Protein and Peptide Letters - Volume 16, Issue 8, 2009

Animal venoms are a rich and complex mixture of toxic and pharmacologically active proteins and peptides. Due to this broad range of biological functions, these biomolecules have been the subject of hundreds of scientific articles in different research fields, including biochemistry, biophysics, pharmacology, toxicology and medicine. This issue is focused on the structural and functional aspects of some animal toxins which could be important for understanding their biological mechanisms and pharmacological properties. In many rural areas in Asia, Latin American and Africa the envenomation by snakes, scorpions, spiders and other venomous animals causes thousands of deaths. This is a serious problem of public health as a result of the associated chronic morbidity (e.g., amputation, deformation and renal failure) causing significant social and economic impact [1]. Even though the patients are treated with anti-venom agents, many of them present serious and permanent physical damage. The deeper study of these compounds could be very important for the development of new and more efficient treatments against animal venoms. Additionally, the pharmacological properties of the peptides and proteins from animal venoms lead to them being used as effective drugs for hypertension, thrombosis and other diseases and are potential drugs for a great variety of diseases including cancer, Alzheimer's, Parkinson's and inflammatory disorders. This issue of Protein and Peptide Letters contains eleven manuscripts describing structural and functional analysis of different proteins and peptides from snakes, spiders, scorpions and wasps. The first review by Magro and colleagues discusses the importance of the oligomeric conformation of snake venoms phospholipases A2 in their biological function. The second review by Lomonte and co-workers is focused in the Phospholipases A2 homologues from snake venoms, emphasizing their biological activities in vivo and in vitro. The review by Oliveira et al. is centered in Calcium-independent membrane damage by snake venom Phospholipases A2 homologues. In the next article, dos Santos et al. analyzed the controversial subject of the biological assembly for Phospholipases A2 homologues from snake venoms focused in the myotoxicity and catalytic inactivity. Rodrigues et al. studied the snake venom Phospholipases A2 as an antitumoral agent while de Paula et al. reviewed snake venoms from the pharmacological and structural perspective. The functional and structural characteristics of snake venom Lamino acid oxidades are reviewed by Zuliani et al. The review by Soares and Oliveira is focused in the structure-function relationship of the glycoproteins from snake venoms. Cologna et al. presents a general revision of the pharmacological and physiological proprieties of the venom from the most important scorpion specie in South America. The review of dos Santos and Dias et al. describe a proteomic analysis of different proteins from Loxosceles intermedia spider venom. In the last article, Monteiro et al. review wasp venom components and their biological effects. Finally, I hope this issue could have new and useful information about different biological molecules from animal venoms.

One of the main components of snake venoms are the Asp49-phospholipases A2, also known as svPLA2s. The study of these toxins is a matter of great scientific interest due to their wide variety of biological effects. In this work we present strong evidences found in literature and other aspects which strengthen the importance of quaternary assembly for understanding the activities and molecular evolution of svPLA2s.

A particular subgroup of toxins with phospholipase A2 (PLA2) structure, but devoid of this enzymatic activity, is commonly found in the venoms of snakes of the family Viperidae, and known as the PLA2 homologues. Among these, the most frequent type presents a lysine residue at position 49 (Lys49), in substitution of the otherwise conserved aspartate (Asp49) of catalytically-active PLA2s. A brief and updated overview of these toxic PLA2 homologues is presented, emphasizing their various biological activities, both in vivo and in vitro. The relevance of these bioactivities in relation to their possible adaptive roles for the snakes is discussed. Finally, experiments designed to assess the validity of such hypothetical roles are suggested, to stimulate future studies in this field.

Many snake venom phospholipase A2s (vPLA2s) present biological effects that are independent of hydrolytic activity. Here we review the evidence for the calcium-independent membrane damaging activity of vPLA2s, the possible relevance of this activity on their biological effects, and models for the mechanism of membrane permeabilization by these proteins.

