University of Hertfordshire

From the same journal

By the same authors


  • Kunio Kawanishi
  • Sudeshna Saha
  • Sandra Diaz
  • Michael Vaill
  • Aniruddha Sasmal
  • Shoib S Siddiqui
  • Biswa P Choudhury
  • Kumar Sharma
  • Xi Chen
  • Ian C Schoenhofen
  • Chihiro Sato
  • Ken Kitajima
  • Hudson H Freeze
  • Anja Münster-Kühnel
  • Ajit Varki
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Original languageEnglish
Article numbere137681
Number of pages16
JournalJournal of Clinical Investigation
Early online date29 Dec 2020
Publication statusPublished - 1 Mar 2021


Human metabolic incorporation of nonhuman sialic acid (Sia) N-glycolylneuraminic acid into endogenous glycans generates inflammation via preexisting antibodies, which likely contributes to red meat-induced atherosclerosis acceleration. Exploring whether this mechanism affects atherosclerosis in end-stage renal disease (ESRD), we instead found serum accumulation of 2-keto-3-deoxy-d-glycero-d-galacto-2-nonulosonic acid (Kdn), a Sia prominently expressed in cold-blooded vertebrates. In patients with ESRD, levels of the Kdn precursor mannose also increased, but within a normal range. Mannose ingestion by healthy volunteers raised the levels of urinary mannose and Kdn. Kdn production pathways remained conserved in mammals but were diminished by an M42T substitution in a key biosynthetic enzyme, N-acetylneuraminate synthase. Remarkably, reversion to the ancestral methionine then occurred independently in 2 lineages, including humans. However, mammalian glycan databases contain no Kdn-glycans. We hypothesize that the potential toxicity of excess mannose in mammals is partly buffered by conversion to free Kdn. Thus, mammals probably conserve Kdn biosynthesis and modulate it in a lineage-specific manner, not for glycosylation, but to control physiological mannose intermediates and metabolites. However, human cells can be forced to express Kdn-glycans via genetic mutations enhancing Kdn utilization, or by transfection with fish enzymes producing cytidine monophosphate-Kdn (CMP-Kdn). Antibodies against Kdn-glycans occur in pooled human immunoglobulins. Pathological conditions that elevate Kdn levels could therefore result in antibody-mediated inflammatory pathologies.


© 2021 American Society for Clinical Investigation. This article has been published in final form at

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