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Essentials    Blood coagulation is driven by vitamin K (VK)‐dependent proteases.  We have identified and characterized ‘sirtilin’ as an additional VK‐dependent protease.  Sirtilins emerged early in the evolution of the coagulation system of vertebrates.  Ubiquitous occurrence might indicate an important functional role of sirtilins.Summary   Background  Vitamin K ( VK )‐dependent proteases are major players in blood coagulation, including both the initiation and the regulation of the cascade. Five different members of this protease family have been described, comprising the following coagulation factors: factor  VII ,  FIX ,  FX , protein C ( PC ), and prothrombin ( FII ).  FVII ,  FIX ,  FX  and  PC  share a typical domain architecture, with an N‐terminal γ‐carboxyglutamate (Gla) domain, two epidermal growth factor‐like ( EGF ) domains, and a C‐terminal trypsin‐like serine protease ( SP ) domain.    Objectives  We have identified uncharacterized proteins in snake genomes showing the typical Gla– EGF 1– EGF 2– SP  domain architecture but relatively low sequence conservation compared to known  VK ‐dependent proteases. On the basis of sequence analysis, we hypothesized that these proteins are functional members of the  VK ‐dependent protease family.    Methods/results  Using phylogenetic analyses, we confirmed the so‐called ‘sirtilins’ as an additional  VK ‐dependent protease class. These proteases were found in several vertebrates, including jawless fish, cartilaginous fish, bony fish, reptiles, birds, and marsupials, but not in other mammals. The recombinant zymogen form of  Thamnophis sirtalis  sirtilin was produced by  in vitro  renaturation, and was activated with human activated  FXI . The activated form of sirtilin proteolytically cleaved peptide and protein substrates, including prothrombin. Mass spectrometry‐based substrate profiling of sirtilin revealed a narrower sequence specificity than those of  FIX  and  FX .    Conclusions  The ubiquitous occurrence of sirtilins in many vertebrate classes might indicate an important functional role. Understanding the detailed functions of sirtilins might contribute to a deeper understanding of the evolution and function of the vertebrate coagulation system.

Sirtilins – the new old members of the vitamin K‐dependent coagulation factor family