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Chapter Metabolism Metabolism • Page 197 High sensitivity analysis of metabolites in serum using simultaneous SIM and MRM modes in a triple quadrupole GC/MS/MS • Page 202 Analysis of D- and L-amino acids using auto- mated pre-column derivatization and liquid chromatography-electrospray ionization mass spectrometry • Page 208 Characterization of metabolites in microsomal metabolism of aconitine by high-performance liquid chromatography/quadrupole ion trap/ time-of-flight mass spectrometry • Page 213 Simultaneous analysis of primary metabolites by triple quadrupole LC/MS/MS using penta- fluorophenylpropyl column PO-CON1443E High Sensitivity Analysis of Metabolites in Serum Using Simultaneous SIM and MRM Modes in a Triple Quadrupole GC/MS/MS ASMS 2014 ThP 641 Shuichi Kawana1, Yukihiko Kudo2, Kenichi Obayashi2, Laura Chambers3, Haruhiko Miyagawa2 1 Shimadzu, Osaka, Japan, 2 Shimadzu, Kyoto, Japan, 3 Shimadzu Scientic Instruments, Columbia, MD High Sensitivity Analysis of Metabolites in Serum Using Simultaneous SIM and MRM Modes in a Triple Quadrupole GC/MS/MS Introduction Gas chromatography / mass spectrometry (GC–MS) and a gas chromatography-tandem mass spectrometry (GC-MS/MS) are highly suitable techniques for metabolomics because of the chromatographic separation, reproducible retention times and sensitive mass detection. MRM measurement mode Some compounds with low CID efciency produce insufcient product ions for MRM transitions, and the MRM mode is consequently less sensitive than SIM for these compounds. Our suggestion SIM, MRM, and simultaneous SIM/MRM modes are evaluated for analysis of metabolites in human serum. Materials and Method Sample and Sample preparation Sample • Human serum Sample Preparation1) 50uL serum Supernatant 250 µL Add 250 µL water / methanol / chloroform (1 / 2.5 / 1) Freeze-dry Add internal standard (2-Isopropylmalic acid) Stir, then centrifuge Residue Extraction solution 225 µL Add 40 µL methoxyamine solution (20 mg/mL, pyridine) Heat at 30 ºC for 90 min Add 200 µL Milli-Q water Add 20 µL MSTFA Stir, then centrifuge Heat at 37 ºC for 30 min Sample 1) Nishiumi S et. al. Metabolomics. 2010 Nov;6(4):518-528 Instrumentation GC-MS : GCMS-TQ8040 (SHIMADZU) Data analysis : GCMSsolution Ver.4.2 Database : GC/MS Metabolite Database Ver.2 (SHIMADZU) Column : 30m x 0.25mm I.D., df=1.00µm (5%-Phenyl)-methylpolysiloxane 2 High Sensitivity Analysis of Metabolites in Serum Using Simultaneous SIM and MRM Modes in a Triple Quadrupole GC/MS/MS Simultaneous SIM and MRM modes in GC/MS/MS Figure 1 shows the theory of Simultaneous SIM and MRM modes. This analysis mode can measure SIM and MRM data in a single analysis. Q1 Collision Cell Q3 SIM SIM MRM MRM SIM CID SIM Figure 1 The concept of simultaneous SIM and MRM analysis mode. Precursor ion (or SIM) Product ion % % 100 100 361 CID 169 75 73 75 50 50 217 103 25 147 73 103 271 437 25 243 191 243 319 361 0 0 100 200 300 400 100 200 300 Figure 2 Mass Spectrum of Precursor (or SIM) and Product ion Poor sensitivity of MRM in some compounds because of low CID efciency Method Creation using Database and SmartMRM Figure 3 shows the GC/MS Metabolites Database Ver.2. This database involves conditions of SIM and MRM in 186 metabolites and a method creation function we call SmartMRM. SmartMRM creates MRM, SIM, SIM/MRM methods from Database automatically. Figure 3 GC/MS Metabolites Database Ver.2 • Select the MRM, SIM and SIM/MRM conditions of 186 TMS derivatization metabolites from GC/MS Metabolites Database Ver.2. • Select the two transitions (or ions) each metabolite. 3 High Sensitivity Analysis of Metabolites in Serum Using Simultaneous SIM and MRM Modes in a Triple Quadrupole GC/MS/MS Results Comparison of the chromatogram between SIM and MRM in human serum a) Glucuronic acid-meto-5TMS(2) (x100,000) (x10,000) 333.10 333.10>143.10 SIM 3.5 160.10 MRM 1.75 333.10>171.10 3.0 1.50 2.5 1.25 2.0 1.00 1.5 0.75 1.0 0.50 0.5 0.25 21.00 21.25 21.00 21.25 Detected the peak in MRM because of high selectivity b) S-Benzyl-Cysteine-4TMS (x100) (x100,000) (x10,000) 1.75 238.10>91.00 2.00 238.10 218.10>73.00 SIM 218.10 MRM 7.5 238.10>91.00 1.50 1.75 1.25 1.50 1.00 0.75 5.0 1.25 0.50 1.00 0.25 21.00 21.25 21.50 0.75 2.5 0.50 0.25 21.25 21.50 21.00 21.25 21.50 Peak was not detected in MRM because of low CID efciency. A number of Identication metabolites in serum Table 1 shows the identication results of metabolites in human serum using SIM, MRM and simultaneous SIM/MRM analysis modes in GC/MS/MS. In SIM/MRM, the metabolites, which were insufcient sensitivity in MRM, were measured by SIM and the other metabolites were measured by MRM. Table 1 The number of identied metabolites each analysis mode Modes A B C Total SIM 57 51 8 116 MRM 131 14 1 146 SIM/MRM 133 22 1 156 note) A:Target and Conrmation ions were detected.; B: Either Target or Conrmation ion was detected. Another one was overlapped by contaminants.; C: Either Target or Conrmation ion was detected. 