%0 Journal Article %J J Clin Invest %D 2021 %T Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis. %A Kawanishi, Kunio %A Saha, Sudeshna %A Diaz, Sandra %A Vaill, Michael %A Sasmal, Aniruddha %A Siddiqui, Shoib S %A Choudhury, Biswa %A Sharma, Kumar %A Chen, Xi %A Schoenhofen, Ian C %A Sato, Chihiro %A Kitajima, Ken %A Freeze, Hudson H %A Münster-Kühnel, Anja %A Ajit Varki %X

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.

%B J Clin Invest %V 131 %8 2021 Mar 01 %G eng %N 5 %1

https://www.ncbi.nlm.nih.gov/pubmed/33373330?dopt=Abstract

%R 10.1172/JCI137681