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Rapid Quantification of Underivatized Amino Acids in Plasma by Hydrophilic Interaction Liquid Chromatography (HILIC) Coupled with Tandem Mass-Spectrometry

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Rapid Quantification of Underivatized Amino Acids in Plasma by Hydrophilic Interaction Liquid Chromatography (HILIC) Coupled with Tandem Mass-Spectrometry J Inherit Metab Dis DOI 10.1007/s10545-016-9935-z ORIGINAL ARTICLE Rapid quantification of underivatized amino acids in plasma by hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass-spectrometry Hubertus C. M. T. Prinsen1 & B. G. M. Schiebergen-Bronkhorst1 & M. W. Roeleveld 1 & J. J. M. Jans1 & M. G. M. de Sain-van der Velden1 & G. Visser2 & P. M. van Hasselt2 & N. M. Verhoeven-Duif1 Received: 7 December 2015 /Revised: 30 March 2016 /Accepted: 4 April 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract 18 min. Plasma of patients with a known IEM in AA metab- Background Amino acidopathies are a class of inborn errors olism was analyzed and all patients were correctly identified. of metabolism (IEM) that can be diagnosed by analysis of Conclusion Thereportedmethodanalyzes36AAinplasma amino acids (AA) in plasma. Current strategies for AA anal- within 18 min and provides baseline separation of isomeric ysis include cation exchange HPLC with post-column ninhy- AA such as leucine and isoleucine. No separation was obtain- drin derivatization, GC-MS, and LC-MS/MS-related ed for isoleucine and allo-isoleucine. The method is applicable methods. Major drawbacks of the current methods are time- to study defects in AA metabolism in plasma. consuming procedures, derivative problems, problems with retention, and MS-sensitivity. The use of hydrophilic interac- tion liquid chromatography (HILIC) columns is an ideal sep- aration mode for hydrophilic compounds like AA. Here we Introduction report a HILIC-method for analysis of 36 underivatized AA in plasma to detect defects in AA metabolism that overcomes the Amino acids (AA) are important metabolites for the human major drawbacks of other methods. body. The metabolites are building blocks for peptides and Methods A rapid, sensitive, and specific method was devel- proteins, can serve as sources of energy, are precursors for oped for the analysis of AA in plasma without derivatization different metabolites such as neurotransmitters or can act as using HILIC coupled with tandem mass-spectrometry (Xevo neurotransmitters themselves. Disturbances in AA concentra- TQ, Waters). tions are not only related to inborn errors of metabolism Results Excellent separation of 36 AA (24 quantitative/12 (IEM), but AA can also serve as sensitive markers for nutri- qualitative) in plasma was achieved on an Acquity BEH tional status. Besides, AA reflects the function of various or- Amide column (2.1×100 mm, 1.7 μm) in a single MS run of gans (Duran, 2008). To diagnose amino acidopathies and for follow-up of therapy, AA analysis is commonly performed in Communicated by: Jörn Oliver Sass biological specimens like plasma, dried blood spots (DBS), urine, and cerebrospinal fluid. The most commonly used strat- Electronic supplementary material The online version of this article (doi:10.1007/s10545-016-9935-z) contains supplementary material, egies for AA analysis include cation exchange HPLC with which is available to authorized users. post-column ninhydrin derivatization, GC-MS, and LC-MS/ MS related methods (with and without derivatization). With * Hubertus C. M. T. Prinsen respect to time, HPLC with post-column ninhydrin derivati- [email protected] zation is less suitable for the modern laboratory with a require- ment for a rapid turnaround time. Additionally, it is known 1 Section Metabolic Diagnostics, Department of Genetics, University that most of the derivatization methods used for LC-MS have Medical Center (UMC) Utrecht, KC.02.069.1, Lundlaan 6, 3584 major drawbacks, such as derivative instability and insuffi- EA Utrecht, The Netherlands cient reproducibility of the derivative yield (Dolowy and 2 Department of Metabolic Diseases, University Medical Center Pyka 2014;HalketandZaikin2005;Kasparetal2009). (UMC) Utrecht, Utrecht, The Netherlands With the introduction of ion-pairing agents, the separation of JInheritMetabDis AA on a C18-reversed phase column improved. Complex proline, serine, taurine, threonine, tryptophan, tyrosine, valine, derivatization procedures were no longer necessary and good ammoniumformiate, and DTT ((2S, 3S)-1,4- separation of compounds was achieved (Piraud et al 2003; bis(sulfanyl)butane-2,3-diol) were purchased from Sigma- Piraud et al 2005). Unfortunately, problems with retention Aldrich (Zwijndrecht, the Netherlands). Glutamic acid, gluta- time stability and reduction of the sensitivity of the MS- mine, glycine, ornithine, sulfosalicylic acid (SSA), hydrochlo- detector in negative mode arose limiting the use of ion- ric acid (HCl), and formic acid were