EP1481416B1 - Massenspektrometrisches verfahren zur analyse von substanzgemischen - Google Patents

Massenspektrometrisches verfahren zur analyse von substanzgemischen Download PDF

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Publication number
EP1481416B1
EP1481416B1 EP03711878.3A EP03711878A EP1481416B1 EP 1481416 B1 EP1481416 B1 EP 1481416B1 EP 03711878 A EP03711878 A EP 03711878A EP 1481416 B1 EP1481416 B1 EP 1481416B1
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Prior art keywords
process according
mass
ionization
substance
ions
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Expired - Lifetime
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EP03711878.3A
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German (de)
English (en)
French (fr)
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EP1481416A1 (de
Inventor
Tilmann B. Walk
Martin Dostler
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BASF Metabolome Solutions GmbH
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Metanomics GmbH
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Priority claimed from DE2002108626 external-priority patent/DE10208626A1/de
Priority claimed from DE2002108625 external-priority patent/DE10208625A1/de
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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn
    • H01J49/0045—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn characterised by the fragmentation or other specific reaction
    • H01J49/005—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn characterised by the fragmentation or other specific reaction by collision with gas, e.g. by introducing gas or by accelerating ions with an electric field
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes
    • H01J49/34—Dynamic spectrometers
    • H01J49/42—Stability-of-path spectrometers, e.g. monopole, quadrupole, multipole, farvitrons
    • H01J49/4205—Device types
    • H01J49/421—Mass filters, i.e. deviating unwanted ions without trapping

