DOCSLIB.ORG

Enzyme Loss During Evolution Linked to Atherosclerosis Predisposition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Enzyme Loss During Evolution Linked to Atherosclerosis Predisposition RESEARCH HIGHLIGHTS ATHEROSCLEROSIS Enzyme loss during evolution linked to atherosclerosis predisposition Conway/ Carl Credit: Limited Nature Springer Cardiovascular events associated Nissi Varki, Ajit Varki and colleagues which by interaction with circulating with atherosclerosis, such as now show that the loss of CMAH anti- Neu5Gc antibodies potentiates myocardial infarction and stroke, might also predispose to chronic inflammation (termed are the most common cause of death atherosclerosis. xeno sialitis). Cmah–/–Ldlr–/– mice worldwide in humans. However, The researchers found that immunized with Neu5Gc antigens (to these events are rare in other animals, Ldlr–/– mice with CMAH deficiency induce the generation of human-like even in closely related species, such as that were fed a sialic-acid-free, anti-Neu5Gc antibodies) had a ~2.4- chimpanzees, despite having some of high- fat diet (HFD) had a ~1.9-fold fold increase in atherosclerosis when the same risk factors. Environmental increase in atherosclerosis compared fed a Neu5Gc-rich HFD compared and behavioural factors probably with Ldlr–/– mice with CMAH. The with a Neu5Ac-rich diet or a sialic- contribute to these differences. A new increased risk seemed to be driven by acid-free HFD. Blood lipoprotein and study shows that the loss of a single higher levels of macrophage-derived glucose profiles were unchanged. enzyme in humans during evolution cytokines and hyperglycaemia, given In summary, evolutionary loss of might be another contributing factor. loss of CMAH that triglyceride, cholesterol and CMAH and Neu5Gc in humans might Humans have a species-specific also explains lipoprotein levels did not change. be a contributor to atherosclerosis susceptibility via intrinsic and extrinsic deficiency of the sialic acid the increased Interestingly, loss of CMAH N- glycolylneuraminic acid (Neu5Gc) also explains the increased risk of (that is, consumption of Neu5Gc, caused by the loss of a functional risk of cardio- cardiovascular disease associated with primarily from red meat) mechanisms. form of cytidine monophosphate- vascular disease red meat consumption in humans, Irene Fernández- Ruiz N-acetylneuraminic acid hydroxylase associated which does not seem to occur in (CMAH). This loss occurred in other carnivorous animals. Neu5Gc ORIGINAL ArtiCLE Kawanishi, K. et al. Human with red meat species- specific loss of CMP-N -acetylneuraminic hominin ancestors 2–3 million years is present in red meat and can act acid hydroxylase enhances atherosclerosis via ago, an adaptation possibly linked to a consumption as a ‘xeno- autoantigen’ in humans intrinsic and extrinsic mechanisms. Proc. Natl malaria parasite that used Neu5Gc to via metabolic incorporation into Acad. Sci. https://doi.org/10.1073/pnas.1902902116 (2019) invade cells. However, Philip Gordts, cellular glycoproteins and glycolipids, CARDIAC REGENERATION Distinct regulatory pathways are involved in coronary vessel growth Credit: V. Summ ersby /Sp rin Three independent regulatory gene expression to endothelial cells g e r pathways involved in the development of coronary vessels, Nicola Smart, N a t u of the coronary vasculature are Sarah De Val and colleagues identified r e L i activated in the hearts of embryos three distinct signalling cascades m i t e and neonatal mice after myocardial implicated in coronary vessel growth. Importantly, after MI, all d infarction (MI) but repressed in First, sustained expression of three pathways were activated in adult mice. “[This finding] strongly the homeobox protein HLX3:lacZ neonatal mouse hearts, which have indicates a fundamental divergence transgene, which is activated by regenerative potential, but repressed between the regulatory pathways vascular endothelial growth factor A in the injured hearts of adult mice. intrinsically employed in the healthy (VEGFA)–myocyte- specific enhancer “These findings were unexpected and and injured adult heart,” summarize factor 2 (MEF2) signalling in endothelial highly relevant given that the VEGFA the researchers. cells, was detected in both neonatal pathway has been the main pathway The generation of new coronary and adult endocardial- derived targeted in preclinical and clinical vessels after MI can attenuate ischaemic coronary vessels, confirming the role the mecha- studies,” comments Smart. injury and cardiac dysfunction, but the of this pathway in coronary vessel nisms under- To conclude, these results indicate mechanisms underlying vessel growth formation. Development of sinus that distinct pathways are involved in the ischaemic heart are not well venosus (SV)-derived coronary arteries lying vessel in neovascular growth during understood. The cellular processes required activation of the SOXF/RBPJ growth in the developmental coronary vessel involved in coronary vessel formation transcriptional programme. Finally, ischaemic heart formation and ischaemic injury. the bone morphogenetic protein Karina Huynh in the embryonic heart are well are not well characterized, but whether these (BMP)–mothers against decapenta- ORIGINAL ArtiCLE Payne, S. et al. Regulatory pathways can be reactivated in the plegic homologue (SMAD) pathway understood pathways governing murine coronary vessel adult heart is unclear. By analysing was found to be active in SV- derived formation are dysregulated in the injured adult heart. Nat. Commun. 10, 3276 (2019) numerous gene enhancers that drive coronary veins. 580 | OCTOBER 2019 | VOLUME 16 www.nature.com/nrcardio.
