High‐throughput approaches towards the definitive identification of pharmaceutical drug metabolites. 2. An example of how unexpected dissociation behaviour could preclude correct assignment of sites of metabolism
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Abstract S ‐oxidation is a common metabolic route for sulfur‐containing compounds. Whilst investigating the dissociation of a series of chemically synthesised model S ‐oxide metabolites, two unexpected losses of 62 m / z units were observed in the collision‐induced dissociation (CID) product ion spectrum of protonated 3‐dimethylaminomethyl‐4‐(4‐methanesulfinyl‐3‐methylphenoxy)benzenesulfonamide. A single loss was initially assigned using the low‐resolution product ion spectrum, acquired by electrospray ionisation quadrupole ion trap mass spectrometry (ESI‐QIT‐MS), as methanethial, S ‐oxide via a charge‐remote, four‐centred rearrangement. This assignment was consistent with well‐documented hydrogen rearrangements in the literature. Further, the loss was not observed for the parent compound. Thus, it was inferred that the site of metabolism was involved in the dissociation and the attractive nature of the four‐centred rearrangement meant that the loss of methanethial, S ‐oxide was a logical assignment. However, deuterium‐labelling experiments and accurate mass measurements, performed using electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry (ESI‐FT‐ICR‐MS), showed that the nominal loss of 62 m / z units occurs via two distinct dissociation pathways. Neither of these losses was of methanethial, S ‐oxide as initially hypothesised from the low‐resolution product ion spectrum of the protonated molecule. Mechanisms consistent with the experimental findings are postulated. An MS 3 spectrum of the fully exchanged, deuterated species supported the proposed mechanisms by suggesting that 3‐dimethylaminomethyl‐4‐(4‐methanesulfinyl‐3‐methylphenoxy)benzenesulfonamide has multiple sites of protonation in the gas phase. The planar structures of the posited product ions are likely to provide the driving force for the rearrangements. The relevance of the observations with regards to pharmaceutical drug metabolite identification is discussed. Copyright © 2009 John Wiley & Sons, Ltd.Keywords:
Collision-induced dissociation
Quadrupole ion trap
The unique scanning capabilities of a hybrid linear ion trap (Q TRAP) mass spectrometer are described with an emphasis on proteomics applications. The combination of the very selective triple quadrupole based tandem mass spectrometry (MS/MS) scans with the very sensitive ion trap product ion scans allows rapid identification of peptides at low concentrations derived from post-translationally modified proteins on chromatographic time scales. The Q TRAP instrument also offers the opportunity to conduct a variety of ion processing steps prior to performing a mass scan. For example, the enhancement of the multiple-charge ion contents of the ion trap can be performed resulting in a survey mass spectrum dominated by double- and triple-charge peptides. This facilitates the identification of relevant biological species in both separated and unseparated peptide mixtures for further MS/MS experiments.
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Abstract A short DC voltage pulse is applied to one endcap of a quadrupole ion‐trap mass spectrometer to activate trapped ions. High internal‐energy deposition is achieved as evidenced by 91 + /92 + peak ratios in excess of 20 for dissociation of the n‐butylbenzene molecular ion. 1 The amount of internal energy can be controlled directly by vaarying the amplitude of the pulse. Dissociation efficiencies are less than those typically observed for collision‐induced dissociation in the ion trap and range from 50% at low internal energy deposition to 5% at maximum internal energy deposition.
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A critical evaluation of the performance of a 2-D linear ion trap (IT) instrument to two 3-D quadrupole IT instruments with emphasis on identification of rat serum proteins by bottom-up LC-MS/MS is presented. The speed and sensitivity of each of the instruments were investigated, and the effects that each of these have on the bottom-up proteomics identification approach are discussed.
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Ion cyclotron resonance
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Top-down proteomics
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Fragmentation
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Collision-induced dissociation (CID) of ions by resonance activation in a quadrupole ion trap is usually accomplished by resonance exciting the ions to higher kinetic energy, whereby the high kinetic energy ions collide with a bath gas, such as helium or argon, inside the trap and dissociate to fragments. A new ion activation method using a well-defined rectangular wave dipolar potential formed by dividing down the trapping rectangular waveform is developed and examined herein. The mass-selected parent ions are resonance excited to high kinetic energies by simply changing the frequency of the rectangular wave dipolar potential and dissociation proceeds. A relationship between the ion mass and the activation waveform frequency is also identified and described. This highly efficient (CID) procedure can be realized by simply changing the waveform frequency of the dipolar potential, which could certainly simplify tandem mass spectrometry analysis methods.
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Quadrupole ion trap mass analyzer with a simplified geometry, namely, the cylindrical ion trap (CIT), has been shown to be well-suited using in miniature mass spectrometry and even in mass spectrometer arrays. Computation of stability regions is of particular importance in designing and assembling an ion trap. However, solving CIT equations are rather more dif- ficult and complex than QIT equations, so, analytical and matrix methods have been widely used to calculate the stability regions. In this article we present the results of numerical simulations of the physical properties and the fractional mass resolu- tions of the confined ions in the first stability region was analyzed by the fifth order Runge-Kutta method (RKM5) at the optimum radius size for both ion traps. Because of similarity the both results, having determining the optimum radius, we can make much easier to design CIT. Also, the simulated results has been performed a high precision in the resolution of trapped ions at the optimum radius size.
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Collision induced dissociation (CID) in a quadrupole ion trap mass spectrometer using the conventional 30 ms activation time is compared with high amplitude short time excitation (HASTE) CID using 2 ms and 1 ms activation times. As a result of the shorter activation times, dissociation of the parent ions using the HASTE CID technique requires resonance excitation voltages greater than conventional CID. After activation, the rf trapping voltage is lowered to allow product ions below the low mass cut-off to be trapped. The HASTE CID spectra are notably different from those obtained using conventional CID and can include product ions below the low mass cut-off for the parent ions of interest. The MS/MS efficiencies of HASTE CID are not significantly different when compared with the conventional 30 ms CID. Similar results were obtained with a two-dimensional (linear) ion trap and a three-dimensional ion trap.
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In designing an ion trap, geometry and rf source should be optimized such that the trap depth is maximized while the ion remain stable. In a quadrupole linear trap, stable parameters $a$ and $q$ are utilized frequently in describing the stability. However, in a surface trap, the trap have to be mapped to the linear quadrupole trap so that $a$ and $q$ can be evaluated. This work explains how to handle them for surface trap designing and how the geometry and rf source affect it. We conclude that the $q$ parameter should be 0.2~0.22 so that the trap is stable.
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Quadrupole ion trap
Fragmentation
Ion trapping
Hybrid mass spectrometer
Quadrupole mass analyzer
Tandem
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