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

International Journal of Molecular Sciences

Yoshikatsu Eto¹  Torayuki Okuyama²  Ryuichi Mashima²  Daisuke Saigusa³  Yotaro Matsumoto³  Masamitsu Maekawa³  Nariyasu Mano³  Yoshihisa Tomioka³  Hiroaki Yamaguchi³  Kumiko Fujii⁴  Kazutaka Shimoda⁴  Yuji Ozeki⁵  Kousaku Ohno⁶  Aya Narita⁶  Katsumi Higaki⁷  Peter T Clayton⁸  Hidenori Takahashi⁹  Shosei Yamauchi⁹  Ai Abe^1,10  Anna Iwahori^1,10  Isamu Jinnoh^1,10 

[1] Advanced Clinical Research Center, Institute for Neurological Disorders, Furusawa-Miyako 255, Asou-ku, Kawasaki, Kanagawa 215-0026, Japan;Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan;Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan;Department of Psychiatry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan;Department of Psychiatry, Shiga University of Medical Science, Setatsukiwacho, Otsu, Shiga 520-2192 Japan;Division of Child Neurology, Tottori University Hospital, 86 Nishi-machi, Yonago, Tottori 683-8503, Japan;Division of Functional Genomics, Research Centre for Bioscience and Technology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan;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;Koichi Tanaka Mass Spectrometry Research Laboratory, Shimadzu Corporation, 1 Nishinokyo-Kuwabaracho Nakagyo-ku, Kyoto 604-8511, Japan;Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8574, Japan;

关键词: niemann–pick disease type c;    biomarkers;    chemical diagnosis;    lysosphingomyelin-509;    n-acyl-phospholipids;    lc–ms/ms;    had–ms/ms;    chemical derivatization;    identification;    structural determination;   

DOI  :  10.3390/ijms20205018

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown