Innovations in host and microbial sialic acid biosynthesis revealed by phylogenomic prediction of nonulosonic acid structure

Abstract

Sialic acids (Sias) are nonulosonic acid (NulO) sugars prominently displayed on vertebrate cells and occasionally mimicked by bacterial pathogens using homologous biosynthetic pathways. It has been suggested that Sias were an animal innovation and later emerged in pathogens by convergent evolution or horizontal gene transfer. To better illuminate the evolutionary processes underlying the phenomenon of Sia molecular mimicry, we performed phylogenomic analyses of biosynthetic pathways for Sias and related higher sugars derived from 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Examination of Ϸ1,000 sequenced microbial genomes indicated that such biosynthetic pathways are far more widely distributed than previously realized. Phylogenetic analysis, validated by targeted biochemistry, was used to predict NulO types (i.e., neuraminic, legionaminic, or pseudaminic acids) expressed by various organisms. This approach uncovered previously unreported occurrences of Sia pathways in pathogenic and symbiotic bacteria and identified at least one instance in which a human archaeal symbiont tentatively reported to express Sias in fact expressed the related pseudaminic acid structure. Evaluation of targeted phylogenies and protein domain organization revealed that the ''unique'' Sia biosynthetic pathway of animals was instead a much more ancient innovation. Pathway phylogenies suggest that bacterial pathogens may have acquired Sia expression via adaptation of pathways for legionaminic acid biosynthesis, one of at least 3 evolutionary paths for de novo Sia synthesis. Together, these data indicate that some of the long-standing paradigms in Sia biology should be reconsidered in a wider evolutionary context of the extended family of NulO sugars. legionaminic acid ͉ phylogeny ͉ pseudaminic acid ͉ neuraminic acid ͉ biosynthetic pathway

Discovery and characterization ofde novosialic acid biosynthesis in the phylumFusobacterium

“…We provide definitive biochemical proof linking specific gene products with the synthesis of Neu5Ac from ManNAc as well as nucleotide activation of Neu5Ac. Mass spectrometry provided definitive proof that F. nucleatum synthesizes Neu5Ac as opposed to chemically similar di-N-acetylated molecules that are common among microorganisms and have been previously mistaken for Neu5Ac (Samuel et al 2007;Lewis et al 2009). The experiments also demonstrate that F. nucleatum sbsp.…”

“…This is important because many other sialic acid-like molecules (e.g. legionaminic and pseudaminic acids) are also expressed by microorganisms and there are specific examples in the literature where they have been mistaken for Neu5Ac (Samuel et al 2007;Lewis et al 2009). Briefly, sialic acids were released from cultured bacterial cells by mild acid hydrolysis.…”

Structural insights into the regulation of sialic acid catabolism by the Vibrio vulnificus transcriptional repressor NanR

“…Like the nan genes, the genes that encode NeuB and NeuA homologs are found in the V. vulnificus genome (VVMO6_02804 and VVMO6_02799). However, it is still unclear whether V. vulnificus can synthesize Neu5Ac, then activate and incorporate it into cell surface glycoconjugates (47,48), so the potential NeuBA pathway is shown with dotted arrows and a question mark. NanR and DNA are shown as ribbon and surface representations, respectively.…”

Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii , studied in twins

“…For example, all of the M. smithii strains contain the six genes involved in synthesis of pseudaminic acid structures related to sialic acid molecules expressed on host cell surfaces. The resulting surface epitopes are thought to play a role in the adaptation of M. smithii to the gut environment by mimicking the sialic acids that decorate the surfaces of host epithelial cells (46). Adhesin-like proteins (ALPs) are a novel class of proteins with homology to bacterial adhesins that were first identified in the M. smithii type strain.…”