Are hyaluronic acid synthases widely encoded in fungi?

Hyaluronic acid (HA) is a biologically versatile polysaccharide synthesized by vertebrates and several microbial pathogens. To date, Cryptococcus neoformans CPS1p is the only reported bona fide hyaluronic acid synthase (HAS) in fungi, which is functionally related to bacterial HASs. Considering the phylogenetic and biochemical connection between HASs and chitin synthases (CHSs), essential for fungal cell wall synthesis, it is reasonable to hypothesize the former might be more common in fungi than expected. In this work, a comprehensive in silico survey of putative HASs in the Fungal Tree of Life was carried out. 68 putative HASs, mainly in Basidiomycota, were found, although other artificial intelligence-inferred putative HASs were found among Ascomycota. Global fold and arrangement of essential amino acids were shared by all kingdoms' HASs; however, C. neoformas CPS1p and additional putative fungal HASs (fungal HASs) showed exclusive conserved sequence signatures. Moreover, fungal HASs bore an only 3-helices transmembrane pore and their gating loop, which regulates the entrance of substrates to the catalytic site, was directly connected to an also exclusive intrinsically disordered C-terminus. Phylogenetically, fungal HASs were found in a clade different to that of bacterial, animal and viral HASs, and might share a common ancestor with Class I, III or VI CHSs. The atypical features of fungal HASs could influence the size and biological role of the HA they potentially synthesize and also highlight regulatory differences among HASs at the level of the gating loop configuration.