TY - JOUR
T1 - Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis
AU - Kawanishi, Kunio
AU - Saha, Sudeshna
AU - Diaz, Sandra
AU - Vaill, Michael
AU - Sasmal, Aniruddha
AU - Siddiqui, Shoib S.
AU - Choudhury, Biswa
AU - Sharma, Kumar
AU - Chen, Xi
AU - Schoenhofen, Ian C.
AU - Sato, Chihiro
AU - Kitajima, Ken
AU - Freeze, Hudson H.
AU - Münster-Kühnel, Anja
AU - Varki, Ajit
N1 - Funding Information:
This work was supported primarily by NIH grant R01GM32373 (to AV) and by the Rocket Fund and NIH grant R01DK99551 (to HHF), as well as by AMED grant 20ae0101069h0005 (to CS) and DFG grant MU 1849/3-1 (to AMK). MV was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences, by the UCSD Genetics Training Program (T32 GM008666), and by a Training Grant in Gastroenterology (DK007202).
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102139011&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102139011&partnerID=8YFLogxK
U2 - 10.1172/JCI137681
DO - 10.1172/JCI137681
M3 - Article
C2 - 33373330
AN - SCOPUS:85102139011
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
M1 - e137681
ER -