Mammalian phospholipase D: Function, and therapeutics

Abstract

Despite being discovered over 60 years ago, the precise role of phospholipase D (PLD) is still being elucidated. PLD enzymes catalyze the hydrolysis of the phosphodiester bond of glycerophospholipids producing phosphatidic acid and the free headgroup. PLD family members are found in organisms ranging from viruses, and bacteria to plants, and mammals. They display a range of substrate specificities, are regulated by a diverse range of molecules, and have been implicated in a broad range of cellular processes including receptor signaling, cytoskeletal regulation and membrane trafficking. Recent technological advances including: the development of PLD knockout mice, isoform-specific antibodies, and specific inhibitors are finally permitting a thorough analysis of the in vivo role of mammalian PLDs. These studies are facilitating increased recognition of PLD's role in disease states including cancers and Alzheimer's disease, offering potential as a target for therapeutic intervention.

Keywords: Lipid signaling; Membrane transport; Phosphatidic acid; Phospholipase D.

Fig. 1.

A detailed comparison of PLD1 and PLD2 structure. PLD1 and PLD2 display 51% sequence homology and share a conserved structure with 4 conserved PLD regions (CR), of which CRII and IV contain the catalytic sequence HKD. They both contain PX- and PH-domains and a PIP2 binding motif. PLD1 contains a loop sequence between CRII and CRIII absent in PLD2. Known and potential region-specific functions are indicated.

Fig. 2.

PLD regulation and function. PLD activity is regulated by a multitude of factors including proteins and lipids. Its activity results in a diverse range of biological outcomes through production of PtdOH, GEF-activity, and protein-protein interactions.

Fig. 3.

Examples of mammalian PLD function. Mammalian PLDs are involved in a vast array of cellular processes, notably Vesicular trafficking, Golgi-function and cytoskeletal regulation.

Fig. 4.

The role of mammalian PLDs in disease. Mammalian PLDs have been implicated in a number of physiological processes and diseases, including brain function and development, Alzheimer’s disease, cancer, diabetes and stroke.