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Index

Note: The letter following page numbers specify figures, tables, and notes.

AAPtdE (1-alkyl-2-acyl-phosphatidylethanolamine), 381–382, 389t,389f, 391t, 394t

AbsoluteIDQ, 22–23Abundance

changes, monitoring, 180fragment, 42–43ion, 41–42, 212natural, 43–46, 348, 417t, 416–417, 432–433,

434f, 449, 473–474, 474t, 573relative, 72f, 73relative isotopic abundances, 167, 168, 173nSIM-stitching, 159–161, 163t, 163, 165

Accuracycalibration, 165cancer detection, 220, 367Fourier transform mass spectrometry (FTMS),

174–175, 178–180FT-ICR, 159–161, 175tgestational age, 287, 289–290HR-FTMS, 161internal standards, 103lipid analysis, 35–36literature reviews, 175mass, 21, 41, 42, 159–161, 166, 169–170, 175t,

174–175, 180, 230m/z accuracy, 196–197phospholipid analysis, 71–73quantitative, 13–14, 105–106, 322relative isotopic abundances, 167, 168, 173nserum sample assay, 220shotgun lipidomics, 41–46structural elucidation (See Structural

elucidation)Acetaminophen

13C NMR studies, 432–433, 434fion mobility mass spectrometry (IMMS), 199solvent for analysis of, 208spectra of CSF interference by, 258–259

Acetatehuman tissues (HR-MAS studies), 500f,

499–500, 501, 514–515tin saliva, 274t, 275f, 275

Acetic anhydride, 448t, 453–455Acetoacetate, 423–424, 427Acetonitrile in extraction, 86–87, 208N-acetylaspartate

cerebrospinal fluid 1H-NMR studies, 261–263,264–265

human tissues (HR-MAS studies), 497, 498f,508

N-acetylaspartylglutamatecerebrospinal fluid 1H-NMR studies, 260–261,

311–312in genetic metabolic diseases, 311–312

N-acetylated amino acids, 306f, 308t, 309–310Acetylcarnitine, 448t, 449Acetylcholine, 435f, 433–435, 436N-Acetylglutamylneuraminic acid, 303N-Acetyl-L-methionine, 448t, 457–458N-Acetylneuraminic acid (free sialic acid)

cerebrospinal fluid 1H-NMR studies, 303, 311f,310–311

in genetic metabolic diseases, 303, 310–311,311f

Acidsion exchange of strong acids, 239t, 239ion exchange of weak acids, 239t, 239–240

Acquisition time (window), 13, 231, 357–358,385–386, 400–402, 407, 458–462, 464, 505t,506–507, 527f, 526–527, 528, 564–566, 566f,568f, 569f, 570f, 572, 575f, 576f

Activation, 180, 398–399Acute meningitis, 265–266�−cyano-4-hydroxycinnamic acid, 121–122Acylation, 213–214Acylcarnitine, 6, 19–20, 22–23Adenoviridae, 58f, 56–58, 59

585

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586 Index

Adenylosuccinate lyase (ADSL) deficiency, 264Adiabaticity, 462Adrenalin, 508�-Fetoprotein, 282�-Ketoglutarate, 424f, 425f, 424–425, 426, 437AKT/PDK1/mTOR pathway, 69Alanine

human tissues (HR-MAS studies), 500f,499–500, 501, 507, 514–515t

resonance assignment, 573–574in saliva, 274t, 275f, 275

Alcohol, 11, 12, 16, 23–24, 93–95, 211–212, 214,258–259, 264–265, 379, 405–406

Alkaptonuria, 248f, 249f, 248–249Alkenes, ether-linked, 381–382Alkylation, 214Allografts, 357. See also Cancer�-cyano-4-hydroxycinnamic acid, 121–122Alzheimer’s disease, 266, 326–327AMARES, 364–366Ambient pressure ion mobility mass spectrometry

(APIMMS), 186–189AMDIS, 18Amines

dopamine, 198ethanolamine, 380f, 379–380, 381glutamine, 417t, 437histamine, 151phosphatidylethanolamine (See

Phosphatidylethanolamine)polyamines, 199psychotropic phenylalkylamines, 207ttrimethylamine oxide, 274t, 275f, 275

Amino acids, 309–310, 449, 453–4559-Aminoacridine, 121–122Aminoacylase-1, 457–458Aminoacylase 1 deficiency, 305f, 306f, 308t,