purchased from VWR pairing reagents (de Person et al 2008; Piraud et al 2005; (Amsterdam, the Netherlands). Acetonitrile (ACN) and meth- Waterval et al 2009). anol both UPLC-grade were purchased from Biosolve It is known that polar compounds such as AA and carbo- (Valkenswaard, the Netherlands). hydrates obtain good retention and separation by hydrophilic interaction liquid chromatography (HILIC) (Buszewski and Subjects Noga 2012; Greco and Letzel 2013;Kahsayetal2014). Separation principle is based on the strong interaction of polar Blood samples were obtained for routine diagnostic purposes compounds with the hydrophilic phase. A benefit of HILIC is from patients suspected for an IEM and collected by venous the use of an aqueous organic solvent eluent that enhances puncture into heparin containing tubes (Greiner Bio-One, the ionization. With the introduction of HILIC columns for Netherlands). For preparation of quality controls, blood was UPLC new applications, e.g., for AA analysis became within taken from a healthy volunteer. Blood was immediately cen- reach. AA were analyzed semi-quantitative in fruit (Guo et al trifuged and stored at −20 °C. Blood samples were collected 2013;Zhouetal2013), in rat brain (leucine) (Santos-Fandila from (untreated) patients with a known inborn of AA metab- et al 2014), and a subset of AA was analyzed in animal tissue olism including argininosuccinate lyase (ASL) deficiency hydrolysate (Krumpochova et al 2015). However, no such (n = 2), 3-phosphoglycerate dehydrogenase deficiency analysis was performed in human plasma using HILIC. The (n = 4), citrullinemia type I (n = 1), hyperphenylalaninemia or goal of this study was to develop a rapid, sensitive, and spe- phenylketonuria (n = 47), hyperprolinemia type I (n =2), cific method for analysis and quantification of AA in human lysinuric protein intolerance (LPI) (n = 8), methionine plasma without derivatization using HILIC tandem mass- adenosyltransferase (MAT) Ia deficiency (n = 3), maple syrup spectrometry. The method had to be applicable to diagnose urine disease (MSUD) (n = 2), methylenetetrahydrofolate re- patients with inborn errors of amino acid metabolism. We ductase (MTHFR) deficiency (n = 3), non-ketotic validated this method according to ISO-15189 accreditation hyperglycinemia (NKH (n = 6)), ornithine aminotransferase for medical laboratories and compared the results with those (OAT) deficiency (n = 4), ornithine-transcarbamyolase obtained using traditional ion-exchange chromatography. (OTC) deficiency (n = 8), and tyrosinemia type I (n =10).All IEM diagnoses in the control patients were confirmed by DNA-mutation analysis (data not shown). The samples ob- Materials and methods tained from the IEM patients were for routine diagnostics (clinical waste), analyzed anonymously, and not specifically Reagents collected for validation of this study. 15 2,3,3,3-D4-alanine, guanido- N2-arginine:HCl, 2,3,3-D3- 13 aspartic acid, 5- C, 4,4,5,5-D4-citrulline, 2,4,4-D3-glutamic Preparation of calibrators 13 13 acid, 2,3,3,4,4-D5-glutamine, 1,2- C2-glycine, U- C6- 13 15 histidine:HCl.H2O, U- C6,U-D10, N-isoleucine, 5,5,5-D3- For the calibrators, a solution of 22 AA standards including leucine, 4,4,5,5,-D4-lysine:2HCl, methyl-D3-methionine, 5, hydroxy-proline (IS-I and ST-I, Table 1) was made, while for 5-D2-ornithine:HCl, ring-D5-phenylalanine, 2,3,3,4,4,5,5-D7- glutamine and asparagine a separate standard solution (IS-II 13 13 13 15 proline, 3- C-serine, 1,2- C-taurine, U- C4,U-D5, N-thre- and ST-II, Table 1) was prepared. The internal standards for 13 onine, indole-D5-tryptophan, ring-D4-tyrosine, and 1- C-va- IS-I were dissolved in 0.1 M HCl. Subsequently, to 8300 μL line were purchased from Cambridge Isotope Laboratories AA mixture (IS-I), 1700 μL 5 % SSA (final concentration (Massachusetts, USA). D9-pipecolic acid was purchased from 0.85 %) was added. From this 10 mL solution, 20 μLwas CDN-isotopes (Quebec, Canada). D8-homocystine was pur- added to plasma. IS-II was prepared by addition of 1600 μL chased from Buchem (Apeldoorn, the Netherlands), labeled glutamine and 800 μL labeled asparagine to 7600 μL 13 15 C4- N2-asparagine, alanine, delta-aminolevulinic acid, ar- milliQ-water. From this 10 mL solution 20 μL was added to ginine, asparagine, aspartic acid, argininosuccinic acid (ASA), plasma. The final concentrations of the labeled AA (IS-I and citrulline, histidine, homocitrulline, homocysteïne, hydroxy- IS-II) are shown in Table 1. proline, isoleucine, leucine, lysine, methionine, methionine- ST-I was prepared in 0.1 M HCl and ST-II was prepared in sulfoxide, methionine-sulfone, phenylalanine, pipecolic acid, milliQ-water. J Inherit Metab Dis Table 1 Final concentrations for the internal standards (IS-I and IS-II, +MRM-transitions) and final concentrations for the calibrators ST-I and ST-II (IS-I) Amino acid Concentration (μM) MRM-transition (m/z) (ST-I) Amino acid Concentration
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