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Journal of Medicinal Chemistry Article Author Contributions Functions as a Nitrate Transporter in the Plasma Membrane. Proc. F.A., I.M.-T., B.G., and C.A. designed the research. L.D., N.P., Natl. Acad. Sci. U. S. A. 2012, 109, 13434−13439. A.C., I.F., C.D., P.-A.G., R.F., I.M.-T., and C.A. conducted the (9) Miyaji, T.; Echigo, N.; Hiasa, M.; Senoh, S.; Omote, H.; experiments. All authors analyzed the data. F.A., I.M.-T., B.G., Moriyama, Y. Identification of a Vesicular Aspartate Transporter. Proc. and C.A. wrote the paper. Natl. Acad. Sci. U. S. A. 2008, 105, 11720−11724. Funding (10) Lodder-Gadaczek, J.; Gieselmann, V.; Eckhardt, M. Vesicular Uptake of N-Acetylaspartylglutamate Is Catalysed by Sialin This work was supported by the Agence Nationale de la −38. (SLC17A5). Biochem. J. 2013, 454,31 Recherche (grant no. ANR-15-CE14-0001-02 to B.G.), the (11) Bardor, M.; Nguyen, D. H.; Diaz, S.; Varki, A. Mechanism of Association Nationale de la Recherche et de la Technologie Uptake and Incorporation of the Non-Human Sialic Acid N- ̀ (ANRT) and Dassault Systemes BIOVIA (CIFRE PhD Glycolylneuraminic Acid into Human Cells. J. Biol. Chem. 2005, ̀ 280, 4228−4237. scholarship no. 2018/0027 to A.C.), the Ministere de ́ (12) Chou, H.-H.; Takematsu, H.; Diaz, S.; Iber, J.; Nickerson, E.; l’Enseignement Superieur, de la Recherche et de l’Innovation ̂ ́ Wright, K. L.; Muchmore, E. A.; Nelson, D. L.; Warren, S. T.; Varki, (PhD fellowship to P.-A.G.), the Neuropole Region Ile-de- France (PhD fellowship to L.D.), and the Science Ambassador A. A Mutation in Human CMP-Sialic Acid Hydroxylase Occurred ̀ after the Homo-Pan Divergence. Proc. Natl. Acad. Sci. U. S. A. 1998, Program from Dassault Systemes BIOVIA (to A.C. and F.A.). 95, 11751−11756. Notes (13) Dhar, C.; Sasmal, A.; Varki, A. From “Serum Sickness” to The authors declare no competing financial interest. “Xenosialitis”: Past, Present, and Future Significance of the Non- ACKNOWLEDGMENTS Human Sialic Acid Neu5Gc. Front. Immunol. 2019, 10, 807. ■ (14) Kawanishi, K.; Dhar, C.; Do, R.; Varki, N.; Gordts, P. L. S. M.; ̈ ̈ Varki, A. Human Species-Specific Loss of CMP-N-Acetylneuraminic WethankDr.AijaKyttala from the Finnish Institute for Health Acid Hydroxylase Enhances Atherosclerosis via Intrinsic and Extrinsic and Welfare (THL) for acquiring the ethical permissions in Mechanisms. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 16036−16045. Finland and providing Salla fibroblasts for this study. C.B. ̈ thanks the glycoconjugate analysis facility PAGes (http:// (15) Bull, C.; Heise, T.; Adema, G. J.; Boltje, T. J. Sialic Acid and the FRABio research Mimetics to Target the Sialic Acid-Siglec Axis. Trends Biochem. Sci. federation. 2016, 41, 519−531. ̈ (16) Moons, S. J.; Adema, G. J.; Derks, M. T.; Boltje, T. J.; Bull, C. ABBREVIATIONS Sialic Acid Glycoengineering Using N-Acetylmannosamine and Sialic ■ Acid Analogs. Glycobiology 2019, 29, 433−445. Bz, benzoyl; Bzl, benzyl; Cbz, benzyloxycarbonyl; t-Bu, tert- (17) Aula, P.; Gahl, W. A. Disorders of Free Sialic Acid Storage. In butyl; Boc, tert-butoxycarbonyl; CDI, 1,1′-carbonyldimidazole; The Metabolic Molecular Basis of Inherited Disease; Eighth Edition; DIEA, diethylamine; DMF, dimethylformamide; Fmoc, fluo- Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, ren-9-ylmethoxycarbonyl; HBTU, 2-(1H-benzotriazol-1-yl)- K. W., Vogelstein, B., Eds.; McGraw-Hill: New-York, 2001, pp 5109− 1,1,3,3-tetramethyluronium hexafluorophosphate; MOMCl, 5120. ̈ methoxymethyl chloride; RT, room temperature; TFA, (18) Aula, N.; Salomaki, P.; Timonen, R.; Verheijen, F.; Mancini, G.; ̊ trifluoroacetic acid; THF, tetrahydrofuran; TMSCl, trimethyl- Mansson, J.