309–310� -Aminobutyric acid. See GABA

(� -aminobutyric acid)3-Aminopropylphosphonate (3-APP), 352, 363,

364fAMIX, 13, 15Ammonium

acetate, 71, 86–87, 161–163, 176tbicarbonate, 176t, 177–178citrate, 125formate, 176tgroups, 35–36, 237–239, 562, 574hydrogen carbonate, 84–85hydroxide, 67–69salts, 105, 239–240species, 178–180sulfate, 208

Amniotic fluid�-fetoprotein, 282analysis sensitivity, 283–284, 292–293biomarker mining, 282 (See also Biomarkers)Ca2+ complexation, 285choline, 292–293, 294f

choline-esterase, 282chromosomal disorders, 282, 289CPMG (Carr-Purcell-Meiboom-Gill), 284f,

291f, 291–292creatine in, 284f, 290tcystic fibrosis, 282, 289diffusion ordered spectroscopy (DOSY),

284–285electronic reference to access In vivo

concentrations (ERETIC), 286–287fetal gender, 288–289fetal lung maturity, 289, 290–291, 292–293, 294ffetal malformations, 291–292gestational age effects, 287, 289–290gestational diabetes, 291–292healthy pregnancy profile, 284f, 283–284, 285f,

286f, 287, 288f, 290thigh resolution and magic angle spinning

(HR-MAS), 287, 290–291HMQC, 274–275, 5671H NMR Spectroscopy, 284f, 282–284, 285f,

286f, 288f, 291f, 292HRQUEST, 287insulin dependent diabetes mellitus (IDDM),

289–290intestinal atresia, 289LC-NMR, 286fLC-NMR/MS, 284–285lecithin, 293magnetic resonance imaging (MRI), 281–282,

292–293magnetic resonance spectroscopy (MRS),

281–282, 292–293maternal age, 288–289metabolite composition, factors affecting,

288–289metabonomics applications, 281, 293–295multivariate analysis, 281, 289, 291f, 2932D NMR, 283–284partial least squares and discriminant analysis

(PLS-DA), 281, 291f, 291–292phosphatidylcholine, 292phospholipid analysis, 282, 29231P NMR, 292preeclampsia, 289premature rupture of membranes (PROM),

291–292prenatal diseases, 291f, 289–291, 292prenatal disorders, 291f, 289–291, 292preterm delivery, 291–292principal component analysis (PCA), 281, 291f,

291–292sphingomyelin, 292spina bifida, 289–290, 290tsugars in, 284–285, 291–292TOCSY, 283–284, 285ftrisomy 21, 289TSP (trimethylsilyl-propionic-2, 2, 3, 3 acid),

290–291Amplification (in NMR), 61–63, 475




Index 587

Amyotrophic lateral sclerosis, 266Anaerobic glycolysis, 265–266, 339–340, 483,

497–499AnalyzerPro, 18Anaplastic astrocytoma, 438, 439fAnaplerosis, 429f, 428–429, 430f, 432f, 433, 434fAndrogens, 207tAnesthesia

animal preparation, tissue excision, 405, 418f,459t

blood samples, 421cell isolation, 125–126in MS workflow, 121in vivo MRS, 359f, 357–359, 361, 364f

Angina, 428Angiogenesis, 336, 437Animals, experimental

anesthesia, 405, 418f, 459tAplysia californica, 120–121mouse, 417t, 421–422, 423t, 428, 432–433rat, 146, 147f, 149, 417t, 421–422, 423t, 428,

432–433tissue samples, 405Torpedo californica, 144–145in vivo MRS, 475–477 (See also Human tissues

(in vivo MRS studies))Anomers, 235, 312–313, 431, 529, 572Antibodies

binding of, 63cross-reacting, 215–217, 220–221immunodetection, 65–66monoclonal, 65–66polyclonal, 65–66quantitation of, 58, 64fstains, 149

Antidepressants, 207tAntiepileptic drugs, 258–259Antipsychotic medications, 266Antipsychotics, 207tAphelandra squarrosa (zebra plant), 147, 148f,

148–149Aplysia californica, 120–121Apodization, 322, 408f, 408–409, 563Apoptosis, 329, 455–4563-APP (3-aminopropylphosphonate), 352, 363,

