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

Bibliographic Collection: 
CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Kawanishi, Kunio; Saha, Sudeshna; Diaz, Sandra; Vaill, Michael; Sasmal, Aniruddha; Siddiqui, Shoib S; Choudhury, Biswa; Sharma, Kumar; Chen, Xi; Schoenhofen, Ian C; Sato, Chihiro; Kitajima, Ken; Freeze, Hudson H; Münster-Kühnel, Anja; Ajit Varki
Year of Publication: 2021
Journal: J Clin Invest
Volume: 131
Issue: 5
Date Published: 2021 Mar 01
Publication Language: eng
ISSN: 1558-8238

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.

DOI: 10.1172/JCI137681
Alternate Journal: J Clin Invest