Load more

Recommended publications
  • The Effects of Modified Sialic Acids on Mucus and Erythrocytes on Influenza a Virus HA
    bioRxiv preprint doi: https://doi.org/10.1101/800300; this version posted October 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The effects of modified sialic acids on mucus and erythrocytes on influenza A virus HA and NA functions. Karen N. Barnard1, Brynn K. Alford-Lawrence1, David W. Buchholz2, Brian R. Wasik1, Justin R. LaClair1, Hai Yu6, Rebekah Honce4, 5, Stefan Ruhl3, Petar Pajic3, Erin K. Daugherity8, Xi Chen6, 5 Stacey L. Schultz-Cherry4, Hector C. Aguilar2, Ajit Varki7, Colin R. Parrish1* 1) Baker Institute for Animal Health, Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853 2) Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell 10 University, Ithaca, NY 14853 3) Department of Oral Biology, University at Buffalo, Buffalo, NY 14214 4) Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105 5) Department of Microbiology, Immunology, and Biochemistry, University of Tennessee 15 Health Science Center, Memphis, TN 38163 6) Department of Chemistry, University of California-Davis, One Shields Avenue, Davis, CA 95616 7) Glycobiology Research and Training Center, University of California, San Diego, CA 92093 8) Center for Animal Resources and Education, Cornell University, Ithaca, NY 14853 20 *Corresponding Author: [email protected], 607-256-5610. Running Title: Modified sialic acids and influenza A virus. 1 bioRxiv preprint doi: https://doi.org/10.1101/800300; this version posted October 10, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • 1 Human-Like NSG Mouse Glycoproteins Sialylation Pattern Changes the Phenotype of Human
    bioRxiv preprint doi: https://doi.org/10.1101/404905; this version posted August 31, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 1 Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human 2 lymphocytes and sensitivity to HIV-1 infection 3 4 Authors: 5 Raghubendra Singh Dagur1†, Amanda Branch Woods1†, Saumi Mathews1†, Poonam S. Joshi2†, 6 Rolen M. Quadros2, Donald W. Harms2, Yan Cheng1, Shana M Miles3, Samuel J. Pirruccello4, 7 Channabasavaiah B. Gurumurthy2,5, Santhi Gorantla1, Larisa Y. Poluektova1* 8 9 †Contributed equally 10 11 1Department of Pharmacology and Experimental Neuroscience 12 2Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office 13 3Bellevue Medical Center 14 4Department of Pathology and Microbiology 15 5Developmental Neuroscience, Munroe Meyer Institute for Genetics and Rehabilitation, of 16 University of Nebraska Medical Center, Omaha, Nebraska 17 18 E-mail addresses: 19 Raghubendra S Dagur ([email protected]) 20 Amanda Branch Woods ([email protected]) 21 Saumi Mathews ([email protected]) 22 Poonam S Joshi ([email protected]) 23 Rolen M Quadros ([email protected]) 24 Donald W Harms ([email protected]) bioRxiv preprint doi: https://doi.org/10.1101/404905; this version posted August 31, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 2 25 Yan Cheng ([email protected]) 26 Shana M Miles ([email protected]) 27 Samuel J.