Phospholipases A2 homologues are found in the venom of Crotalinae snakes, being their main action related to myonecrosis induction. Although many studies on these toxins had already been performed, their mechanism of action remains unclear. Here, important aspects about these toxins are reviewed, including their correct biological assembly and how essential is the natural substitution D49K for their catalytic inactivity.

Phospholipases A2 (PLA2) are enzymes of high medical scientific interest due to their involvement in a large number of human inflammatory diseases. PLA2 constitute a diverse family of enzymes which catalyses the hydrolysis of the sn-2 ester bond in glycerophospholipids and exhibit a wide range of physiological and pathological effects. The ubiquitous nature of PLA2 highlights the important role they play in many biological processes, as cell signaling and cell growth, including the generation of proinflammatory lipid mediators such as prostaglandin and leukotrienes, regulation of lipid mediators. The activity and expression of several PLA2 isoforms are increased in several human cancers, suggesting that these enzymes have a central role in both tumor development and progression and can be targets for anti-cancer drugs. On the other hand, some PLA2 isolated from Viperidae venoms are capable to induce antitumoral activity. In summary PLA2 from snake venoms can be a new class of anticancer agents and provide new molecular and biological insights of cancer development.

Phospholipases A2 enzymes are found in many biological sources, including snake venoms. Here we reviewed aspects of PLA2s including biological and structural features, interaction with binding receptors, inhibitors used on structure- function relationship studies and highlighting the mechanism of action and role of the snake venom PLA2s products, the lysophosphatidylcholine.

Snake Venom L-amino acid oxidases (LAAOs E.C. 1.4.3.2) are flavoenzymes broadly found in various snake venom compositions. LAAOs have become an attractive subject for molecular biology, biochemistry, physiology and medicine due to their actions on various cells and biological effects on platelets, apoptosis, hemorrhage and others. In this review we try to summarize some of these reports, with special emphasis on apoptosis, anti-protozoa, bactericidal and anti-viral activities.

Protein glycosylation represents one of the most important post-translational events, and is a mean of diversifying a protein without recourse to the genome. The venoms produced by snakes contain an abundance of glycoproteins with N-linked carbohydrates. N-linked glycosylation can ensure the correct folding of important functional domains. Characterization of carbohydrates structures aids in development of human therapeutics by snake venom toxins.

Tityus serrulatus is considered the most dangerous scorpion in South America and responsible for most of the fatal cases. This review will focus on Tityus serrulatus scorpion venom (Tsv), its long-chain Na+-channel toxins (NaTx), which include α- and β-neurotoxins, short-chain K+-channel toxins (KTx), hyaluronidase, proteases and other peptides hitherto identified.

Loxosceles intermedia spider venom was subjected to proteomic analysis through a MudPIT shot-gun approach to identify the protein composition. Were identified 39 proteins which seem to responsible by the lesion of different types of tissues, to some physiopathological actions and by the prevention of structural damage to the toxin structures.

Venoms of several animals have been used to study various physiopathologic processes, and also to offer opportunity to design and develop new therapeutic drugs. We briefly review certain wasp venom components and their biological effects, which may be potential sources of novel pharmacologically active compounds.

Secondary structural elements like α-helix and β-sheet constitute the major components of proteins. Here we present a systematic position wise analysis of the structural and sequence characteristics of alpha-helices and beta-sheets. Helix and sheet are found to follow a complementary distribution pattern along the protein chain length. We have calculated the conformational parameters of the amino acids forming helices and sheets. Other properties like hydrophobicity, temperature-factor and relative entropy are found to be correlated with the distribution pattern of these secondary structures. This gives an insight about the conservation or variation of the secondary structure in proteins, which may have significant implications on de novo protein design.