-E.; Aula, P.; Peltonen, L. The Spectrum of SLC17A5- silyl chloride; Trt, trityl Gene Mutations Resulting in Free Sialic Acid−Storage Diseases Indicates Some Genotype-Phenotype Correlation. Am. J. Hum. Genet. REFERENCES 2000, 67, 832−840. ■ (19) Renlund, M.; Tietze, F.; Gahl, W. A. Defective Sialic Acid (1) Reimer, R. J. SLC17: A Functionally Diverse Family of Organic Egress from Isolated Fibroblast Lysosomes of Patients with Salla Anion Transporters. Mol. Aspects Med. 2013, 34, 350−359. Disease. Science 1986, 232, 759−762. (2) Iharada, M.; Miyaji, T.; Fujimoto, T.; Hiasa, M.; Anzai, N.; (20) Varho, T. T.; Alajoki, L. E.; Posti, K. M.; Korhonen, T. T.; Omote, H.; Moriyama, Y. Type 1 Sodium-Dependent Phosphate ̈̈ Renlund, M. G.; Nyman, S. R. G.; Sillanpaa, M. L.; Aula, P. P. Transporter (SLC17A1 Protein) Is a Cl–Dependent Urate Exporter. Phenotypic Spectrum of Salla Disease, a Free Sialic Acid Storage J. Biol. Chem. 2010, 285, 26107−26113. Disorder. Pediatr. Neurol. 2002, 26, 267−273. (3) Blakely, R. D.; Edwards, R. H. Vesicular and Plasma Membrane ̈ (21) Zielonka, M.; Garbade, S. F.; Kolker, S.; Hoffmann, G. F.; Ries, Transporters for Neurotransmitters. Cold Spring Harbor Perspect. Biol. M. A Cross-Sectional Quantitative Analysis of the Natural History of 2012, 4, a005595. Free Sialic Acid Storage Diseasean Ultra-Orphan Multisystemic (4) Sawada, K.; Echigo, N.; Juge, N.; Miyaji, T.; Otsuka, M.; Omote, Lysosomal Storage Disorder. Genet. Med. 2019, 21, 347−352. H.; Yamamoto, A.; Moriyama, Y. Identification of a Vesicular ̈ ̈ ̈ Nucleotide Transporter. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, (22) Sonninen, P.; Autti, T.; Varho, T.; Hamalainen, M.; Raininko, 5683−5686. R. Brain Involvement in Salla Disease. Am. J. Neuroradiol. 1999, 20, (5) Verheijen, F. W.; Verbeek, E.; Aula, N.; Beerens, C. E. M. T.; 433−443. Havelaar, A. C.; Joosse, M.; Peltonen, L.; Aula, P.; Galjaard, H.; Van (23) Prolo, L. M.; Vogel, H.; Reimer, R. J. The Lysosomal Sialic Der Spek, P. J.; Mancini, G. M. S. A New Gene , Encoding an Anion Acid Transporter Sialin Is Required for Normal CNS Myelination. J. Transporter , Is Mutated in Sialic Acid Storage Diseases. Nat. Genet. Neurosci. 2009, 29, 15355−15365. 1999, 23, 462−465. (24) Stroobants, S.; Van Acker, N. G. G.; Verheijen, F. W.; Goris, I.; ̀ Daneels, G. F. T.; Schot, R.; Verbeek, E.; Knaapen, M. W. M.; De (6) Morin, P.; Sagne, C.; Gasnier, B. Functional Characterization of ̈ Wild-Type and Mutant Human Sialin. EMBO J. 2004, 23, 4560− Bondt, A.; Gohlmann, H. W.; Crauwels, M. L. A.; Mancini, G. M. S.; 4570. Andries, L. J.; Moechars, D. W. E.; D’Hooge, R. Progressive (7) Wreden, C. C.; Wlizla, M.; Reimer, R. J. Varied Mechanisms Leukoencephalopathy Impairs Neurobehavioral Development in Underlie the Free Sialic Acid Storage Disorders. J. Biol. Chem. 2005, Sialin-Deficient Mice. Exp. Neurol. 2017, 291, 106−119. 280, 1408−1416. (25) Morland, C.; Nordengen, K.; Larsson, M.; Prolo, L. 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Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin - Page 17 Amino Acids Bearing Aromatic or Heteroaromatic Substituents as a New Class of Ligands for the Lysosomal Sialic Acid Transporter Sialin Page 16 Page 18