    [Show full text]
  • The Origin of Malignant Malaria
    The origin of malignant malaria Stephen M. Richa,1, Fabian H. Leendertzb, Guang Xua, Matthew LeBretonc, Cyrille F. Djokoc,d, Makoah N. Aminaked, Eric E. Takangc, Joseph L. D. Diffoc, Brian L. Pikec, Benjamin M. Rosenthale, Pierre Formentyf, Christophe Boeschg, Francisco J. Ayalah,1, and Nathan D. Wolfec,i,1 aLaboratory of Medical Zoology, Division of Entomology (PSIS), University of Massachusetts, Amherst, MA 01003; bDepartment Emerging Zoonoses, Robert Koch Institute, Nordufer 20, D-13353 Berlin, Germany; cGlobal Viral Forecasting Initiative, San Francisco, CA 94104; dBiotechnology Centre, University of Yaounde I, Yaounde, Cameroon; eAnimal Parasitic Diseases Laboratory, Agricultural Research Service, US Department of Agriculture, Beltsville, MD 20705; fEbola Taï Forest Project, World Health Organization (WHO), WHO Office in Abidjan, Coˆte d’Ivoire; gDepartment of Primatology, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany; hDepartment of Ecology and Evolutionary Biology, University of California, Irvine, CA, 92697; and iProgram in Human Biology, Stanford University, Stanford, CA 94305 Contributed by Francisco J. Ayala, July 13, 2009 (sent for review June 29, 2009) Plasmodium falciparum, the causative agent of malignant malaria, parasites, which appear to have originated in Old World mon- is among the most severe human infectious diseases. The closest keys (4, 5). The close phylogenetic relationship between P. known relative of P. falciparum is a chimpanzee parasite, Plasmo- falciparum and P. reichenowi, their distinctness from the other dium reichenowi, of which one single isolate was previously human malaria parasites, and their remoteness from bird or known. The co-speciation hypothesis suggests that both parasites lizard parasites was soon confirmed by other studies (6–8).
    [Show full text]
  • Human-Like NSG Mouse Glycoproteins Sialylation Pattern Changes The
    Dagur et al. BMC Immunology (2019) 20:2 https://doi.org/10.1186/s12865-018-0279-3 RESEARCHARTICLE Open Access Human-like NSG mouse glycoproteins sialylation pattern changes the phenotype of human lymphocytes and sensitivity to HIV-1 infection Raghubendra Singh Dagur1†, Amanda Branch-Woods1†, Saumi Mathews1†, Poonam S. Joshi2†, Rolen M. Quadros2, Donald W. Harms2, Yan Cheng1, Shana M. Miles3, Samuel J. Pirruccello4, Channabasavaiah B. Gurumurthy2,5, Santhi Gorantla1 and Larisa Y. Poluektova1* Abstract Background: The use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases such as HIV-1 and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes in the mouse glycoproteins’ chemistry affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection are not known. −/− Results: We mutated mouse CMAH in the NOD/scid-IL2Rγc (NSG) mouse strain, which is widely used for the transplantation of human cells, using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed no effect on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8.
    [Show full text]
  • Loss of CMAH During Human Evolution Primed the Monocyte–Macrophage Lineage Toward a More Inflammatory and Phagocytic State
    Published February 1, 2017, doi:10.4049/jimmunol.1601471 The Journal of Immunology Loss of CMAH during Human Evolution Primed the Monocyte–Macrophage Lineage toward a More Inflammatory and Phagocytic State ,†,‡ ,†,‡ , ,‖ Jonathan J. Okerblom,* Flavio Schwarz,* Josh Olson,x { William Fletes,* , , #, ,†† ,†,‡ , , Syed Raza Ali,* x { Paul T. Martin, ** Christopher K. Glass,* Victor Nizet,* x { and Ajit Varki*,†,‡ Humans and chimpanzees are more sensitive to endotoxin than are mice or monkeys, but any underlying differences in inflammatory physiology have not been fully described or understood. We studied innate immune responses in Cmah2/2 mice, emulating human loss of the gene encoding production of Neu5Gc, a major cell surface sialic acid. CMP–N-acetylneuraminic acid hydroxylase (CMAH) loss occurred ∼2–3 million years ago, after the common ancestor of humans and chimpanzees, perhaps contributing to speciation of the Downloaded from genus Homo. Cmah2/2 mice manifested a decreased survival in endotoxemia following bacterial LPS injection. Macrophages from Cmah2/2 mice secreted more inflammatory cytokines with LPS stimulation and showed more phagocytic activity. Macrophages and whole blood from Cmah2/2 mice also killed bacteria more effectively. Metabolic reintroduction of Neu5Gc into Cmah2/2 macrophages suppressed these differences. Cmah2/2 mice also showed enhanced bacterial clearance during sublethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killed Escherichia coli and ingested E. coli BioParticles better. Metabolic reintroduction of http://www.jimmunol.org/ Neu5Gc into human macrophages suppressed these differences. Although multiple mechanisms are likely involved, one cause is altered expression of C/EBPb, a transcription factor affecting macrophage function.
