Phospholipase structure

Some other hydrolytic enzymes, in addition to proteases, that are important drug targets include protein phophatases, phosphodiesterases, nucleoside hydrolases, acetylhydolases, glycosylases, and phospholipases. Structure-based inhibitor design is currently being applied to a number of these enzymes. The last three mentioned have been successfully tar-... 

I 2 Phospholipase Structures, Physiological and Patho-physiological Roles in Mammals... 

Ferguson, K.M., et al. Structure of the high affinity complex of inositol triphosphate with a phospholipase C pleckstrin homology domain. Celt 83 1037-1046, 1995. 

Pseudopterosin A is a member of a group of marine natural products which show potent antiinflammatory properties, but which are not prostaglandin biosynthesis inhibitors. Structurally similar to phosphatidyl inositol, they may function as phospholipase inhibitors, and, as such, may be the forerunners of a new class of therapeutic agents. 

Phospholipases. Figure 3 Representation ofthe domain structure of phospholipase D1 (adapted from [4]). 

Exton JH (2002) Phospholipase D - structure, regulation and function. Rev Physiol Biochem Pharmacol 144 1-94... 

Walker, C.H. (1994b). Interactions between pesticides and esterases in humans. In M.I. Mackness and M. Clerc (Eds.) Esterases, Lipases, and Phospholipases from Structure to Clinical Significance. NATO ASI Series. Series A, Life Sciences. New York Plenum Press 91-98. 

Hentze H-P, Co CC, McKelvey CA, Kaler EW (2003) Templating Vesicles, Microemulsions and Lyotropic Mesophases by Organic Polymerization Processes. 226 197-223 Hergenrother PJ, Martin SE (2000) Phosphatidylcholine-Preferring Phospholipase C from B. cereus. Eunction, Structure, and Mechanism. 2ii 131 -167 Hermann C, see Kuhlmann J (2000) 211 61-116... 

Case 1 An ideal density map, that is, a calculated map from the known structure of protein BP2 (bovine pancreatic phospholipase A2) which contains 123... 

Kubelka, V., Altmann, F., Staudacher, E., Tretter, V., Marz, L., Hard, K., Kamerling, J.P. and Vliegenthart, F.G. (1993) Primary structure of the A-linked carbohydrate chains from honeybee venom phospholipase A2. European Journal of Biochemistry 213, 1193—1204. 

Gelb, M.H., Cho, W. and Wilton, D.C. (1999) Interfacial binding of secreted phospholipase A2 more than electrostatics and a major role for tryptophan. Current Opinion in Structural Biology 9, 428-432. 

Fig. 4.12(a). An outline structure of a protein (here the enzyme phospholipase A2), showing a-helical runs of amino acids as cylinders (A-E) and anti-parallel P-sheet runs as heavy black arrows. Disulfide cross-links are shown (the enzyme is extracellular), and runs of no a/p secondary structure appear as thin lines. The structure is relatively immobile, and binds calcium in a constrained loop. (Reproduced with permission from Professor J. Drenth.)... 

A bacterial phosphatidylinositol specific phospholipase C (PI-PLC) had been available for many years before it was demonstrated to strip a number of membrane-bound proteins from eukaryotic cell surfaces [1], Such proteins are anchored by a PI moiety in which the 6 position of inositol is glycosidically linked to glucosamine, which in turn is bonded to a polymannan backbone (Fig. 3-10). The polysaccharide chain is joined to the carboxyl terminal of the anchored protein via amide linkage to ethanolamine phosphate. The presence of a free NH2 group in the glucosamine residue makes the structure labile to nitrous acid. Bacterial PI-PLC hydrolyzes the bond between DAG and phosphati-dylinositols, releasing the water-soluble protein polysac charide-inositol phosphate moiety. These proteins are tethered by glycosylphosphatidylinositol (GPI) anchors. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Katan, M. Families of phosphoinositide-specific phospholipase C structure and function. Biochim. Biophys. Acta 1436 5-17,1998. 

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