Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.2.717

Neurotoxins Affecting Neuroexocytosis

Micro total analysis systems. Recent developments.

Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

1.1. Discovery of the Phospholipase A2 Superfamily
Phospholipases represent one of the earliest enzyme activities to be identified and studied and the phospholipase A2 (PLA2) superfamily (see defining specificity1 in Figure 1) traces its roots to the identification of lytic actions of snake venom at the end of the 19th century. The enzyme was first purified and characterized from cobra venom and later from rattlesnake venom. As protein sequencing methodologies advanced in the 1970’s, it became apparent that these enzymes had an unusually large number of cysteines (over 10% of the amino acids) and as secreted enzymes, that they were all in the form of disulfide bonds. It was further recognized that in the case of PLA2, cobras and rattlesnakes had six disulfides in common, but one disulfide bond is located in distinctly different locations. This led to the designation of Type 1 and Type 2 for cobras (old world snakes) and rattlesnakes (new world snakes), respectively.2 During that same period, studies on the porcine pancreatic digestive enzyme that hydrolyzes phospholipids led to the determination that this mammalian enzyme (and also the human pancreatic enzyme) had the same disulfide bonding pattern as cobras and hence the designation as IB with the cobra enzyme as IA.






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Figure 1


The specific reaction catalyzed by phospholipase A2 at the sn-2 position of the glycerol backbone is shown. X, any of a number of polar headgroups; R1, fatty acids, or alkyl, or alkenyl groups and R2, fatty acids or acyl moieties.

/pdf/phospholipase-a2-enzymes-physical-structure-biological-usiwyw5zej.pdf

Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.

The phospholipase A2 superfamily and its group numbering system

Toxinology resources on the Internet: Virtual Venom and Toxin Research and Information Centre.

By using the combination of gel filtration, ion-exchange and reveres-phase chromatography, a novel trypsinlike serine proteinase was isolated from the venom of Buthus martensii Karsch and named BMK-CB. The apparent molecular weight of BMK-CB was identified as 32 kDa by SDSPAGE. The N-terminal sequence of 40 amino acids was obtained by Edman degradation. The sequence shows highest similarity to proteinase from insect source. The purified BMKCB was found to bind to the cancer cell line MCF-7 and the cell binding ability was dose-dependent. To our knowledge, BMK-CB forms the first trypsin-like serine proteinase from the scorpion venom.

A Novel Trypsin-like Serine Proteinase from the Venom of the Chinese Scorpion Buthus martensii Karsch

L'invention concerne un peptide isole comprenant la sequence d'acides amines de SEQ ID NO: 2 ou une variante, un derive et/ou un fragment de cette derniere ayant la fonction d'inhibiteur de reductase HMGCoA, d'inhibiteur de phosphomevalonate, reduisant l'accumulation de cholesterol dans la voie de biosynthese de cholesterol et/ou reduisant le niveau de cholesterol serique. L'invention concerne egalement une composition pharmaceutique comprenant le peptide ayant la sequence SEQ ID NO:2 ou une variante, un derive et/ou un fragment de cette derniere. L'invention concerne enfin un procede de traitement ou de prevention de troubles caracterises par l'accumulation de cholesterol, ses sous-produits et/ou ses produits derives de lipidiques connexes et comportant l'administration a un patient en ayant besoin d'au moins un peptide contenant la sequence d'acides amines de SEQ ID NO: 2 ou une variante, un derive et/ou un fragment de cette derniere.

Modulateurs de la voie biosynthese de cholesterol et leurs utilisations

T2D development and progression is widely known to be caused by pancreatic beta cell dysfunction, whether in the presence or absence of insulin resistance. There are however limited diabetes drugs that directly target the beta cell. Hence, there is a need to discover yet untapped pathways to increase or rescue beta cell function. Animal venoms provide a rich resource of bioactive compounds, many of which are highly potent and selective. Venom peptides have been harnessed for therapeutic drug development, such as the blockbuster diabetes drug, exenatide, a GLP-1 receptor agonist, being a synthetic form of exendin-4 that was first isolated from the saliva of the Gila monster. We hypothesize that we can further discover and develop new therapeutic agents that promote pancreatic beta cell function based on venom-derived compounds. We studied up to seven animal venoms from snakes, bees and scorpions. Pancreatic beta cells (including EndoC-βH1 cells, human islets, and MIN6 cells) were treated with crude animal venoms from each species and evaluated for insulin secretion capacity. We used a range of doses that elicit insulin secretion without causing cellular damage. Venoms from Apis mellifera (honey bee) and Naja naja (Indian cobra) were shown to robustly stimulate insulin secretion in a dose-dependent manner without affecting cell viability. Treatment with these venoms were also able to rescue diabetic cell models. We prioritized these two venoms for fractionation via gel filtration and reverse phase HPLC. After subsequent screening of the venom sub-fractions in insulin secretion assays, we pinpointed specific sub-fractions responsible for stimulating insulin release. Ongoing work is in progress to identify and validate selected peptides for insulinotropic activity, safety and stability. The insulinotropic peptides (and any modifications) may represent new therapeutic strategies for tackling T2D in future.
 
 
 N.Ng: Stock/Shareholder; BetaLife. C.Koh: None. C.Ching: None. P.Gopalakrishnakone: None. A.Teo: None.
 
 
 
 A*STAR Career Development Fund (202D800020)


Ponnampalam Gopalakrishnakone

Papers

Toxinology resources on the Internet: Virtual Venom and Toxin Research and Information Centre.

A Novel Trypsin-like Serine Proteinase from the Venom of the Chinese Scorpion Buthus martensii Karsch

Modulateurs de la voie biosynthese de cholesterol et leurs utilisations

1760-P: Mining Animal Venoms as a Source of Insulinotropic Peptides for Potential Diabetes Therapy

Burkholderia pseudomallei Toxins and Clinical Implications