    [Show full text]
  • Microrna Dysregulation in Liver and Pancreas of CMP-Neu5ac Hydroxylase Null Mice Disrupts Insulin/PI3K-AKT Signaling
    Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 236385, 12 pages http://dx.doi.org/10.1155/2014/236385 Research Article MicroRNA Dysregulation in Liver and Pancreas of CMP-Neu5Ac Hydroxylase Null Mice Disrupts Insulin/PI3K-AKT Signaling Deug-Nam Kwon,1 Byung-Soo Chang,2 and Jin-Hoi Kim1 1 Department of Animal Biotechnology, Konkuk University, Hwayang-dong, Kwangjin-gu, Seoul 143-701, Republic of Korea 2 Department of Cosmetology, Hanseo University, Seosan, Chungnam 356-706, Republic of Korea Correspondence should be addressed to Jin-Hoi Kim; [email protected] Received 16 April 2014; Revised 2 June 2014; Accepted 18 July 2014; Published 28 August 2014 AcademicEditor:X.Li Copyright © 2014 Deug-Nam Kwon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. CMP-Neu5Ac hydroxylase (Cmah)-null mice fed with a high-fat diet develop fasting hyperglycemia, glucose intolerance, and pancreatic -cell dysfunction and ultimately develop characteristics of type 2 diabetes. The precise metabolic role of the Cmah gene remains poorly understood. This study was designed to investigate the molecular mechanisms through which microRNAs (miRNAs) regulate type 2 diabetes. Expression profiles of miRNAs in Cmah-null mouse livers were compared to those of control mouse livers. Liver miFinder miRNA PCR arrays (=6) showed that eight miRNA genes were differentially expressed between the two groups. Compared with controls, seven miRNAs were upregulated and one miRNA was downregulated in Cmah-null mice. Specifically, miR-155-5p, miR-425-5p, miR-15a-5p, miR-503-5p, miR-16-5p, miR-29a-3p, and miR-29b-3p were significantly upregulated in the liver and pancreas of Cmah-null mice.
    [Show full text]
  • One-Step Generation of Multiple Gene-Edited Pigs by Electroporation of the CRISPR/Cas9 System Into Zygotes to Reduce Xenoantigen Biosynthesis
    International Journal of Molecular Sciences Article One-Step Generation of Multiple Gene-Edited Pigs by Electroporation of the CRISPR/Cas9 System into Zygotes to Reduce Xenoantigen Biosynthesis Fuminori Tanihara 1, Maki Hirata 1, Nhien Thi Nguyen 1, Osamu Sawamoto 2, Takeshi Kikuchi 2 and Takeshige Otoi 1,* 1 Faculty of Bioscience and Bioindustry, Tokushima University, 2272-1 Ishii, Myozai-gun, Tokushima 779-3233, Japan; [email protected] (F.T.); [email protected] (M.H.); [email protected] (N.T.N.) 2 Research and Development Center, Otsuka Pharmaceutical Factory, Inc., 115 Muya-cho, Naruto, Tokushima 772-8601, Japan; [email protected] (O.S.); [email protected] (T.K.) * Correspondence: [email protected]; Tel.: +81-88-635-0963 Abstract: Xenoantigens cause hyperacute rejection and limit the success of interspecific xenografts. Therefore, genes involved in xenoantigen biosynthesis, such as GGTA1, CMAH, and B4GALNT2, are key targets to improve the outcomes of xenotransplantation. In this study, we introduced a CRISPR/Cas9 system simultaneously targeting GGTA1, CMAH, and B4GALNT2 into in vitro- fertilized zygotes using electroporation for the one-step generation of multiple gene-edited pigs without xenoantigens. First, we optimized the combination of guide RNAs (gRNAs) targeting GGTA1 and CMAH with respect to gene editing efficiency in zygotes, and transferred electroporated embryos Citation: Tanihara, F.; Hirata, M.; with the optimized gRNAs and Cas9 into recipient gilts. Next, we optimized the Cas9 protein concen- Nguyen, N.T.; Sawamoto, O.; Kikuchi, tration with respect to the gene editing efficiency when GGTA1, CMAH, and B4GALNT2 were targeted T.; Otoi, T.
