Discovery of biosynthetic enzymes for β-D-manno-heptoses across kingdoms: novel agonists for ALPK1/NF-κB-dependent immune response

A recent study by Tang et al. ¹ in Science reveals the cross-kingdom widespread occurrence of functional nucleotide-diphosphate (NDP)-heptose biosynthetic enzymes (HBEs) that accounts for the synthesis of NDP-heptoses to activate the alpha-protein kinase 1 (ALPK1)-dependent innate immune response. This study not only highlights the importance of the metabolite β-D-manno-heptose as pathogen-associated molecular patterns (PAMPs) but also raises the question of possibly other biological roles, especially in the different kingdoms (Fig. 1).

Fig. 1

New findings on NDP-heptoses as agonists for the immune response. Small molecule metabolites such as ADP-heptose are synthesized by HBEs exhibiting isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Of note, three subgroups of HBEs with nucleotidyltransferase activity (HENases) exist, exhibiting solely this activity or combined with kinase, or isomerase/kinase activities. In bacteria, where HBEs were first reported, they catalyzed the four-step biosynthesis of ADP-heptose starting from D-sedoheptulose 7-phosphate. Functional HBEs are prevalent in bacteria, archaea, viruses, and some eukaryotes. The authors discovered the presence of a widely conserved arginine residue at the fifth N-terminal position of the (F/L)XXGXSTT motif (STT_R5) in HENases that enable them to synthesize also CDP- and UDP-heptoses. A striking feature of the NDP-heptoses is their ability to act as immunostimulants. Pathogenic organisms deliver NDP-heptoses into mammalian cells, where they are detected by ALPK1, triggering its kinase activity. The ensuing TIFA phosphorylation initiates a signaling cascade to activate NF-κB, leading to the release of cytokines and chemokines that result in the recruitment of immune cells. In addition, NDP-heptoses could also serve as building blocks for protein glycosylation, or the production of LPS or antibiotics. The figure is created with BioRender.com

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