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• hisF gene product: a single protein, many cellular implications. • HisF TIM-barrel architecture as the result of molecular evolution events. • HisF:HisH complex interconnects different metabolic routes. • HisF role in bacterial filamentation, pathogenesis and nodule formation. Histidine biosynthesis is an ancestral pathway that was assembled before the appearance of the Last Universal Common Ancestor; afterwards, it remained unaltered in all the extant histidine-synthesizing (micro)organisms. It is a metabolic cross-road interconnecting histidine biosynthesis to nitrogen metabolism and the de novo synthesis of purines. This interconnection is due to the reaction catalyzed by the products of hisH and hisF genes. The latter gene is an excellent model to study which trajectories have been followed by primordial cells to build the first metabolic routes, since its evolution is the result of different molecular rearrangement events, i.e. gene duplication, gene fusion, gene elongation, and domain shuffling. Additionally, this review summarizes data concerning the involvement of hisF and its product in other different cellular processes, revealing that HisF very likely plays a role also in cell division control and involvement in virulence and nodule development in different bacteria. From the metabolic viewpoint, these results suggest that HisF plays a central role in cellular metabolism, highlighting the interconnections of different metabolic pathways. [ABSTRACT FROM AUTHOR]