    [Show full text]
  • Sexual Selection by Female Immunity Against Paternal Antigens Can Fix
    Sexual selection by female immunity against paternal antigens can fix loss of function alleles Darius Ghaderia,1, Stevan A. Springerb,1, Fang Maa,1, Miriam Cohena, Patrick Secresta, Rachel E. Taylora, Ajit Varkia, and Pascal Gagneuxa,2 aCenter for Academic Research and Training in Anthropogeny, Glycobiology Research and Training Center and Departments of Medicine and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093; and bDepartment of Biology, University of Washington, Seattle, WA 98195 Edited by Michael Lynch, Indiana University, Bloomington, IN, and approved September 13, 2011 (received for review February 9, 2011) Humans lack the common mammalian cell surface molecule N-gly- ment involved in the mutation yielded an age of >2.5 million years colylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, (9). Subsequent analyses of genomic DNA from 40 global pop- which occurred approximately three million years ago. Modern ulations estimated that the CMAH(−) mutation occurred 3.2 Mya humans produce antibodies specific for Neu5Gc. We hypothesized and was fixed as far back as 2.9 Mya (10). The relatively short time < CMAH − that anti-Neu5Gc antibodies could enter the female reproductive span of 0.3 My between the origin of the ( ) mutation and fi tract and target Neu5Gc-positive sperm or fetal tissues, reducing its xation was interpreted as evidence of strong selection favoring CMAH − reproductive compatibility. Indeed, female mice with a human-like the ( ) allele. However, it is to yet to be determined what Cmah − − form of selection could have driven this rapid fixation. CMAH ( / ) mutation and immunized to express anti-Neu5Gc anti- − − bodies show lower fertility with Neu5Gc-positive males, due to ( / ) individuals lacking Neu5Gc might have experienced an initial selective advantage by avoiding pathogens targeting host prezygotic incompatibilities.
    [Show full text]
  • Live Fetal Stem Cells Therapy, Anti-Neu5gc Responses and Impact on Human Heart, Brain and Immune System
    ell Rese C a m rc te h S & f T o h l e a r n r a Journal of Stem Cell Research & p u y o J ISSN: 2157-7633 Therapy Review Article Live Fetal Stem Cells Therapy, Anti-Neu5Gc Responses and Impact on Human Heart, Brain and Immune System Balbir Bhogal1,2*, Daniel Royal2, Robert Boer 2, Ann Knight 1 1Stem Cell Applied Technologies, Eastern Ave, Las Vegas, NV; 2THB Clinics, 2121 E Flamingo Rd, Suite 112, Las Vegas, NV; ABSTRACT Fetal stem cells used for clinical applications in humans can cause xenogenic immune reactions and impact vital organs by immune dysregulation. Animal stem/fetal cells express glycan antigens, such as Neu5Gc. Humans do not produce these antigens. Two major sialic acids are described in mammalian cells, Neu5Gc, the N-glycolylneuraminic acid, and Neu5Ac the N-acetylneuraminic acid. Neu5Gc synthesis starts from the N-acetylneuraminic acid (Neu5Ac) precursor modified by a hydroxylic group addition catalyzed by cytidinemonophospho-N-acetyl-neuraminic acid hydroxylase-Neu5Ac hydroxylase enzyme (CMAH). CMAH was inactivated by a 92 base pairs deletion over 2 million years ago and is non-functional in humans, Neu5Gc as well as the peptides derived from fetal cells is remarkably immunogenic for humans and promotes inflammation, arthritis, cancer. Accumulating evidence shows that xeno- transplantation of animal stem cells results in inflammation autoimmune responses and immune-rejection and may cause death. Here we highlight the serious deleterious effects of the presence of Neu5Gc antigen in animal fetal cells and the effects of presence and absence of Neu5Gc antibodies in humans acquired through the consumption of animal products.
