Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis

J Clin Invest. 2021 Mar 1;131(5):e137681. doi: 10.1172/JCI137681.


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.

Keywords: Glycobiology; Metabolism; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / metabolism*
  • N-Acetylneuraminic Acid / biosynthesis*
  • N-Acetylneuraminic Acid / genetics
  • Polysaccharides / biosynthesis*
  • Polysaccharides / genetics


  • Polysaccharides
  • N-Acetylneuraminic Acid