Definitions

  • the present invention relates to a mass spectrometric method for the analysis of substance mixtures with a triple quadrupole mass spectrometer.
  • the analyst In the analysis of complex mixtures of substances of biological and / or chemical origin, the analyst, in addition to the task of identifying the structure of individual substances contained in the mixture, repeatedly encounters the problem of detecting and possibly quantifying all substances present in the mixture. This should be done as quickly as possible and with a high degree of accuracy, ie with a small error deviation. This becomes all the more important when information about a biological system is to be obtained, for example, from a microorganism grown under certain fermentation conditions or from a plant grown under different environmental conditions or from a wild-type organism such as a microorganism or a plant compared to its genetically altered mutant , Such comparisons are required to allow assignment of mutations of unknown genes in the genome of these organisms to a particular metabolic phenotype.
  • a major problem of this analysis is the rapid, simple, reproducible and quantifiable identification of the substances contained in the mixtures.
  • TLC thin-layer chromatography
  • HPLC high-performance liquid chromatography
  • GC gas chromatography
  • NMR mass spectrometry
  • the samples can be used for the aforementioned analyzes and individual substances in selected samples can be identified and quantified.
  • HTS high-throughput screening
  • An advantage of very precise methods, such as NMR or IR spectroscopy, is that they provide information both about the structure and optionally about the quantity of a substance.
  • mass spectrometric methods are known from the prior art, for example, from the Analysis of synthetic, petrochemical, environmental and biological samples. However, these methods are only used for the analysis of individual known compounds in these samples. Broad measurement series, for example in the context of an HTS or in the identification and quantification of a variety of compounds in these samples are not described.
  • High molecular weight materials such as coal tar, humic acid, fulvic acid or kerogen can also be analyzed ( Zenobie and Bone Must, Mass Spec. Rev., 1998, 17, 337-366 ). Both the identity and the structure of substances can be determined, although the structural analysis is not always clear, so it must be confirmed by other methods, for example NMR.
  • ELEsmans et al. discloses in particular LC-MS methods for the analysis of nucleobases, nucleosides, nucleotides, oligonucleotides and DNA.
  • the collision chamber constantly contains collision gas.
  • a disadvantage of the structure determination is that a known mass of a precursor ion, a fragment or an ion adduct is required.
  • the starting structure of the substance to be investigated for the HPLC / MS should be known in these experiments. Since the HPLC / MS alone is not suitable for the absolute structure determination. However, if the structure of the parent compound is known, statements can be made about the structure of any metabolites. Since the structure of the substance to be developed as an active ingredient is known, statements about the structure of the unknown metabolites of the drug can be made with some certainty. However, the statement is hampered or prevented by possible overlays other than impurities existing compounds of the same mass. Quantification of the compounds is not possible with this method.
  • US 6,140,638 describes a method of reducing isobaric interference signals by constructing a filter on the collision cell by applying an appropriate field that excludes at least some precursor and intermediate ions that would otherwise result in isobaric interference.
  • substance mixtures according to the invention are in principle all mixtures containing more than one substance to understand, such as complex reaction mixtures of chemical syntheses such as synthesis products from combinatorial chemistry or substance mixtures of biological origin such as fermentation broths of an aerobic or anaerobic fermentation, body fluids such as blood, lymph Urine or stool, reaction products a biotechnological synthesis with one or more free or bound enzymes, extracts of animal material such as extracts from various organs or tissues or plant extracts such as extracts of the entire plant or individual organs such as root, stalk, leaf, flower or seed or their mixtures.
  • substance mixtures of biological origin such as extracts of animal or plant origin, advantageously of plant origin, are analyzed in this process.
  • the mass spectrometers usable in the method generally comprise a sample inlet system, an ionization chamber, an interface, an ion optics, one or more mass filters and a detector.
  • ion sources known to the person skilled in the art can be used to generate ions in the process.
  • these ion sources are coupled via a so-called interface to the following components of the mass spectrometer, for example the ion optics, the mass filter (s) or the detector.
  • the interposition of an interface has the advantage that the analysis can be carried out without delay.
  • nonvolatile and / or volatile, preferably nonvolatile substances can be brought directly into the gas phase by the ion source.
  • the samples to be analyzed or the substances contained therein can thereby also be enriched.
  • a wide range of solvents can be processed with minimal loss of sample.
  • Electrospray ionization is a very gentle method. At ESI, ions are continuously formed. This continuous ion formation has the advantage that it can be easily coupled in conjunction with almost any analyzer type and that it can easily be combined with chromatographic separation such as separation by capillary electrophoresis (CE), liquid chromatography (LC) or high pressure liquid chromatography (HPLC) because it has a good tolerance for high flow rates up to 2 ml / min eluate.
  • CE capillary electrophoresis
  • LC liquid chromatography
  • HPLC high pressure liquid chromatography
  • the spraying of the eluent is pneumatically supported by a so-called nebulizing gas, for example nitrogen.
  • the gas is blown under a pressure of up to 4 bar, advantageously up to 2 bar from a capillary, which encloses the inlet capillary of the eluent.
  • so-called normal phase eg silica gel, alumina, aminodeoxyhexitol, aminodeoxy-d-glucose, triethylenetetramine, polyethylene oxide or aminodicarboxy columns
  • / or reversed-phase columns are preferably reversed-phase columns. Columns such as columns with a C 4 , C 8 or C 18 stationary phase are preferred.
  • the electrospray technique leads to the (quasi-) molecular ion due to the extremely gentle ionization.
  • These are usually adducts with ions already present in the sample solution (eg protons, alkali ions and / or ammonium ions).