364fApparent rate constant, 452–453Arabidopsis thaliana

LAESI studies, 147material collection, 89–90, 94f

D-Arabinitol, 259–260Arabitol

cerebrospinal fluid 1H studies, 259–260,261–263

in genetic metabolic diseases, 305f, 306f,308t

Arginine:glycine amidinotransferase (AGAT)deficiency, 263–264

Aromatic carbons, 577–578Aromatic protons, 235, 577–578

Arrhenius equation, 398–399Arrhenius plot, 399Artifacts, 84–85, 477Artificial seawater, 123Ascorbic acid (Vitamin C), 258–259, 500f,

499–500, 501, 514–515tAspartate, 417t, 423tAstrocytoma, 476f, 484fAtmospheric pressure ionization, 141Azide, 11

Background signal, 263–264Bacteria. See specific organisms by nameBacterial contamination, 11, 84. See also specific

organismsBalanced steady-state free precession (BSSFP),

460tBaseline (correction of), 13–14, 47, 130–131, 322,

408–409, 422, 505t, 508–509Bases

ion exchange of strong bases, 237–239, 239tion exchange of weak bases, 239t, 239

Batch growth, 82t, 81–82, 83B0 correction, 461–462Benign prostatic hyperplasia (BPH), 218f,

218–220Benzodiazepines, 207tBetaine

13C NMR studies, 435f, 433–435, 436in genetic metabolic diseases, 303–304, 305f,

308t�-glucuronidase, 209–210�-glucuronidase/arylsulfatase, 209–210�-hydroxyisobutyrate (BHIB,

3-hydroxyisobutyrate), 265–266Bicarbonate, 448t, 450, 455–456Binning

in chemometrics, 246, 248f, 248–249, 249f, 252f,252

human tissue analysis, 509–510Biobanks, 97, 497–499Biochemical. See also Biochemistry

amniotic fluid (See Amniotic fluid)biomarkers (See Biomarkers)capillary electrophoresis (CE), 120, 122, 150cell analysis, 149 (See also under Cell; MALDI

(cell analysis))cellular membrane bilayer characteristics, 30clinical, mammalian analysis, 95 (See also

Clinical, mammalian based samplepreparation)

13C NMR (See 13C NMR studies)CSF (See Cerebrospinal fluid (CSF) 1H NMR

studies)diseases (See specific disease by name)electrochemical detection, 119–120, 149empirical formulae assignments, 167–168energy metabolism, 340–341enzyme properties, 66–67human tissues (See under Human tissues)




588 Index

Biochemical (cont.)IEMs (See Inborn errors of metabolism)imaging, 79–80IMMS (See Ion mobility mass spectrometry

(IMMS))magnetic resonance spectroscopy (MRS) (See

Magnetic resonance spectroscopy (MRS))monitoring, 205–208networks, 525–526, 578–580pathway mapping, 47–49peak assignment, prior knowledge, 170,

217–218phosphoinositide abbreviations, 379–381plant analysis, 87–89, 90–91 (See also Plants)quenching, 140radiotracers, 415sample degradation, 80, 126, 210, 319, 477, 491f,

497–500, 500f, 501, 502–504, 506–507tumor oxygen tension, 363–364urine (See Urinalysis)urocanylglycine, 308t, 312

Biochemistry, 66, 119, 140, 282, 329, 416, 449. Seealso Biochemical

BioCyc, 161Biofluids. See also specific fluids

contamination, 12ion mobility mass spectrometry (IMMS), 194f,

192–194, 200fpH in, 300–301, 303relaxation, 284f, 283–284, 293, 301retention, 100–101salts in, 10–11, 208sample preparation, 8–11, 300serum, plasma sample preparation, 100–101specialization in, 5

Biohazards, 11Bioinformatics

adducts, 167annotation, 168apodization, 164calibration, 165, 166databases, 161, 169–170, 173ndata processing, 162DI nESI FT-ICR MS, 163direct infusion, 162dynamic range, 163empirical formulae, 167–168, 173nfast Fourier transform, 165Fourier transform ion cyclotron resonance

(FT-ICR) (See Fourier transform ioncyclotron resonance (FT-ICR))

identificationnonstructural, 161, 166–168putative, 161, 169–170structural, 161, 169–170

ions, 167, 173nisotopes, 167, 173nmass spectra measurement, 163metabolite extraction, 161–163metabolite identification, 166–168

nanoelectrospray, 162Orbitrap, 159–161peak detection, quantitation, 165, 169–170,

173nregular expressions, 173nrelative isotopic abundances, 167, 168, 173nsignal filtering, 163, 165–166SIM-stitching, 159–161, 163t, 163, 165software, 159–161, 162, 173ntools, 161, 173ntransient summation, 164Xcalibur, 159–161zero-filling, 164

