Non-targeted metabolomics by high resolution mass spectrometry in HPRT knockout mice

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• 作者：Sarah K. Tschirner^a ; ^{tschirner.sarah@mh-hannover.de" class="auth_mail" title="E-mail the corresponding author} ; Heike Bä ; hre^a ; ^b ; ^{baehre.heike@mh-hannover.de" class="auth_mail" title="E-mail the corresponding author} ; Alexander Kaever^c ; ^{alex@gobics.de" class="auth_mail" title="E-mail the corresponding author} ; Erich H. Schneider^a ; ^{schneider.erich@mh-hannover.de" class="auth_mail" title="E-mail the corresponding author} ; Roland Seifert^a ; ^{seifert.roland@mh-hannover.de" class="auth_mail" title="E-mail the corresponding author} ; Volkhard Kaever^a ; ^b ; ^{kaever.volkhard@mh-hannover.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：1-MI4AA ; 1-methylimidazole-4-acetic acid ; AICAR ; 5-aminoimidazole-4-carboxamide ribotide ; ATIC ; AICAR transformylase/IMP cyclohydrolase ; cps ; counts per second ; CSF ; cerebrospinal fluid ; csv ; comma-separated values ; CVQC ; coefficient of variation for quality control injections ; FAICAR ; 5&prime ; -phosphoribosyl-5-formamido-4-imidazolecarboxamide ; FDR ; false discovery rate ; HMDB ; Human Metabolome Database ; HPLC ; high performance liquid chromatography ; HPRT ; hypoxanthine-guanine phosphoribosyltransf
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：156
• 期：Complete
• 页码：68-73
• 全文大小：431 K

文摘

Lesch-Nyhan disease (LND) is characterized by hyperuricemia as well as neurological and neuropsychiatric symptoms including repetitive self-injurious behavior. Symptoms are caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a result of a mutation on the X chromosome. To elucidate the pathophysiology of LND, we performed a metabolite screening for brain and serum extracts from HPRT knockout mice as an animal model for LND.

Main methods

Analyses were performed by high performance liquid chromatography (HPLC)-coupled quadrupole time-of-flight mass spectrometry (QTOF-MS).

Key findings

In brain extracts, we found six metabolites with significantly different contents in wild-type and HPRT-deficient mice. Two compounds we could identify as 5-aminoimidazole-4-carboxamide ribotide (AICAR) and 1-methylimidazole-4-acetic acid (1-MI4AA). Whereas AICAR was accumulated in brains of HPRT knockout mice, 1-MI4AA was decreased in these mice.

Significance

Both metabolites play a role in histidine metabolism and, as a consequence, histamine metabolism. AICAR, in addition, is part of the purine metabolism. Our findings may help to better understand the mechanisms leading to the behavioral phenotype of LND.