  • multiply charged ions can also be detected so that ions with a molecular weight of up to one hundred thousand daltons can be detected; molecular weights in a range from 1 to 10,000 daltons, preferably in a range of 50, can advantageously be used in the process according to the invention detect up to 8,000 daltons, more preferably in a range of 100 to 4000 daltons.
  • Other exemplary methods include ion spray ionization, atmospheric pressure ionization (APCI) or thermospray ionization.
  • the ionization process proceeds under atmospheric pressure and is divided essentially into three phases: First, the solution to be analyzed in a strong electrostatic field by generating a potential difference of 2-10 kV, preferably 2-6 kV between the inlet capillary and a counter electrode is generated, sprayed. An electric field between the inlet capillary tip and the mass spectrometer penetrates the analyte solution and separates the ions in an electric field. Positive ions are attracted to the surface of the liquid in so-called positive mode, negative ions in the opposite direction or vice versa Measurements in the so-called positive mode. The positive ions accumulated on the surface are subsequently drawn further in the direction of the cathode.
  • an aerosol which consists of analyte and solvent.
  • the desolvation of the formed drops takes place, which leads to the successive reduction of the droplet size.
  • the evaporation of the solvent is effected by thermal action, e.g. by supplying hot inert gas, achieved.
  • thermal action e.g. by supplying hot inert gas, achieved.
  • the charge density on the surface of the sprayed substance mixture droplets constantly increases. If, finally, the charge density or its charge repulsive forces exceed the surface tension of the droplets (so-called Raleigh limit), then (Coulomb explosion) these droplets explode into smaller droplets.
  • This process "solvent evaporation / Coulomb explosion” is repeated several times until finally the ions go into the gas phase.
  • the gas flow in the interface, the applied heating temperature, the flow rate of the heating gas, the pressure of the nebulizing gas and the capillary voltage must be precisely monitored and controlled.
  • APCI ionization ionization occurs in a so-called corona discharge.
  • thermospray or electrospray method the electrospray method being particularly preferred.
  • the ionization space is connected via an interface, that is to say via a micro-opening (100 ⁇ m) with the following mass spectrometer.
  • the nitrogen collides with the ions generated, for example, by electrospray, which were generated in the substance mixture.
  • By blowing the curtain gas is advantageously prevented that neutral particles are sucked into the high vacuum of the subsequent mass spectrometer. Furthermore, the curtain gas promotes the desolvation of the ions.
  • the method according to the invention can be carried out with all quadrupole mass spectrometers known to the person skilled in the art, such as the triple quadrupole mass spectrometers.
  • Triple quadrupole instruments are the standard tools for low energy collision activation studies.
  • these devices consist of a first quadrupole, which is suitable for analyzing the mass / charge quotient (m / z) of the ions contained in the substance mixture after ionization in a high vacuum (about 10 -5 Torr), the mass (s) individual ions, several or all ions can be measured.
  • Q0 quadrupoles
  • Another Q1 following quadrupole serves as a collision chamber.
  • the ions are advantageously fragmented by applying a fragmentation voltage.
  • ionization potentials in the range of 5-11 electron volts (eV), preferably 8-11 electron volts (eV) are applied.
  • Q2 is also filled for fragmentation in the process according to the invention with a collision gas such as a noble gas such as argon or helium or other gas such as CO 2 or nitrogen or mixtures of these gases such as argon / helium or argon / nitrogen.
  • argon and / or nitrogen is preferred.
  • the collision gas is present in the process according to the invention at a pressure of 1 ⁇ 10 -5 to 1 ⁇ 10 -1 Torr, preferably 10 -2 .
  • Particularly preferred is nitrogen.
  • this Q3 either the m / z quotients of individual selected fragments, several or all of the m / z quotients present in the substance mixtures after ionization (in this application for simplicity's sake referred to as mass or masses) can be determined. Also between quadrupole Q2 and Q3 there may be more quadrupoles or cones for steering the ions.
  • individual quadrupoles for collecting ions can also be operated as ion traps, from which the ions are then released again for analysis after some time.
  • the quadrupoles used in the triple quadrupole mass spectrometers generate a three-dimensional electric field in which the generated ions can be held. They usually consist of 4, 6 or 8 rods or rods with their help an oscillating electric field is generated, opposite rods are electrically connected.
  • the terms hexa- or octapol are also used. In the present application, these terms should be included when the term quadrupole is used.
  • only low acceleration voltages of a few volts, preferably of a few 10 volts are required in the quadrupoles of the triple quadrupole mass spectrometer for guiding the ions.
  • Substance mixtures such as animal or vegetable extracts, preferably vegetable extracts, are advantageously used in the process according to the invention.
  • FIG. 1 the sequence of the method according to the invention can be seen.
  • process steps (a) to (c) and (d) are advantageously carried out at least once within 0.1 to 10 seconds, preferably within 0.2 to 6 seconds at least once, particularly preferably within 0.2 to 2 Seconds, most preferably at least once within 0.3 to less than 2 seconds.
  • the process steps are run through within two to three times, preferably three times, within 0.2 to 6 seconds.
  • the quadrupole Q2 acting as a collision chamber is constantly filled with collision gas. As the own measurements showed, this has no negative influence on the reproducibility of the measurements.
  • step (a) between 1 and 100 mass / charge quotients of different ions formed and selected in step (a) can be analyzed in the method according to the invention.
  • at least 20 m / z quotients, preferably at least 40 m / z quotients, more preferably at least 60 m / z quotients, most preferably at least 80 m / z quotients of different ions or more are identified and / or quantified.
  • Purification of the substance mixtures is in principle not required in the process according to the invention.
  • the substance mixtures can be measured directly after introduction into an ion source. This also applies to complex mixtures of substances. It is also not necessary to add to the substance mixtures as internal standards any labeled or unlabeled pure substances of possible substances contained in the mixtures, although this is of course possible and simplifies subsequent quantification of the substances contained in the mixtures.
