Inhibition of protein kinase C by snake venom toxins: comparison of enzyme inhibition, lethality and hemolysis among different cardiotoxin isoforms.
Cardiotoxins, neurotoxins and phospholipase A2 (PLA2) are three major classes of toxic components present in the Taiwan cobra, Naja naja atra of the Elapidae family. Cardiotoxins (or called cytotoxins), a group of major polypeptides of around 60 amino-acid residues present abundantly in the elapid family of snakes, comprise about 45-55% of the crude venom of Taiwan cobra. In contrast to another prominent group of structurally similar neurotoxins with well-established acetylcholine receptors and modes of action, cardiotoxins showed no defined cellular targets and very diverse pharmacological functions. A systematic structure/function comparison of these toxins was made by their relative inhibitory effects on protein kinase C (PKC) isolated from mouse brains. Lethality and hemolysis of various cardiotoxin isoforms were also compared in order to shed some insight on the biological targets and mechanisms of these surface-active amphiphilic polypeptides. A structure comparison of these cardiotoxins based on computer model-building revealed that some defined and subtle differences can be detected upon the superposition of these three-dimensional polypeptide chains, which may reflect the intrinsic differences in the hydrophobic peptide segments present on the surface loops of toxin molecules. The differences seem to correlate with different inhibitory activities exhibited by cardiotoxins in contrast to the lack of activity by cobrotoxin and PLA2 on PKC.
Chiou
S H
SH
Institute of Biochemical Sciences, National Taiwan University, Academia Sinica, Taipei.
Chuang
M H
MH
Hung
C C
CC
Huang
H C
HC
Chen
S T
ST
Wang
K T
KT
Ho
C L
CL
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003039:Cobra Neurotoxin Proteins / Q000633:toxicity; D003603:Cytotoxins / Q000737:chemistry / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects; D006168:Guinea Pigs; D006461:Hemolysis / Q000187:drug effects*; D007928:Lethal Dose 50; D051379:Mice; D008956:Models, Chemical; D010741:Phospholipases A / Q000494:pharmacology; D054467:Phospholipases A2; D011487:Protein Conformation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012910:Snake Venoms / Q000737:chemistry*
D003039:Cobra Neurotoxin Proteins; D003603:Cytotoxins; D012910:Snake Venoms; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2