Snake Venom Kunitz-type Inhibitors and Cystatins – Structure and Function

Natural inhibitors are ubiquitous components with low or medium molecular masses, existing in a variety of plants, animals and microorganisms. Kunitz-type inhibitors (KTIs) are a group of proteins that bear remarkable homology to bovine pancreatic trypsin inhibitor. Classical features of this protein family include three disulfide bridges and a reactive site (P1 site) that might be responsible for substrate-like inhibition of its cognate enzyme – namely, a protease. Interestingly, adaptive evolution has resulted in extensive functional diversity among these proteins, which includes the highly specialized neurotoxic KTIs that can block voltage-gated K⁺ and Ca²⁺ ion channels but have lost their protease-inhibitory function. The KTIs have demonstrated pharmacological properties that include anti-hemostatic, antitumor and voltage-gated ion channel binding activities. Other relevant protease inhibitors are the cystatins. Two groups within this superfamily have been identified in snake venom – the cystatins and cystatin/fetuins. These molecules act as competitive inhibitors that modulate the biological activity of cysteine proteases involved in proteolytic processes. Collectively, snake venom and snake serum cystatins display a wide range of functions, including cysteine protease and metalloprotease inhibition. Even though the known snake cystatins are limited in number, the ones that have been described demonstrated anti-hemorrhagic and antitumor activities, thus amplifying the understanding of this family structure and function. Overall, snake venom KTIs and cystatin superfamilies are not well known and warrant further investigation. This chapter highlights key details regarding their structure and function and discusses the status quo of biomedical applications for them.