  • coupling of purification methods is advantageously between 1 ⁇ l / min to 2000 ⁇ l / min, preferably between 5 ⁇ l / min to 600 ⁇ l / min, more preferably between 10 ⁇ l / min to 500 .mu.l / min, for example, possible. Even lower or higher flow rates can be used without difficulty in the process according to the invention.
  • Suitable solvents are, for example Solvents carrying little or no charge, such as aprotic apolar solvents, characterized by a low dielectric constant (E t ⁇ 15), low dipole moments ( ⁇ ⁇ 2.5D), and low E T N values (0.0-0.5 ) are characterized. But also dipolar organic solvents or mixtures thereof are suitable as solvents for the inventive method. Examples of suitable solvents are methanol, ethanol, acetonitrile, ethers, heptane.
  • weak acid solvents such as 0.01 - 0.1% formic acid, acetic acid or trifluoroacetic acid are suitable.
  • weakly basic solvents such as 0.01 to 0.1% triethylamine or ammonia are also suitable.
  • Strongly acidic or strongly basic solvents such as 5% HCl or 5% triethylamine are also suitable in principle as solvents.
  • mixtures of the aforementioned solvents are advantageous.
  • the customary in biochemical buffers are suitable as solvents, wherein advantageously buffer ⁇ 200 mM, preferably ⁇ 100 mM, more preferably ⁇ 50 mM, most preferably ⁇ 20 mM are used.
  • buffers> 100 mM are used for the preparation of the substance mixtures that the buffers are completely or partially removed, for example via dialysis.
  • suitable buffers include acetate, formate, phosphate, tris, MOPS, HEPES or mixtures thereof. High buffers and / or salt concentrations have a negative effect on the ionization processes and may need to be avoided.
  • the substance mixtures for the method according to the invention which are otherwise poorly or not at all detectable, can be derivatized before the analysis and thus finally analyzed.
  • Derivatization is particularly advantageous in cases in which hydrophilic groups are introduced into hydrophobic or volatile compounds, for example, such as esters, amides, lactones, aldehydes, ketones, alcohols, etc., which advantageously still carry an ionizable functionality.
  • Examples of such derivatizations are reactions of aldehydes or ketones to oximes, hydrazones or their derivatives or alcohols to give esters, for example with symmetrical or mixed anhydrides.
  • the detection spectrum of the method can advantageously be extended.
  • an internal standard such as e.g. Peptides, amino acids, coenzymes, sugars, alcohols, conjugated alkenes, organic acids or bases added.
  • This internal standard advantageously allows the quantification of the compounds in the mixture. Substance mixture containing substances can thus be more easily analyzed and ultimately quantified.
  • an internal standard advantageously labeled substances are used, but in principle also non-labeled substances are suitable as an internal standard.
  • Such similar chemical compounds are, for example, so-called compounds of a homologous series whose members differ only by, for example, an additional methylene group.
  • at least one isotope selected from the group 2 is preferably H, 13 C, 15 N, 17 O, 18 O, 33 S, 34 S, 36 S, 35 Cl, 37 Cl, 29 Si, 30 Si, 74 Se or mixtures thereof used labeled substances.
  • 2 H or 13 C is preferably used as the isotope.
  • This internal standard does not need to be complete for the analysis, that is, to be fully marked. A partial marking is completely sufficient.
  • a ratio of analyte to internal standard is set in a range from 10: 1 to 6: 1, preferably in a range from 6: 1 to 4: 1, particularly preferably in a range from 2: 1 to 1: 1.
  • the substance mixture samples in the process according to the invention can be prepared manually or advantageously automatically with conventional laboratory robots.
  • the analysis with the mass spectrometer after optional chromatographic separation can be carried out manually or advantageously automatically.
  • mass spectrometry can advantageously be used for the rapid screening of various substance mixtures, for example plant extracts in the so-called high-throughput screening.
  • the method according to the invention is characterized by a high sensitivity, a good quantifiability, an excellent reproducibility, with the lowest sample consumption.
  • the method can thus rapidly mixtures of biological origin, for example, new mutants known or unknown enzymatic activities after a mutagenesis, for example, a classical mutagenesis with chemical agents such as NTG, radiation such as UV radiation or X-rays or after a so-called site-directed mutagenesis, PCR mutagenesis , Transposon mutagenesis or so-called gene shuffling.
  • a mutagenesis for example, a classical mutagenesis with chemical agents such as NTG, radiation such as UV radiation or X-rays or after a so-called site-directed mutagenesis, PCR mutagenesis , Transposon mutagenesis or so-called gene shuffling.
  • MRM Multiple Reaction Monitoring
  • FS Full Scan
  • TIC Total Ion Chromatogram
  • XIT Sum of Multiple Total Ion Chromatograms.
  • a quality control sample was measured. This type of sample contains a defined number of analytes. These analytes were purchased and dissolved in known concentrations in appropriate solvent.
  • the selected representation of the measurement shows the summation of the intensities (y-axis) measured at the detector at the respective times (x-axis) from the two mass-spectrometric experiments of Multiple Reaction Monitoring (MRM) and Full Scan (FS).
  • MRM Multiple Reaction Monitoring
  • FS Full Scan
  • FIG. 3 the total ion chromatogram of the MRM experiment from an MRM + FS measurement is shown.
  • the selected representation of the MRM measurement shows the summation of the intensities (y-axis) measured at the detector at the respective times (x-axis) from all predefined mass transitions of the MRM experiment.
  • selected representation shows the respective measurement results of each mass transition (here 30 pieces) in a coordinate system.
  • the FS experiment measured in change to the MRM experiment is in the TIC in FIG. 5 shown.
  • FIG. 6 the TIC of the FS experiment is shown.
  • FIG. 8 is like in FIG. 3 a total ion chromatogram of an MRM + full scan measurement. A calibration sample was measured.
  • the selected representation of the measurement shows the summation of the intensities (y-axis) measured at the detector at the respective times (x-axis) from the mass-spectrometric experiment of multiple reaction monitoring.
  • FIG. 9 returns an extracted chromatogram identifying coenzyme Q 10.
  • FIG. 10 and FIG. 11 give the identification of each capsanthin and bixin again.
  • FIG. 12 returns a Total Ion Chromatogram of a full scan of a plant extract.
  • FIGS. 13 to 15 show the masses of different analytes in the extracted chromatogram whose assignment to a specific structure has yet to be made.

