The origin and evolution of eucaryal HIS7 genes: from metabolon to bifunctional proteins?

The fifth step of histidine biosynthesis is catalysed by an imidazole glycerol-phosphate (IGP) synthase. In Archaea and Bacteria, the active form of IGP synthase is a stable 1:1 dimeric complex constituted by a glutamine amidotransferase (GAT) and a cyclase, the products of hisH and hisF. In Eucarya, the two activities are associated with a single bifunctional polypeptide encoded by HIS7. In this work, we report a comparative analysis of the amino acid sequence of all the available HisH, HisF and HIS7 proteins, which allowed depicting a likely evolutionary pathway leading to the present-day bifunctional HIS7 genes. According to the model that we propose, the bifunctional HIS7 gene is the outcome of a gene fusion event between two independent ancestral cistrons encoding an amidotransferase and a cyclase, respectively. The phylogenetic distribution of the eucaryal HIS7 genes and the analysis of all the available prokaryotic counterparts (hisH and hisF) revealed the absence of such fusions in prokaryotes, suggesting that the fusion event very likely occurred in an early stage of eucaryal evolution and was fixed in the nucleated cells. The biological significance of this gene fusion is also discussed.