In some classes of the phylum Porifera, sea sponges have an extracellular structure consisting of needle shaped siliceous spicules organized in unique patterns. Enzymes for both the formation and degradation of silica control its organization and patterning, which is the only known enzymatic process of biosilicification. Silicatein, the enzyme that catalyzes the condensation of orthosilicic acid into silica for the formation of spicules, has inspired many mimetic approaches to silicon dioxide formation. Highly homologous to the papain family of proteases, silicatein is capable of hydrolyzing silicon alkoxide precursors in vitro to form silica networks. Here we explore the proteases papain and trypsin, enzymes with similar hydrolytic mechanisms as proposed for silicatein in vitro, as potential biomimics. We investigate these hydrolytic proteins’ reactivity with metal and semi-metal oxide precursors, to determine how these enzymes interact with non-native substrates in the formation of oxide materials. We have determined that while both enzymes are native hydrolytic enzymes, they do not necessarily behave as such with non-native substrates.