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  • Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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EP03711878.3A 2002-02-28 2003-02-10 Massenspektrometrisches verfahren zur analyse von substanzgemischen Expired - Lifetime EP1481416B1 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10208625 2002-02-28
DE2002108626 DE10208626A1 (de) 2002-02-28 2002-02-28 Massenspektrometrisches Verfahren zur Analyse von Substanzgemischen
DE10208626 2002-02-28
DE2002108625 DE10208625A1 (de) 2002-02-28 2002-02-28 Massenspektrometrisches Verfahren zur Analyse von Substanzgemischen
PCT/EP2003/001274 WO2003073464A1 (de) 2002-02-28 2003-02-10 Massenspektrometrisches verfahren zur analyse von substanzgemischen

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EP1481416A1 EP1481416A1 (de) 2004-12-01
EP1481416B1 true EP1481416B1 (de) 2016-06-15

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US (1) US7196323B2 (ja)
EP (1) EP1481416B1 (ja)
JP (3) JP2005526962A (ja)
AU (1) AU2003218649B2 (ja)
CA (1) CA2476597C (ja)
ES (1) ES2590759T3 (ja)
IL (1) IL163290A (ja)
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WO (1) WO2003073464A1 (ja)

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JP2014041142A (ja) 2014-03-06
US20050103991A1 (en) 2005-05-19
IL163290A (en) 2014-01-30
WO2003073464A1 (de) 2003-09-04
US7196323B2 (en) 2007-03-27
AU2003218649B2 (en) 2007-09-06
ES2590759T3 (es) 2016-11-23
CA2476597C (en) 2011-05-17
EP1481416A1 (de) 2004-12-01
JP2005526962A (ja) 2005-09-08
AU2003218649A1 (en) 2003-09-09
JP2010019848A (ja) 2010-01-28
NO20043943L (no) 2004-09-21

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