Phospholipase D

Phospholipase D (PLD) is associated with hydrolysis of the phosphodiester bond of the glycerolipid phosphatidylcholine (PC) to form phosphatidic acid (PA) and choline. PLD superfamily catalyzes a transphosphatidylation reaction that, depending on the specific gene product, can employ a wide variety of primary alcohol-like nucleophiles such as water, ethanol, 1-butanol, glycerol, and diacylglycerol to synthesize phosphatidic acid (PA), phosphatidyl alcohols, and other lipids. Also, PLD superfamily members hydrolyze substrates including cardiolipin, DNA, and covalently-linked stalled DNA-topoisomerase complexes. PLD genes are found in all species, from viruses and bacteria to plants and animals. The wide spectrum of roles has implicated PLD in a number of disease-associated processes, including diabetes, atherogenesis, obesity, oncogenesis, immunological responses, and neuroendocrine function. Furthermore, PA has been linked to a diverse range of cellular processes using methodology that relies on the use of primary alcohols to divert PLD to generate phosphatidylalcohols instead of PA, or on a variety of relatively non-specific inhibitors such as ceramide or neomycin, expression of dominant-negative isoforms, and RNAi. Therefore, PLD has been demonstrated to be important for many cellular processes. Immune responses and tumorigenesis represent two key physiological areas for which PLD may be a good drug target through development of specific inhibitors, and play a role in immune function and cancer inhibition.