The CYTH superfamily of proteins was named after its two founding members, the CyaB adenylyl cyclase from Aeromonas hydrophila, and the human 25-kDa thiamine triphosphatase (ThTPase). Members of this superfamily of proteins exist in all organisms, including bacteria, archaeons, fungi, plants, and animals (except birds), and can be traced back to the last universal common ancestor. Their sequences include several charged residues involved in divalent cation and triphosphate binding. Indeed, all members of the CYTH superfamily that have been characterized act on triphosphorylated substrates and require at least one divalent metal cation for catalysis. In most cases, the enzyme-substrate complex adopts a tunnel-like (β-barrel) conformation. The Nitrosomonas europaea, Escherichia coli and Arabidopsis thaliana CYTH proteins are specific inorganic tripolyphosphatases. We propose that inorganic tripolyphosphate, the simplest triphosphate compound, is the primitive substrate of CYTH proteins, other enzyme activities, such as adenylate cyclase (in A. hydrophila and Yersinia pestis), mRNA triphosphatase (in fungi and protozoans), and ThTPase (in metazoans), being secondary acquisitions. ThTPase activity is not limited to mammals, as sea anemone and zebrafish CYTH proteins are specific ThTPases. The acquisition of this enzyme activity is linked to the presence of a tryptophan involved in the binding of the thiazolium heterocycle of the thiamine molecule. Furthermore, we propose a conserved catalytic mechanism between a bacterial inorganic tripolyphosphatase and metazoan ThTPases, based on a catalytic dyad comprising a lysine and a tyrosine, explaining the alkaline pH optimum of these enzymes.
Keywords: adenylate cyclase; mRNA triphosphatase; thiamine triphosphatase; tripolyphosphatase.
© 2013 FEBS.