2. Academic Validation
  3. Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann-Pick Disease Type C

Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann-Pick Disease Type C

  • Int J Mol Sci. 2019 Oct 10;20(20):5018. doi: 10.3390/ijms20205018.
Masamitsu Maekawa 1,  Isamu Jinnoh 2,  Yotaro Matsumoto 3 4,  Aya Narita 5,  Ryuichi Mashima 6,  Hidenori Takahashi 7,  Anna Iwahori 8,  Daisuke Saigusa 9 10,  Kumiko Fujii 11,  Ai Abe 12,  Katsumi Higaki 13,  Shosei Yamauchi 14,  Yuji Ozeki 15,  Kazutaka Shimoda 16,  Yoshihisa Tomioka 17 18,  Torayuki Okuyama 19,  Yoshikatsu Eto 20,  Kousaku Ohno 21,  Peter T Clayton 22,  Hiroaki Yamaguchi 23 24,  Nariyasu Mano 25 26
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. m-maekawa@tohoku.ac.jp.
  • 2 Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8574, Japan. i.jin.1994.s@gmail.com.
  • 3 Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. yotaro.matsumoto.a5@tohoku.ac.jp.
  • 4 Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-Ku, Sendai, Miyagi 980-8578, Japan. yotaro.matsumoto.a5@tohoku.ac.jp.
  • 5 Division of Child Neurology, Tottori University Hospital, 86 Nishi-machi, Yonago, Tottori 683-8503, Japan. aya.luce@nifty.com.
  • 6 Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. mashima-r@ncchd.go.jp.
  • 7 Koichi Tanaka Mass Spectrometry Research Laboratory, Shimadzu Corporation, 1 Nishinokyo-Kuwabaracho Nakagyo-ku, Kyoto 604-8511, Japan. th1128ca@shimadzu.co.jp.
  • 8 Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8574, Japan. anna.iwahori.t8@dc.tohoku.ac.jp.
  • 9 Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. saigusa@tohoku.ac.jp.
  • 10 Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. saigusa@tohoku.ac.jp.
  • 11 Department of Psychiatry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. fujii@dokkyomed.ac.jp.
  • 12 Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8574, Japan. ai.abe.q2@dc.tohoku.ac.jp.
  • 13 Division of Functional Genomics, Research Centre for Bioscience and Technology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan. kh4060@med.tottori-u.ac.jp.
  • 14 Koichi Tanaka Mass Spectrometry Research Laboratory, Shimadzu Corporation, 1 Nishinokyo-Kuwabaracho Nakagyo-ku, Kyoto 604-8511, Japan. shosei-y@shimadzu.co.jp.
  • 15 Department of Psychiatry, Shiga University of Medical Science, Setatsukiwacho, Otsu, Shiga 520-2192 Japan. ozeki@belle.shiga-med.ac.jp.
  • 16 Department of Psychiatry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. shimoda@dokkyomed.ac.jp.
  • 17 Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. yoshihisa.tomioka.a6@tohoku.ac.jp.
  • 18 Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-Ku, Sendai, Miyagi 980-8578, Japan. yoshihisa.tomioka.a6@tohoku.ac.jp.
  • 19 Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. okuyama-t@ncchd.go.jp.
  • 20 Advanced Clinical Research Center, Institute for Neurological Disorders, Furusawa-Miyako 255, Asou-ku, Kawasaki, Kanagawa 215-0026, Japan. yosh@sepia.ocn.ne.jp.
  • 21 Division of Child Neurology, Tottori University Hospital, 86 Nishi-machi, Yonago, Tottori 683-8503, Japan. ohno@sanmedia.or.jp.
  • 22 Inborn Errors of Metabolism, Clinical and Molecular Genetics Unit, UCL Great Ormond Street Institute of Child Health. 30 Guilford Street, University College London, WC1N 1EH London, UK. peter.clayton@ucl.ac.uk.
  • 23 Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. hiroaki.yamaguchi@med.id.yamagata-u.ac.jp.
  • 24 Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8574, Japan. hiroaki.yamaguchi@med.id.yamagata-u.ac.jp.
  • 25 Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. mano@hosp.tohoku.ac.jp.
  • 26 Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8574, Japan. mano@hosp.tohoku.ac.jp.
PMID: 31658747 DOI: 10.3390/ijms20205018
Abstract

Niemann-Pick disease type C (NPC) is an autosomal recessive disorder caused by the mutation of cholesterol-transporting proteins. In addition, early treatment is important for good prognosis of this disease because of the progressive neurodegeneration. However, the diagnosis of this disease is difficult due to a variety of clinical spectrum. Lysosphingomyelin-509, which is one of the most useful biomarkers for NPC, was applied for the rapid and easy detection of NPC. The fact that its chemical structure was unknown until recently implicates the unrevealed pathophysiology and molecular mechanisms of NPC. In this study, we aimed to elucidate the structure of lysosphingomyelin-509 by various mass spectrometric techniques. As our identification strategy, we adopted analytical and organic chemistry approaches to the serum of patients with NPC. Chemical derivatization and hydrogen abstraction dissociation-tandem mass spectrometry were used for the determination of function groups and partial structure, respectively. As a result, we revealed the exact structure of lysosphingomyelin-509 as N-acylated and O-phosphocholine adducted serine. Additionally, we found that a group of metabolites with N-acyl groups were increased considerably in the serum/plasma of patients with NPC as compared to that of Other groups using targeted lipidomics analysis. Our techniques were useful for the identification of lysosphingomyelin-509.

Keywords

HAD–MS/MS; LC–MS/MS; N-acyl-phospholipids; Niemann–Pick disease type C; biomarkers; chemical derivatization; chemical diagnosis; identification; lysosphingomyelin-509; structural determination.

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