4 High Sensitivity Analysis of Metabolites in Serum Using Simultaneous SIM and MRM Modes in a Triple Quadrupole GC/MS/MS Fig.4 shows a number of metabolites in each mode can be measured. In metabolites with low CID efciency, SIM are superior to MRM if there are no interfering substances to the target metabolites. MRM SIM 40 106 10 Metabolites with Metabolites with low CID interference in SIM efciency in MRM Figure 4 Detected metabolites in human serum each analysis mode. The reproducibility(n=6) in MRM and SIM/MRM Table 2 Comparison of the reproducibility results from MRM and SIM/MRM analysis. A number of detected metabolites involves A, B and C in Table 1. %RSD MRM SIM/MRM Improvement - 4.99% 73 76 +3 5 - 9.99% 26 30 +4 10 - 14.99% 8 10 +2 15 - 19.99% 9 10 +1 > 20% 30 30 0 146 156 +10 Conclusions • Analytical results from the SIM and MRM modes identied 116 and 146 metabolites, respectively. • In metabolites with poor CID efciency, the sensitivity of SIM is more than 10 times higher than MRM. • Simultaneous SIM and MRM modes in a single analysis (SIM/MRM) improves the sensitivity and reproducibility for analysis of metabolites in human serum compared to MRM alone. • A novel SIM/MRM expands the utility of a triple quadrupole GC/MS/MS First Edition: June, 2014 For Research Use Only. Not for use in diagnostic procedures. The content of this publication shall not be reproduced, altered or sold for any commercial purpose without the written approval of Shimadzu. The information contained herein is provided to you "as is" without warranty of any kind including without limitation warranties as to its accuracy or completeness. Shimadzu does not assume any responsibility or liability for any damage, whether direct or indirect, relating to the use of this publication. This publication is based upon the information available to Shimadzu on or before the date of publication, and subject to change without notice. www.shimadzu.com/an/ © Shimadzu Corporation, 2014 PO-CON1451E Analysis of D- and L-amino acids using automated pre-column derivatization and liquid chromatography-electrospray ionization mass spectrometry ASMS 2014 MP739 Kenichiro Tanaka1; Hidetoshi Terada2; Yoshiko Hirao2; Kiyomi Arakawa2; Yoshihiro Hayakawa2 1. Shimadzu Scientic Instruments, Inc., Columbia, MD; 2. Shimadzu Corporation, Kyoto, Japan Analysis of D- and L-amino acids using automated pre-column derivatization and liquid chromatography-electrospray ionization mass spectrometry Introduction Recently, several species of D- amino acids have been good reliability. One of the drawbacks of pre-column found in mammals including humans and their derivatization is less reproducibility due to the tedious physiological functions have been elucidated. Quantitating manual procedure and human errors. We have launched each enantiomer of amino acids is indispensable for such an autosampler for a UHPLC system equipped with an studies. In order to diagnose diseases, it is desirable that D- automated pretreatment function that allows overlapping and L-amino acid can be separately quantitated and injections in which the next derivatization proceeds during applied to metabolic analysis. the current analysis for saving total analytical time. We Pre-column derivatization with o-phthalaldehyde (OPA) and have applied this autosampler and its function to fully N-acetyl-L-cysteine(NAC) is widely utilized for the analysis automate pre-column derivatization for the determination of D- and L- amino acids since the method can be of amino acids. In this study, we developed a methodology performed with a rapid reversed phase separation on a which enabled the automated procedure of pre-column relatively simple hardware (U)HPLC conguration with chiral derivatization of D- and L- amino acids. Experimental Instruments The system used was a SHIMADZU UHPLC Nexera workstation (LabSolutions, Shimadzu Corporation, Japan) pre-column Amino Acids (AAs) system consisting of so that selected conditions can be seamlessly translated LC-30AD solvent delivery pump, DGU-20A5R degassing into method les and registered to a batch queue, ready unit, SIL-30AC autosampler, CTO-30A column oven, and for instant analysis. A 1.9um YMC-Triart C8 column (2.0 SHIMADZU triple quadrupole mass spectrometer mm x 150 mm L.) was used for the analysis. LCMS-8040. The software is integrated in the LC/MS/MS Derivatization Method Derivatizing solutions: 0.1 mol/L boric acid buffer was prepared by dissolving 6.18 mg of o-phthalaldehyde in 0.3 mL of ethanol, adding 0.7 g of boric acid and 2.00 g of sodium hydroxide in 1 L of mL of the 0.1 mol/L boric acid buffer and 4 mL of water.
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