Studies on Two Convergently Evolved Cysteate Synthases in Sulfonolipid Biosynthesis

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Capnine-like sulfonolipids are sulfonate-containing analogs of sphingolipids found in many Bacteroidetes bacteria, where they govern essential functions such as gliding motility, outer membrane polysaccharide assembly, and antibiotic susceptibility. In gut-associated anaerobic Bacteroidetes, these sulfonolipids also modulate host–microbe interactions. In aerobic bacteria, the capnine precursor cysteate is produced by a pyridoxal phosphate (PLP)-dependent cysteate synthase (CapA1), a close homologue of cystathionine β-synthase (CBS). By contrast, the mechanism of cysteate production in anaerobic Bacteroidetes bacteria has not been biochemically studied. Herein, we report the characterizations of archaeal cysteate synthase homologue from the anaerobic bacteria Alistipes finegoldii ( Af CapA2). Biochemical assays confirm its ability to catalyze the conversion of O -phosphoserine (OPS) to cysteate. Crystal structures of Af CapA2 in complex with PLP and OPS-PLP identify essential catalytic residues and reveal a structural similarity to threonine synthase, unlike CapA1, which is more similar to CBS. Comparative analysis of CapA1 and this nonorthologous CapA2, including structural differences, catalytic versatility, and phylogenetic distribution across Bacteroidetes, suggests convergent evolution of cysteate synthase activity. Our work clarifies the details of sulfonolipid synthesis in anaerobic bacteria and the biochemical origins of this structurally distinctive lipid in the gut microbiome.

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