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ResearchIn-Press PreviewMetabolismNephrology Free access | 10.1172/JCI137681

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

Kunio Kawanishi,1 Sudeshna Saha,2 Sandra Diaz,2 Michael Vaill,2 Aniruddha Sasmal,2 Shoib S. Siddiqui,2 Biswa P. Choudhury,3 Kumar Sharma,4 Xi Chen,5 Ian C. Schoenhofen,6 Chihiro Sato,7 Ken Kitajima,7 Hudson H. Freeze,8 Anja Münster-Kühnel,9 and Ajit Varki2

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Kawanishi, K. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Saha, S. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Diaz, S. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Vaill, M. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Sasmal, A. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Siddiqui, S. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Choudhury, B. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Sharma, K. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Chen, X. in: JCI | PubMed | Google Scholar |

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Schoenhofen, I. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Sato, C. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Kitajima, K. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Freeze, H. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Münster-Kühnel, A. in: JCI | PubMed | Google Scholar

1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, United States of America

3Glychotechnology Research and Training Center, University of California San Diego, La Jolla, United States of America

4Department of Medicine, University of California San Diego, La Jolla, United States of America

5Department of Chemistry, University of California-Davis, Davis, United States of America

6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Canada

7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan

8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States of America

9Department of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

Find articles by Varki, A. in: JCI | PubMed | Google Scholar |

Published December 29, 2020 - More info

J Clin Invest. https://doi.org/10.1172/JCI137681.
Copyright © 2020, American Society for Clinical Investigation
Published December 29, 2020 - Version history
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Abstract

Human metabolic incorporation of non-human sialic acid (Sia) N-glycolylneuraminic acid into endogenous glycans generates inflammation via pre-existing antibodies, likely contributing to red-meat-induced atherosclerosis acceleration. Exploring if 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. Levels of Kdn precursor mannose also increased but within normal range in ESRD patients. Mannose ingestion by healthy volunteers raised urinary mannose and Kdn. Kdn production pathways remain conserved in mammals but were diminished by a M42T substitution in a key biosynthetic enzyme, N-acetylneuraminate synthase. Remarkably, reversion to the ancestral methionine then occurred independently in two lineages, including humans. However, mammalian glycan databases contain no Kdn-glycans. We hypothesize that potential toxicities of excess mannose in mammals is partly buffered by conversion to free Kdn. Thus, mammals likely conserved Kdn biosynthesis and modulated it in lineage-specific manner, not for glycosylation, but to control physiological mannose intermediates/metabolites. However, human cells can be forced to express Kdn-glycans, via genetic mutations enhancing Kdn utilization, or by transfection with fish enzymes producing 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.

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