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Neurotoxicity and other pharmacological activities of the snake venom phospholipase A2 OS2: the N-terminal region is more important than enzymatic activity.
- Source :
-
Biochemistry [Biochemistry] 2006 May 09; Vol. 45 (18), pp. 5800-16. - Publication Year :
- 2006
-
Abstract
- Several snake venom secreted phospholipases A2 (sPLA2s) including OS2 exert a variety of pharmacological effects ranging from central neurotoxicity to anti-HIV activity by mechanisms that are not yet fully understood. To conclusively address the role of enzymatic activity and map the key structural elements of OS2 responsible for its pharmacological properties, we have prepared single point OS2 mutants at the catalytic site and large chimeras between OS2 and OS1, a homologous but nontoxic sPLA2. Most importantly, we found that the enzymatic activity of the active site mutant H48Q is 500-fold lower than that of the wild-type protein, while central neurotoxicity is only 16-fold lower, providing convincing evidence that catalytic activity is at most a minor factor that determines central neurotoxicity. The chimera approach has identified the N-terminal region (residues 1-22) of OS2, but not the central one (residues 58-89), as crucial for both enzymatic activity and pharmacological effects. The C-terminal region of OS2 (residues 102-119) was found to be critical for enzymatic activity, but not for central neurotoxicity and anti-HIV activity, allowing us to further dissociate enzymatic activity and pharmacological effects. Finally, direct binding studies with the C-terminal chimera, which poorly binds to phospholipids while it is still neurotoxic, led to the identification of a subset of brain N-type receptors which may be directly involved in central neurotoxicity.
- Subjects :
- Amino Acid Sequence
Animals
Chickens
Drosophila
Electrophoresis, Polyacrylamide Gel
Escherichia coli drug effects
HIV drug effects
HIV physiology
Male
Models, Molecular
Molecular Sequence Data
Phospholipases A metabolism
Phospholipases A pharmacology
Phospholipases A2
Plasmodium falciparum drug effects
Protein Conformation
Sequence Homology, Amino Acid
Virus Replication drug effects
Phospholipases A chemistry
Phospholipases A toxicity
Snake Venoms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2960
- Volume :
- 45
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16669624
- Full Text :
- https://doi.org/10.1021/bi060217r