Biojava, 173nBiomarkers

in amniotic fluid, 282 (See also Amniotic fluid)cancer, 218f, 220f, 218–220, 326, 328–329clinical, mammalian sample preparation, 98functional markers, 525HILIC-NMR, 241identification by multivariate analysis, 54LAESI discovery of, 145metabolic disorders, 220–221metabolomic strategy for data mining, 217–218in neurodegenerative diseases, 266in saliva, 276toxicity evaluation, 218, 219f

Biopsy samplesbuffers, 502–504contamination, 502–504CPMG (Carr-Purcell-Meiboom-Gill), 498f,

504–506, 507, 511f, 511–512, 513f, 517fheterogeneity, 496–497kidney, 503f, 511–512, 513f, 514–515t, 516treproducibility, 497–499salts in, 502–504, 529

Biopython, 173nBioRad’s KnowItAll Metabolomics Edition, 217tBioreactors, 82t, 83, 356–357Blood. See Serum, plasma (blood)Blood brain barrier, 455. See also BrainBlood volume

cerebral, 455plasma, 206–207

BluGnome’s BluFuse, 217tBMRB peaks server, 15Bolus, 271, 453, 455–456, 458–462, 464–465Boyden chamber, 356–357Brachypodium distachyon, 89–90Bradbury-Nielson (BN) gate, 187Brain

blood brain barrier, 455cancer, 476f, 483, 484f, 485f13C NMR studies, 418t, 421–422, 423t, 435f,

433–435, 436compartment, 433–434glia, 433–436grey matter, 263–264, 383–385, 403–405, 477metabolism, intermediary, 418f, 433–436MRS studies, 259–260




Index 589

neurotransmitters, 122, 144–145, 146, 257–258,429, 433–436 (See also specificneurotransmitters)

pig, 418f, 420–421white matter, 260, 261, 264, 312, 383–385,

403–405, 477Brain metabolic compartmentation, 434–435Brassica oleracea, 93–95Breast cancer, 337f, 336–337, 486f, 486–487, 487fBSA (bovine serum albumin), 37, 63, 65, 213BSSFP (balanced steady-state free precession),

460tBucketing

in chemometrics, 246, 248f, 248–249, 249f, 252f,252

human tissue analysis, 509–510Buffers

benefits of, 3biopsy samples, 502–504cell culture, 101–102, 348–349in chemometrics, 251–252ChoK� assay, 67–69conjugated metabolite hydrolysis, 208–210contamination, 11culture quenching, 101–102dissolution, 447, 459tgene expression analysis, 60–61, 63, 65–66HILIC, 177–178, 179f, 184nhomogenization, 36–38LC-MS, 175, 176t, 176, 184n (See also LC-MS)lipid extraction, 71membrane blocking, 65NMR sample preparation, 300–301, 447, 459tPI3K analysis, 70plasmid vectors, 55–56protein removal, 208protonated organic, 12removal, 231RPLC, 176–177, 184nsaliva, 277–278solid-phase extraction (SPE), 210–211, 232fin statistical analysis, 251–252tissue extraction, 34, 319

13C (carbon-13)enrichment, 446labeling, 423–42431P detected, 335–336

13C NMR studiesacetaminophen, 432–433, 434facetylcholine, 435f, 433–435, 436acetyl-CoA labeling, 423–424advantages of, 415–416�-ketoglutarate, 424f, 425f, 424–425, 426, 437anaplastic astrocytoma, 438, 439fanaplerosis, 429f, 428–429, 430f, 432f, 433, 434faspartate, 417t, 423tbasic principles of, 417t, 416–417, 418f, 419betaine, 435f, 433–435, 436brain, 417t, 421–422, 423t, 435f, 433–435, 436

cancer metabolism, 343–344, 348, 360f, 360–361,363, 435f, 436–438, 439f, 473t

cancer metabolites detected, 348, 360f, 360–361,363, 474t

chemical shifts, 417t, 417, 418fcholine, 435f, 433–435, 436choline phospholipid metabolism, 339, 437–438citrate, 417tcitric acid cycle (See Krebs cycle)diabetes, 427–428drug effects, 428energy metabolism, 417t, 421–422, 423tethanol, 417texperimental conditions, 417t, 421–422, 423tfatty acids, 426f, 426–427fumarate, 417t, 424f, 425f, 424–425, 426,

