Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis
Kunio Kawanishi, … , Anja Münster-Kühnel, Ajit Varki
Kunio Kawanishi, … , Anja Münster-Kühnel, Ajit Varki
Published December 29, 2020
Citation Information: J Clin Invest. 2021;131(5):e137681. https://doi.org/10.1172/JCI137681.
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Research Article Metabolism Nephrology

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

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.

Authors

Kunio Kawanishi, Sudeshna Saha, Sandra Diaz, Michael Vaill, Aniruddha Sasmal, Shoib S. Siddiqui, Biswa Choudhury, Kumar Sharma, Xi Chen, Ian C. Schoenhofen, Chihiro Sato, Ken Kitajima, Hudson H. Freeze, Anja Münster-Kühnel, Ajit Varki

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Figure 2

DMB-HPLC profiling of serum samples from patients on hemodialysis compared with serum from healthy individuals.

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DMB-HPLC profiling of serum samples from patients on hemodialysis compar...
Serum samples from (A) healthy volunteers (Control) (n = 14) and patients with ESRD on hemodialysis (ESRD) (n = 58) were analyzed by DMB-HPLC. Each dot represents each serum sample. Levels of the serum free (and CMP-) forms of (B) Kdn and (C) Neu5Ac were calculated with DMB-HPLC. (D) Serum mannose levels (normal range, 40–80 μM) were measured by GC-MS. Control (n = 8) versus ESRD (n = 16). Data are shown as the mean (SD). **P < 0.01, by 1-way ANOVA (A) and unpaired t test (B–D).