@article {324645,
	title = {Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis.},
	journal = {J Clin Invest},
	volume = {131},
	year = {2021},
	month = {2021 Mar 01},
	abstract = {<p>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.</p>
},
	issn = {1558-8238},
	doi = {10.1172/JCI137681},
	author = {Kawanishi, Kunio and Saha, Sudeshna and Diaz, Sandra and Vaill, Michael and Sasmal, Aniruddha and Siddiqui, Shoib S and Choudhury, Biswa and Sharma, Kumar and Chen, Xi and Schoenhofen, Ian C and Sato, Chihiro and Kitajima, Ken and Freeze, Hudson H and M{\"u}nster-K{\"u}hnel, Anja and Ajit Varki}
}
