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Pharmacology > Metabolomics Q and A > Flashcards

Metabolomics Q and A Flashcards

1
Q

Which molecules can be seen?

A
  • Biochemicals (Metabolites)
    -> organic or inorganic
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2
Q

What are typical applications of metabolomics?

A

-> investigate several human diseases, improve their diagnosis and prevention -> design better therapeutic strategies/”personalized metabolic phenotyping”
- nutritional analysis
- clinical blood/urine analysis
- cholesterol testing
- drug safety

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3
Q

Why is metabolomics analytically more complex than proteomics or genomics?

A
  • no simple building blocks
  • huge number of chemicals possible
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4
Q

If you compare genomics, proteomics and metabolomics:
a) Which has the greatest variety of compounds?
b) For which do we have the best analytical coverage, for which the worst?

A

A) metabolomics 8x10^5
B) metabolomics -> proteomics -> genomics

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5
Q

Which factors influence the human metabolome?

A

-> Nährstoffangebot, Effekte von Wirksubstanzen, Umweltfaktoren

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6
Q

Why and how is metabolomics used to assess food quality? Which information can be gained?

A

Zusammensetzung, Reinheit, Herkunft

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7
Q

Describe a metabolomics workflow

A

1) samples
2) record chemical data
3) process dataset
4) analyse/model data/identity
5) interpret the result

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8
Q

Describe the difference between targeted and untargeted metabolomics

A

UNTARGETED ANALYSIS
- no Prior knowledge of metabolites of interest
- finger printing (binned spectra) or profiling (concentrations of all quantifiable metabolites)
- statistical approach
and then multivariate analysis or univariate analysis

TARGETED ANALYSIS
- Prior knowledge of metabolites of interest
- statistical approach

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9
Q

How is the resolving power in MS defined?

A

delta M/M

-> the ability of an instrument or measurement procedure to distinguish between two peaks at m/z values differing by a small amount and expressed at the peak width in mass units

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10
Q

Name two common ionization methods for MS

A
  • Chemical ionization (CI)
  • electron impact (EI)
  • electron spray ionization (ESI)
  • matrix-assisted laser desorption ionization (MALDI)
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11
Q

Why does GC-MS require derivartization?

A

The compounds have first to be in the gaseous phase in order to get analyzed

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12
Q

What are the detection limits for GC-MS, LC-MS and NMR

A

GC-MS: LOD = 100 nM - organic and inorganic classes
LC-MS: LOD = 5 nM - organic and inorganic classes
NMR: LOD = 5 µM -quantitativ-organic classes

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13
Q

Which substances are seen in NMR spectra of blood serum that are strictly not metabolites?

A

Glycoproteins and lipoproteins

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14
Q

What is the difference between multivariate and univariate statistics?

A

multivariate = mehrere statistische Variablen zugleich

univariate = einzelne Variablen ohne sich um eventuell vorhandene Einflussgrößen oder Zusammenhänge zu kümmern

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15
Q

How can one get a homonuclear decoupled 1D?

A

J-RES: Tilt, symmetrise, projection

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16
Q

Which extra information can be gained from J-RES spectra

A
  • couplings in 2D mode, decoupling after tilt and projection
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17
Q

What is the effect of CPMG?

A

Get rid of broad lines from proteins, T2 filter

18
Q

NMR spectroscopy -> advantages and disadvantages

A
  • solution state (plasma, urine, extracts)
  • MAS (tissue extracts, tissue)
  • MRI in vivo chemical shift imaging
  • relatively robust

ADVANTAGES
-simple sample preparation
- highly reproducible
- quantitative
- can detect any metabolite above 5 µM
- structure elucidation of unknown compounds
- High throughout (50 samples per day)

DISADVANTAGES
- limited sensitivity (5 µM), limited number of metabolites (50 - 200)
- complex data deconvolution

19
Q

Mass spectrometry (MS)

A
  • GC-MS
  • LC-MS
  • more analytically< sensitive (5 nM)
  • potentially truly global
  • problems with ionization
  • standardisation is challenging

ADVANTAGES
- structural elucidation of unknown compounds (accurate mass fragments)
- large number of metabolites detected and quantified
- automation requires massive quality control
- high throughput - 100 samples per day

DISADVANTAGES
- many different variants, data from different sources not comparable
- not as robust as NMR
- high level of QC needed

20
Q

Which 2D spectra can be used for metabolomics?

