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

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

Research output: Contribution to journalArticlepeer-review

9 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere137681
Number of pages16
JournalJournal of Clinical Investigation
Volume131
Issue number5
Early online date29 Dec 2020
DOIs
Publication statusPublished - 1 Mar 2021

Fingerprint

Dive into the research topics of 'Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis'. Together they form a unique fingerprint.

Cite this