436GABA (� -aminobutyric acid), 417t, 423t, 435f,

433–435, 436glioblastoma, 437glioma, 437gluconeogenesis, 417t, 421–422, 423t, 429f,

428–429, 430f, 432f, 433, 434fglucose, 417t, 431, 432fglutamate, 417t, 421–422, 423t, 424f, 425f,

424–425, 426f, 427, 429f, 428–429, 430f,432f, 433, 434f, 437

glutamine, 417t, 437glutathione, 437heart, 417t, 421–422, 423t, 427–428hydroxyglutaric acid, 436hyperpolarized NMR spectroscopy, 360–361,

438–439, 460t (See also HyperpolarizedNMR spectroscopy)

ischemia, reperfusion effects, 428isocitrate dehydrogenase, 436isotopic labeling, 339–340, 343–344, 348, 356,

363, 418f, 419–420, 421, 423–424, 425f, 426f,426–427, 430f, 428–430, 433, 449, 461–462,465–466, 563–564, 576–577, 578–579, 579f,580

isotopomers, 418f, 420–421, 423t, 425f, 424–425,426f, 427

J (spin-spin, scalar) coupling, 419lactate, 417t, 423t, 435f, 433–435, 436line widths, 416–417liver, 417t, 421–422, 423t, 429f, 428–429, 430f,

432f, 433, 434fmetabolic pathway assessment, 419–420metabolite quantitation, 419mouse, 417t, 421–422, 423t, 428, 432–433multiplets, 419–420, 437nuclear spin, 416–417oxaloacetate, 424f, 425f, 424–425, 426, 430f,

428–430, 432f, 433, 434foxidation, 419–420, 421, 423t, 424f, 425f,

426fparaganglioma, 436perhexiline, 428phenylacetate, 432–433




590 Index

13C NMR studies (cont.)pheochromocytoma, 436phosphocholine, 435f, 433–435, 436phosphoenolpyruvate carboxykinase (PEPCK),

432propionate, 429f, 428–429, 430f, 432f, 433, 434fpyruvate, 417t, 421–422, 423t, 426f, 426–427,

430f, 428–430, 432f, 434f, 433–434, 435f,436

radiotracer studies historically, 415rat, 417t, 421–422, 423t, 428, 432–433relaxation times, 416–417, 465–466resonance assignment, 527f, 526–527, 528f, 564,

566f, 569f, 572–573, 575f, 574–575, 576Saccharomyces cervesiae, 419–420scalar coupling, 419, 436–437sensitivity, 360–361, 416–417, 419, 426–427, 430,

436–437, 438–439SF188 cells, 437succinate, 417t, 424f, 425f, 424–425, 426, 436

Caffeine, 200, 201fCAFSA (cerebellar ataxia with elevated

cerebrospinal free sialic acid), 260, 308t,310–311, 311f

Calibrate. See CalibrationCalibration

accuracy, 165external, 13, 18–19, 129, 159–161, 165, 175tfive-point curve, 161H NMR, 227, 504–506internal, 13, 125–126, 128, 165, 166mass and mobility, 190–191m/z accuracy, 196–19731P NMR, 401quantitative, 7t, 378recalibration, 130–131reference solutions, 13, 346–347, 377, 508sets, creation of, 254–255shotgun lipidomics, 41–42solvents, 401TWIMS, 199–200

Camo’s The Unscrambler, 217tCanavan disease, 261–263Cancer

allografts, 357AMARES, 364–366anaplastic astrocytoma, 438, 439fanticancer treatment, 361, 362fastrocytoma, 476f, 484fbiomarkers, 218f, 218–220, 220f, 326, 328–329bioreactors, 356–357brain, 476f, 483, 484f, 485fbreast, 337f, 336–337, 486f, 486–487, 487fcell, tumor tissue extracts (See Tissue extracts)cell cultures, 346, 348, 355f, 354–355, 357cell death, 361cell perfusion, 343–344, 348cervical, 488f, 487–488chemically selective saturation (CHESS),

358–360

chemical shift imaging (CSI), 335–336, 357–358,363–364

CHESS water suppression, 356, 358–360choline, total (tCho), 336–337, 344–345, 345f,

