Serpins and other serine protease inhibitors

In a recent Trends article, Salzet, Vieau and Stefano discuss the concept that serpins have evolved over a long period of time as part of a natural host defence mechanism1xSerpins: an evolutionarily conserved survival strategy. Salzet, M. et al. Immunol. Today. 1999; 20: 541–544Abstract | Full Text | Full Text PDF | PubMed | Scopus (36)See all References1. However, the authors confuse the meaning of the word ‘serpin’ as they mistakenly use it interchangeably with ‘serine protease inhibitor’. Although the original derivation of the word serpin was from serine protease inhibitor, serpins are just one of at least 23 distinct families of naturally occurring protein inhibitors of serine proteases2xWhat can structures of enzyme-inhibitor complexes tell us about the structures of enzyme-substrate complexes?. Laskowski, M. Jr. and Qasim, M.A. Biochim. Biophys. Acta Moll. Cell Res. 2000; 1477: 324–337PubMedSee all References2. Therefore, not all serine protease inhibitors are serpins.Of the serine protease inhibitors discussed only α1-antitrypsin (also called α1-proteinase inhibitor), α1-antichymotrypsin, α2-antiplasmin, antithrombin, C1-inhibitor, protease nexin I, and the Schistosome serpin, belong to the serpin family. As the authors correctly point out serpins have a core domain of about 350 amino acids in which there is much sequence homology between members. The serpins shown in Table 1 in their paper have been studied extensively, in part because their relatively high concentrations in plasma make them amenable to purification in large quantities, and because of the physiological and clinical significance of the proteolytic pathways they regulate. In addition, as is mentioned, some serpins, such as angiotensinogen and thyroxine binding globulin, do not inhibit proteases but have other functions. The properties of these and many other serpins have been reviewed extensively3xSerpins: Structure, function and biology. Gettins, P.G.W. et al. See all References3.The authors mention numerous other serine protease inhibitors, none of which are members of the serpin family. For example, aprotinin (also called bovine pancreatic trypsin inhibitor and Trasylol) and protease nexin II are both members of the Kunitz (BPTI) family. Much focus is given to protease inhibitors from invertebrates, although none of the proteins shown in Tables 3 and 4 are serpins. This is not to say however, that invertebrates do not produce serpins. It is becoming increasingly apparent that serpins play important roles in many invertebrates, such as Drosophila4xConstitutive activation of toll-mediated antifungal defense in serpin-deficient Drosophila. Levashina, E.A. et al. Science. 1999; 285: 1917–1919Crossref | PubMed | Scopus (322)See all References4 and Brugia malayi5xA novel serpin expressed by blood-borne microfilariae of the parasitic nematode Brugia malayi inhibits human neutrophil serine proteinases. Zang, X.X. et al. Blood. 1999; 94: 1418–1428PubMedSee all References5. Serpins are also critical to the life cycle of various pox-viruses. The understanding that viral serpins inhibit apoptosis has been very useful in determining the role played by caspases in this process6xSerpins and regulation of cell death. Bird, P.I. Results Probl. Cell Differ. 1998; 24: 63–89Crossref | PubMedSee all References6. The cowpox virus serpin crmA was found to inhibit interleukin 1-β converting enzyme, which is now called caspase-1. It is possible that mammalian intracellular serpins might also play a role in regulating apoptosis. In mammals the functions being ascribed to serpins are growing beyond their original description as serine protease inhibitors, with immune modulation7xEffects of endometrial serpin-like proteins on immune responses in sheep. Skopets, B. et al. Am. J. Reprod. Immunol. 1995; 33: 86–93Crossref | PubMedSee all References7, tumour suppression8xMaspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Zou, Z.Q. et al. Science. 1994; 263: 526–529Crossref | PubMedSee all References8, and angiogenesis inhibition9xAntiangiogenic activity of the cleaved conformation of the serpin antithrombin. O’Reilly, M.S. et al. Science. 1999; 285: 1926–1928Crossref | PubMed | Scopus (375)See all References9 being examples.Finally, Salzet et al. propose that serpins evolved earlier than had been thought, hence their abundance in invertebrates. Although in this context they are referring to serine protease inhibitors in general, it has already been suggested that the serpin family evolved at least 500 million years ago (see pages 4–10 of Gettins et al.3xSerpins: Structure, function and biology. Gettins, P.G.W. et al. See all References3 for the original references). An analysis of the nucleotide sequence homology between related rodent serpins, revealed that the region of the serpin which directly interacts with the serine proteinase and defines the target protease specificity of the serpin (the reactive centre loop) had diverged more than would be expected. It was suggested that such positive Darwinian evolution, resulted from a need for the serpins to adapt to newly encountered exogenous proteases from infectious agents or parasites10xAccelerated evolution in the reactive centre regions of serine protease inhibitors. Hill, R.E. and Hastie, N.D. Nature. 1987; 326: 96–99Crossref | PubMedSee all References10. One curious footnote to considerations of serpin evolution is that serpins have yet to be found in any bacteria or archaea. This could be indicative of when serpins first evolved or could merely represent that they have yet to be discovered.