The genome of Plasmodium falciparum, a malarial parasite, is atypical as many of the encoded proteins have diverged extensively from their homologues in other organisms. Hence homology-based information transfer is not entirely successful and presently, proper function annotation is unavailable for over 50% of the proteome. It has been hypothesized that enzymes participating in nearly 69 metabolic steps are not yet identified. In this paper we report detection of some of the “missing metabolic enzymes” of P. falciparum. Our approach for remote homology detection to recognize the “missing” P. falciparum enzymes employs multiple profiles for every protein domain family. A blind assessment of the approach to recognize known metabolic proteins of P. falciparum resulted in 94% success rate. Using this approach we have successfully recognized 14 of the “missing” enzymes. Results of protein fold recognition and information from microarray and protein-protein interaction datasets are consistent with our predictions. In a few cases we also provide the list of functionally important residues extrapolated on the basis of homology.

How to correctly and efficiently determine small molecules' biological function is a challenge and has a positive effect on further metabonomics analysis. Here, we introduce a computational approach to address this problem. The new approach is based on AdaBoost method and featured by function group composition to the metabolic pathway analysis, which can fast and automatically map the small chemical molecules back to the possible metabolic pathway that they belong to. As a result, jackknife cross validation test and independent set test on the model reached 73.7% and 73.8%, respectively. It can be concluded that the current approach is very promising for mapping some unknown molecules' possible metabolic pathway. An online predictor developed by this research is available at http://chemdata.shu.edu.cn/pathway.

Reversible acetylation on lysine residues, a crucial post-translational modification (PTM) for both histone and non-histone proteins, governs many central cellular processes. Due to limited data and lack of a clear acetylation consensus sequence, little research has focused on prediction of lysine acetylation sites. Incorporating almost all currently available lysine acetylation information, and using the support vector machine (SVM) method along with coding schema for protein sequence coupling patterns, we propose here a novel lysine acetylation prediction algorithm: LysAcet. When compared with othermethods or existing tools, LysAcet is the best predictor of lysine acetylation, with K-fold (5- and 10-) and jackknife cross-validation accuracies of 75.89%, 76.73%, and 77.16%, respectively. LysAcet's superior predictive accuracy is attributed primarily to the use of sequence coupling patterns, which describe the relative position of two amino acids. LysAcet contributes to the limited PTM prediction research on lysine η-acetylation, and may serve as a complementary in-silicon approach for exploring acetylation on proteomes. An online web server is freely available at http://www.biosino.org/LysAcet/.

Identification of ligand-binding pockets in proteins is pivotal to protein function definition and drug discovery. In this study, we focus on determining the binding pockets in proteins for potential ligands without any a priori knowledge. Three methods based upon residue preference concept are proposed to predict ligand-binding pockets, where we deal with three types of residue preference (residue based, atom based and atom-contact-pair based preference), respectively. Two test sets were chosen to examine the proposed methods. Two different identification rules (named Top1 and Top2) are used to detect ligand-binding pockets. The results show that the atom-contact-pair method has good accuracy and high efficiency, better than the other two methods. By means of preference analysis for amino acids and atom-contactpairs, we find that Gly and atom-contact-pairs on aromatic residues appear at ligand-binding pockets more frequently. The former favors pocket flexibility, and the latter shows that aggregate hydrophobic surface may play an important role in complex formation.

Macromolecular events like protein aggregation are complex processes involving physico-chemical properties of their constituting residues. In this study, we used 5-dimensional physico-chemical property (PCP-descriptors) descriptors of amino acids, derived from 237 physico-chemical properties, to develop linear (LM) and neural network (NM) based regression models. We demonstrate their prediction performance in log values of aggregation rates ( ψ ) for 15 human muscle acyl-phosphatase (AcP) mutants. The correlation coefficient between the predicted and the observed ψ - values of the point mutations by LM and NM was 0.81 (p-value<0.001) and 0.71 (p-value<0.002) respectively. Using LM, we calculated ψ -values for all possible mutations and performed an average linkage cluster analysis. We identified three groups of amino acids that differ in tolerance to mutations, resulting in increased or decreased aggregation rates. We suggest that our linear regression model can be applied to predict the aggregation propensity of point mutants where only sequence information is known. We also show that sequences containing beta-sheet classes of Structural Classification of Proteins (SCOP) have a higher propensity for aggregation.