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 Choudhury, Kumar Sharma, Xi Chen, Ian C. Schoenhofen, Chihiro Sato, Ken Kitajima, Hudson H. Freeze, Anja Münster-Kühnel, Ajit Varki
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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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 6

A single aa in Sia 9-phosphate synthase that alters the rate of mannose-to-Kdn conversion is restored independently by convergent evolution in 2 mammalian lineages including humans.

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A single aa in Sia 9-phosphate synthase that alters the rate of mannose-...
Phylogenetic tree topology of vertebrate NANS nt sequences obtained using the maximum likelihood method. The tree was rooted on nonmammalian vertebrates (●) and is not drawn to scale. Human NANS with methionine or leucine at position 42 shows Kdn-9P synthase activity. Species with methionine or leucine at the position aligned to M42 in human NANS are shaded in light blue, and species with threonine (T42) or valine (V42) are shaded in light and dark gray, respectively. Predicted nt encoding the aa at the respective position in the ancestors are given at the nodes. Human NANS is shown in red. Latin species names are italicized and common names are given in uppercase letters. Mammals are further classified in orders and all vertebrates in classes.