    [Show full text]
  • Hydroxylase-Deficient Mice of September 28, 2021
    Immunological Property of Antibodies against N-Glycolylneuraminic Acid Epitopes in Cytidine Monophospho −N -Acetylneuraminic Acid This information is current as Hydroxylase-Deficient Mice of September 28, 2021. Hiroyuki Tahara, Kentaro Ide, Nabin Bahadur Basnet, Yuka Tanaka, Haruo Matsuda, Hiromu Takematsu, Yasunori Kozutsumi and Hideki Ohdan J Immunol 2010; 184:3269-3275; Prepublished online 19 Downloaded from February 2010; doi: 10.4049/jimmunol.0902857 http://www.jimmunol.org/content/184/6/3269 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2010/02/15/jimmunol.090285 Material 7.DC1 References This article cites 43 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/184/6/3269.full#ref-list-1 by guest on September 28, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association
    [Show full text]
  • Evolutionary Conservation of Human Ketodeoxynonulosonic Acid Production Is Independent of Sialoglycan Biosynthesis
    The Journal of Clinical Investigation RESEARCH ARTICLE Evolutionary conservation of human ketodeoxynonulosonic acid production is independent of sialoglycan biosynthesis Kunio Kawanishi,1,2 Sudeshna Saha,1,2 Sandra Diaz,1,2 Michael Vaill,1,2,3 Aniruddha Sasmal,1,2 Shoib S. Siddiqui,1,2 Biswa Choudhury,1 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 Varki1,2,3,10 1Glycobiology Research and Training Center, 2Department of Cellular and Molecular Medicine, and 3Center for Academic Research and Training in Anthropogeny, University of California, San Diego (UCSD), La Jolla, California, USA. 4Center for Renal Precision Medicine, Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, Texas, USA. 5Department of Chemistry, University of California, Davis (UCD), Davis, California, USA. 6Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, Ontario, Canada. 7Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan. 8Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA. 9Clinical Biochemistry, Hannover Medical School, Hannover, Germany. 10Department of Medicine, UCSD, La Jolla, California, USA. 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.
    [Show full text]
  • Improving Product Safety Profiles: Host Cell Lines Deficient in CMP-N-Acetylneuraminic Acid Hydroxylase (CMAH) and Alpha-1-3-Galactosyltransferase (GGTA1)
    Improving Product Safety Profiles: Host Cell Lines Deficient in CMP-N-Acetylneuraminic Acid Hydroxylase (CMAH) and Alpha-1-3-Galactosyltransferase (GGTA1) Mascarenhas, J., Achtien, K., Richardson, S., Sealover, N., Kaiser, J., Borgschulte, T., George, H., Kayser, K. and Lin, N Cell Sciences and Development, SAFC Sigma Aldrich2909 Laclede Avenue, Saint Louis, MO 63103, USA Introduction Results and Discussion Genetic Disruption of Cmah and GGTA1 Using ZFNs Post-translational modifications have been shown to affect the bioactivity, clearance rates, immunogenicity and safety Analytical Detection of α-Gal and Neu5Gc profiles of therapeutic glycoproteins. For example anti- N-glycolylneuraminic acid (Neu5Gc or NGNA) antibodies in Workflow of Cmah GGTA1 Double KO Figure 2 Figure 3 humans can interact with Neu5Gc sialylated therapeutic proteins (for example: Cetuximab) produced in non-human Figure 10 CHO K1 NS0 DN20 GS -/- parental cell line 1 Biallelic Cmah KO clone mammalian expression systems causing clinical complications. This is because of an inactivating mutation in humans mAb1 and Fc fusion samples of the gene cytidine monophosphate-N-acetylneuraminic acid hydroxylase (Cmah), an enzyme responsible for Neu5Gc Cmah ZFN RNA transfection GGTA1 ZFN RNA transfection biosynthesis from the N-acetylneuraminic acid (Neu5Ac or NANA) form of sialic acid. Cmah is expressed in CHO cells N-linked glycans cleaved using and the Neu5Gc glycan moiety has been detected on several biologics produced in CHO. Another example of an SSC PNGase F after Trypsin cleavage immunogenic modification on N-glycans is the addition of a terminal galactose-α-1-3 galactose moiety (or α-Gal) mediated Single Cell Cloned and screened by the α-1,3 galactosyltransferase (GGTA1) gene.
    [Show full text]