Snake venoms are cocktails of enzymes and non‐enzymatic proteins used for both the immobilization and digestion of prey. The most common snake venom enzymes include acetylcholinesterases,l‐amino acid oxidases, serine proteinases, metalloproteinases and phospholipases A₂. Higher catalytic efficiency, thermal stability and resistance to proteolysis make these enzymes attractive models for biochemists, enzymologists and structural biologists. Here, we review the structures of these enzymes and describe their structure‐based mechanisms of catalysis and inhibition. Some of the enzymes exist as protein complexes in the venom. Thus we also discuss the functional role of non‐enzymatic subunits and the pharmacological effects of such protein complexes. The structures of inhibitor–enzyme complexes provide ideal platforms for the design of potent inhibitors which are useful in the development of prototypes and lead compounds with potential therapeutic applications.

Branching enzyme catalyzes the formation of α-1,6 branch points in either glycogen or starch. We report the 2.3-Å crystal structure of glycogen branching enzyme fromEscherichia coli. The enzyme consists of three major domains, an NH₂-terminal seven-stranded β-sandwich domain, a COOH-terminal domain, and a central α/β-barrel domain containing the enzyme active site. While the central domain is similar to that of all the other amylase family enzymes, branching enzyme shares the structure of all three domains only with isoamylase. Oligosaccharide binding was modeled for branching enzyme using the enzyme-oligosaccharide complex structures of various α-amylases and cyclodextrin glucanotransferase and residues were implicated in oligosaccharide binding. While most of the oligosaccharides modeled well in the branching enzyme structure, an approximate 50° rotation between two of the glucose units was required to avoid steric clashes with Trp²⁹⁸ of branching enzyme. A similar rotation was observed in the mammalian α-amylase structure caused by an equivalent tryptophan residue in this structure. It appears that there are two binding modes for oligosaccharides in these structures depending on the identity and location of this aromatic residue.

Sphingomyelinases D (SMases D) from Loxosceles spider venom are the principal toxins responsible for the manifestation of dermonecrosis, intravascular hemolysis, and acute renal failure, which can result in death. These enzymes catalyze the hydrolysis of sphingomyelin, resulting in the formation of ceramide 1-phosphate and choline or the hydrolysis of lysophosphatidyl choline, generating the lipid mediator lysophosphatidic acid. This report represents the first crystal structure of a member of the sphingomyelinase D family from Loxosceles laeta (SMase I), which has been determined at 1.75-Å resolution using the “quick cryo-soaking” technique and phases obtained from a single iodine derivative and data collected from a conventional rotating anode x-ray source. SMase I folds as an (α/β)₈ barrel, the interfacial and catalytic sites encompass hydrophobic loops and a negatively charged surface. Substrate binding and/or the transition state are stabilized by a Mg²⁺ ion, which is coordinated by Glu³², Asp³⁴, Asp⁹¹, and solvent molecules. In the proposed acid base catalytic mechanism, His¹² and His⁴⁷ play key roles and are supported by a network of hydrogen bonds between Asp³⁴, Asp⁵², Trp²³⁰, Asp²³³, and Asn²⁵².