC) by ARF-activated PLD produces phosphatidic acid (PA). PA subsequently recruits molecules that shape the inner face of the lipid bilayer, facilitating vesicle formation. Local enrichment of acidic phospholipids help recruit adaptor proteins (AP) and coat proteins (CP) to the membrane, initiating the budding of the vesicle. Vesicle fission is ultimately mediated by dynamin, which itself is a downstream effector of PA.
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