A

HSQC before all others; HSQC-TOCSY, HMBC

21
Q

Why can lipoproteins be separated by HPLC?

A

Size exclusion

22
Q

Which groups can be detected by NMR lipoprotein analysis

A

VLDL, LDL, HDL, with subfractions, IDL, cholesterol, triglycerides, phospholipids

23
Q

Which other protein class shows up in NMR spectra of blood?

A

Glycoproteins

24
Q

How are these complex signals of lipoproteins analysed?

A
  • Complex line-shape fitting, different versions
25
Q

P-values - understand qualitatively

A

The probability that the observed result was obtained by chance (i.e. the H0 is true) -> if the p-value is small, it suppress the observed result cannot be easily explained by chance

26
Q

What information does a t-test give

A

used to compare the mean of two independent groups

27
Q

What is STOCSY?

A
  • statistical correlation spectroscopy (STOCSY)
  • generates a pseudo 2D-NMR spectrum that displays the correlation among the intensities of the various peals across the whole sample
28
Q

PLS vs PCA

A

PCA
- unsupervised method
- used for clustering
- shows similarities in variables
- maximizing the variance that is explained by the model

PLS
- supervised method
- used for classification
- shows discrimination between variables
- maximizing the covariance

29
Q

1D Noesy

A

water suppression

30
Q

CPMG

A

removal of large proteins

31
Q

diffusion-edited spectra

A

removal of small molecules

32
Q

J-resolved spectra (tilted and projection)

A

2D spectrum with couplings in 2nd dimension -> after processing: 1D without couplings

33
Q

Diffusion-ordered spectroscopy (DOSY)

A

separation of diffusion coefficient

34
Q

Derivatization

A
  • goal: make the analyte more volatile (pre-column)
  • in the case of amino acids derivatization replaces the OH, NH2 and SH functional groups with a non-polar moiety
    -> Silylation is a very common derivatization
    -> Trimethylsilylation is the most common approach which can be achieved using bromotrimethylsilane (TMBS) or chloretrimethylsilane (TMCS)
35
Q

Massenspektrometrie: Rund um den Molekülpeak werden Satelliten beobachtet -> erklären Sie den Effekt

A

ISOTOPENVERTEILUNG
- 12C -> 13C
- 1H -> 2H
- 14N -> 15N
- 16O -> 17O

36
Q

PCA

A
  • finds the largest correlations between variables within a data set
  • the PCA is equivalent to fitting an m-dimensional ellipsoid to the data, where the eigenvectors of the covariance matrix of the data set are the axes of the ellipsoid -> the eigenvalues represent the distribution of the variance among each of the eigenvectors

C*V = gamma * V
C = covariance matrix
V = corresponding eigenvector

37
Q

Therapeutic Ratio

A

LD50/ED50

38
Q

Therapeutic Index

A

LD25/ED75
LD10/ED80

39
Q

Statine

A
  • Cholesterinsenker
  • Lipidsenker
40
Q

Massenspektrometrie

A

Basispeak = höchster Peak -> zeigt die Häufigkeit des häufigsten Ions
-> wird auf 100 % gesetzt und alle anderen peaks werden darauf bezogen

Molekülpeak = Molekülion, das die höchste Masse des Spektrums hat -> zeigt die relative Molekülmasse der Verbindung

Isotopenpeak = zeigt die natürliche Häufigkeit der Isotope -> rechts vom Molekülpeak (die kleinen Peaks)

  • Molekülion zerbricht bevorzugt an chemischen Bindungen mit funktionellen Gruppen
41
Q

Non-competitive antagonists

A
  • decrease Emax of the agonist
  • the ED50 of the agonist is NOT changed
42
Q

Competitive antagonist

A
  • lead to a parallel shift in the dose-response curve of the agonist (ED50 will increase)
  • the Emax of the agonist is NOT affected

Pharmacology (22 decks)

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