BACKGROUND: Histidine biosynthesis is one of the best characterized anabolic 
pathways. There is a large body of genetic and biochemical information 
available, including operon structure, gene expression, and increasingly larger 
sequence databases. For over forty years this pathway has been the subject of 
extensive studies, mainly in Escherichia coli and Salmonella enterica, in both 
of which details of histidine biosynthesis appear to be identical. In these two 
enterobacteria the pathway is unbranched, includes a number of unusual 
reactions, and consists of nine intermediates; his genes are arranged in a 
compact operon (hisGDC [NB]HAF [IE]), with three of them (hisNB, hisD and hisIE) 
coding for bifunctional enzymes. We performed a detailed analysis of his gene 
fusions in available genomes to understand the role of gene fusions in shaping 
this pathway.
RESULTS: The analysis of HisA structures revealed that several gene elongation 
events are at the root of this protein family: internal duplication have been 
identified by structural superposition of the modules composing the TIM-barrel 
protein. Several his gene fusions happened in distinct taxonomic lineages; hisNB 
originated within gamma-proteobacteria and after its appearance it was 
transferred to Campylobacter species (epsilon-proteobacteria) and to some 
Bacteria belonging to the CFB group. The transfer involved the entire his 
operon. The hisIE gene fusion was found in several taxonomic lineages and our 
results suggest that it probably happened several times in distinct lineages. 
Gene fusions involving hisIE and hisD genes (HIS4) and hisH and hisF genes 
(HIS7) took place in the Eukarya domain; the latter has been transferred to some 
delta-proteobacteria.
CONCLUSION: Gene duplication is the most widely known mechanism responsible for 
the origin and evolution of metabolic pathways; however, several other 
mechanisms might concur in the process of pathway assembly and gene fusion 
appeared to be one of the most important and common.