Phospholipase D

Class of enzymes

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

a phosphatidylcholine + H2O = choline + a phosphatidate

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 (PA), and soluble choline in a cholesterol dependent process called substrate presentation. Plants contain numerous genes that encode various PLD isoenzymes, with molecular weights ranging from 90 to 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 type activity was first reported in 1947 by Donald J. Hanahan and I. L. Chaikoff. More than half a century of biochemical studies have implicated phospholipase D and PA activity in a wide range of physiological processes and diseases, including inflammation, diabetes, phagocytosis, neuronal & cardiac signaling, and oncogenesis.

Plant and animal PLDs have a consistent molecular structure, characterized by sites of catalysis surrounded by an assortment of regulatory sequences. phosphatidylserine synthase, bacterial PLDs, and viral proteins. Each of these appears to possess a domain duplication which is apparent by the presence of two HKD motifs containing well conserved histidine, lysine, and asparagine residues which may contribute to the active site aspartic acid. An Escherichia coli endonuclease (nuc) and similar proteins appear to be PLD homologues but possess only one of these motifs. PLD genes additionally encode highly conserved regulatory domains: the phox consensus sequence (PX), the pleckstrin homology domain (PH), and a binding site for phosphatidylinositol 4,5 bisphosphate (PIP2). Increased PIP2 or a decrease in cholesterol causes the enzyme to translocate to PIP2 micro domains near its substrate PC. Hence PLD can is primarily activated by localization within the plasma membrane rather than a protein conformational change. Disruption of lipid domains by anesthetics. or mechanical force. each encoded by distinct genes. PLDs regulated by these phospholipids are commonly involved in intracellular signal transduction. And ethanol transphosphatidylation was shown to be up regulated in alcoholics and the family members of alcoholic. s This ethanol transphosphatidylation mechanism recently emerged as an alternative theory for alcohol's effect on ion channels. Many ion channels are regulated by anionic lipids. and the competition of PEtOH with endogenous signaling lipids is thought to mediate the effect of ethanol on ion channels in some instances and not direct binding of the free ethanol to the channel.

Phospholipase D is a regulator of several critical cellular processes, including vesicle transport, endocytosis, exocytosis, cell migration, and mitosis.