Phospholipase peptides

Bumble bee venom contains also a phospholipase A2 with partial identity to bee venom phospholipase Aj and a protease, but no melittin. Instead there are several small peptides called bombolitins [9]. There is limited cross-reactivity between honey bee and bumblebee venoms [2]. 

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... 

The G-protein that has been termed Gp, and that is linked to phospholipase C activation, may in fact be Gaj 2 or Gc. 3. Ga is designated as the G-protein responsible for activation of phospholipase A2, which results in arachidonic acid release. Some experimental evidence indicates that, at least in HL-60 cells, different agonists can preferentially activate different phospholipases, and some of these are responsible for the activation of secretion. In neutrophils, the two pertussis-toxin-sensitive Ga-proteins (Gaj-2 and G j 3) have been identified by peptide mapping of proteolytic digests of the proteins, by peptide sequencing and by immunoblotting. Complementary-DNA clones for the mRNA of these two molecules have also been isolated from an HL-60 cDNA library. Gai-2 is five to ten times more abundant than Gai.3, the former component comprising 3% of the total plasma membrane proteins. It is possible that these two different Ga-subunits are coupled to different phospholipases (e.g. phospholipases C and D). Pertussis toxin inhibits the secretion of O2 after stimulation of neutrophils by fMet-Leu-Phe, but pertussis-toxin-insensitive G-proteins are also present in neutrophils. These may be members of the Gq family and may be involved in the activation of phospholipase Cp (see 6.3.1). 

Billah, M. M., Eckel, S., Mullmann, T. J., Egan, R. W., Siegel, M. I. (1989). Phosphatidylcholine hydrolysis by phospholipase D determines phosphatidate and diglyceride levels in chemotactic peptide-stimulated human neutrophils. Involvement of phosphatidate phosphohydrolase in signal transduction. J. Biol. Chem. 264, 17069-77. 

It is obvious why the spectroscopist wants to investigate the structure of integral membrane proteins or enzymes, whose biological action is linked to the presence of phospholipids such as phospholipase, in a membrane-mimicking environment Why such an environment should also be used for other peptides like hormones becomes more clear when we take into account the membrane compartment theory [10-12] as postulated by R. Schwyzer. This theory states that peptides that target membrane-embedded receptors... 

Muller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, Blaser K Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol 1998 101 747-754. 

Since predators of snakes (and humans) have to deal with snake venoms as defenses, they are included here, even though they serve in predation. Snake venoms are primarily enzymes (proteins), especially of the phospholipase A2 type, which breaks down cell membrane phospholipids hydrolytically. Other snake venoms such as cobrotoxin contain peptides with 60-70 amino acid residues. Pharmacologically, they have neurotoxic, cytotoxic, anticoagulant, and other effects. The neurotoxins, in turn, can have pre- or postsynaptic effects. Snake venoms with both neurotoxic and hemolytic effects on the heart are known as cardiotoxins. Cytotoxins attach to the cells of blood vessels and cause hemorrhage. Snake venom factors may stimulate or inhibit blood clotting. Finally, platelet-active factors can contribute to hemorrhage. 

Snakes Phospholipases A2 Proteins, peptides (cobrotoxin), amino acids Neurotoxins... 

Chloroquine (Aralen) is one of several 4-aminoquino-line derivatives that display antimalarial activity. Chloroquine is particularly effective against intraerythrocytic forms because it is concentrated within the parasitized erythrocyte. This preferential drug accumulation appears to occur as a result of specific uptake mechanisms in the parasite. Chloroquine appears to work by intercalation with DNA, inhibition of heme polymerase or by interaction with Ca++-calmodulin-mediated mechanisms. It also accumulates in the parasite s food vacuoles, where it inhibits peptide formation and phospholipases, leading to parasite death. 

Fig. 8.11. Recognition of phosphotyrosine-containing substrate peptides by SH2 domains of Src kinase and phospholipase Cyl. Binding of phosphotyrosine-containing peptides to SH2 is shown schematically, based on crystal structures of the complexes. The SH2 domain of Src kinase has a basic binding pocket for the phosphotyrosine residue and a hydrophobic pocket for the isoleucine residues at position -1-3 of the peptide substrate. The SH2 domain of PL-Cyl has a hydrophobic binding surface to which the C-terminal part of the peptide P-Tyr-Ile-Ile-Pro-Leu-Pro-Asp binds. According to Cohen, (1995).

The actions of U-II are mediated by a G protein-coupled receptor referred to as the UT receptor. UT receptors are widely distributed in the brain, spinal cord, heart, vascular smooth muscle, skeletal muscle, and pancreas. Some effects of the peptide including vasoconstriction are mediated by the phospholipase C, IP3-DAG signal transduction pathway. 

Prostanoid receptors and their signaling pathways. fMLP, formylated MetLeuPhe, a small peptide receptor PLC-3, phospholipase C-3. All of the receptors shown are of the 7-transmembrane, G-protein coupled type. The terms "relaxant," "contractile," and "inhibitory" refer to the phylogenetic characterization of their primary effects. AII EP3 isoforms couple through G but some can also activate Gs or G12/13 pathways. RhoGEF, rho guanine nucleotide exchange factor. See text for additional details. 

Drissi, H., Lasmoles, F., Le Mellay, V., Marie, P.J., Lieberherr, M. Activation of phospholipase C-beta1 via Galphaq/11 during calcium mobilization by calcitonin gene-related peptide, J. Biol. Chem. 1998, 273, 20168-20174. 

G,i. Gi2, Gi3 Norepinephrine, prostaglandins, opiates, angiotensin, many peptides Adenylate cyclase Phospholipase C Phospholipase A2 K+ channels... 

Thwin M. M., Ong W. Y., Fong C. W., Sato K., Kodama K., Farooqui A. A., and Gopalakrishnakone P. (2003). Secretory phospholipase A2 activity in the normal and kainate injected rat brain, and inhibition by a peptide derived from python serum. Exp. Brain Res. 150 427-433. 

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