{"doi":"10.1172/jci137681","title":"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.","journal":"Journal of Clinical Investigation","year":2020,"id":102846,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":406675,"name":"Sudeshna Saha","orcid":"0000-0002-8195-6981","position":1,"is_corresponding":false},{"id":502279,"name":"Sandra Diaz","orcid":null,"position":2,"is_corresponding":false},{"id":501536,"name":"Michael Vaill","orcid":"0000-0002-4714-9254","position":3,"is_corresponding":false},{"id":501537,"name":"Aniruddha Sasmal","orcid":"0000-0001-5446-8192","position":4,"is_corresponding":false},{"id":501538,"name":"Shoib Sarwar Siddiqui","orcid":"0000-0002-7028-290X","position":5,"is_corresponding":false},{"id":279898,"name":"Biswa Choudhury","orcid":null,"position":6,"is_corresponding":false},{"id":292969,"name":"Kumar Sharma","orcid":"0000-0002-7550-8525","position":7,"is_corresponding":false},{"id":313621,"name":"Xi Chen","orcid":"0000-0002-3160-614X","position":8,"is_corresponding":false},{"id":408017,"name":"Ian C. Schoenhofen","orcid":null,"position":9,"is_corresponding":false},{"id":501539,"name":"Chihiro Sato","orcid":"0009-0002-0426-5674","position":10,"is_corresponding":false},{"id":501540,"name":"Ken Kitajima","orcid":"0000-0002-8541-6798","position":11,"is_corresponding":false},{"id":32931,"name":"Hudson H. Freeze","orcid":"0000-0001-6316-0501","position":12,"is_corresponding":false},{"id":501541,"name":"Anja Münster-Kühnel","orcid":"0000-0003-0991-7627","position":13,"is_corresponding":false},{"id":313878,"name":"Ajit Varki","orcid":"0000-0002-2206-975X","position":14,"is_corresponding":false},{"id":501535,"name":"Kunio Kawanishi","orcid":"0000-0003-3502-3467","position":0,"is_corresponding":true}],"reference_count":103,"raw_metadata":null,"created_at":"2026-07-18T22:41:53.173268Z","pmid":"33373330","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}