357–358, 359f, 361–362, 362f, 364–366, 476f,483, 486–487, 488–489

choline phospholipid metabolism, 337f,336–337, 339, 344–345, 345f, 437–438

choline transporter-like protein-1 (CTL1), 337f,338

13C MRS, 343–344, 348, 360f, 360–361, 363,435f, 436–438, 439f, 474t

CPMG (Carr-Purcell-Meiboom-Gill), 482–483,488f, 489f, 490f

creatine in, 473f, 476f, 483, 484f, 485f, 486f, 487f,490f, 491f, 497, 514–515t

CTP:phosphocholine cytidylyltransferase(CCT), 337f, 338

cytosolic PC-PLA2 (cPC-PLA2), 337f,338–339

deconvolution, mass spectrometry, 218–220detection accuracy, 220, 367detection sensitivity, 360, 367, 477diacylglycerol (DAG), 210, 623, 342f, 341–342,

343f, 343diphosphodiester (DPDE), 345f, 346–347docetaxel, 361, 362f, 486f, 487fenergy metabolism, 340–341ependymoma, 485fglioblastoma, 484f, 517f, 516–517, 518f,

518glioma, 437glucose/lactate metabolism, 340f, 339–340glutamine, 417t, 437glutathione, 437glycerophosphocholine, 336–337, 337f, 345f,

344–345, 346–347glycerophosphoethanolamine, 345f, 346–347glycolysis, 339–340, 340f, 360f, 360–361hepatocellular carcinoma (HCC), 463–464hexamethyldisiloxane (HMDSO), 363–364histology, 476f1H MRS studies, 367, 497, 498fhsp90, 361, 362fhypoxia, 363–364hypoxia inducible factor alpha (HIF-1�),

339–340, 340fisocitrate dehydrogenase, 436lactate, 346lipid droplets, 342f, 341–342, 343f, 343, 345–346,

347flipid profiling, 326, 328–329live cell MRS

cell suspensions, pellets, 353–354perfused cell cultures, 355f, 354–355,

357lymphoma, 464–465lysophospholipase (LYPLA), 337f, 338–339magnetic resonance spectroscopic imaging

(MRSI), 335–336, 357–358, 364–366, 367




Index 591

magnetic resonance spectroscopy (MRS),335–336, 367

medulloblastoma, 485fmetabolic pathways, 335–336, 436–437metabolic phenotype characterization, 336MN58b, 345f, 361–362MRS method comparison, 366–367, 472MRUI, 364–366oligodendroglioma, 497, 498f, 517f, 516–517,

518f, 518oncogenes, 56–57, 336–337, 340f, 339–340, 357,

436organic cation transporters (OCTs, SLC22),

337f, 338ovarian, 218–220, 336–337, 337foxidative phosphorylation, 340–341oxygen in metabolism, 218–220, 355f, 363–364,

436–438paraganglioma, 436p53 gene, 436pheochromocytoma, 436pH in, 346–347, 363, 364f, 365fphosphatidate, 343f, 341–343phosphatidylcholine (PtdCho), 337f, 336–337,

339, 342f, 343f, 348phosphatidylethanolamine (PtdEth), 341–343,

343fphosphatidylserine (PtdSer), 343f, 341–343phosphocholine (PC), 336–337, 337f, 345f,

344–345, 348phosphodiester (PDE), 345f, 346–347, 360phospholipids, 345f, 346–347phosphomonoester (PME), 345f, 346–347, 360,

436–43731P MRS, 343–344, 345f, 346–347, 352, 355f,

356, 360, 363, 364f, 365f, 366preclinical model systems

isotopic labeling, 343–344metabolites detected by 13C MRS, 348, 360f,

360–361, 363, 474tmetabolites detected by 1H MRS, 345f,

344–345, 346, 347f, 364–366metabolites detected by 31P MRS, 345f,

346–347, 360, 363, 364f, 365foverview, 343–344solvents, 343–344

PRESS (Point RESolved Spectroscopy),357–358

prostate, 489f, 488–489, 490fPtdCho-specific phospholipase A2 (PC-PLA2),

337f, 338–339PtdCho-specific phospholipase C (PC-PLC),

337f, 338–339PtdCho-specific phospholipase D (PC-PLD),

337f, 338–339purines, 345f, 346–347pyrimidines, 345f, 346–347sample contamination, 490f, 511–512sample degradation, 477, 491f, 497–500, 500f,

501

SF188 cell studies, 437signal intensity, factors affecting,

335–336SNR (signal-to-noise ratio) in, 483spatial localization, 335–336sphingomyelinase, 337f, 338–339stimulated echo pulse sequence (STEAM),

355f, 356, 357–358TCA cycle (See Krebs cycle)TF-MISO (2-Nitro-�-[(2, 2,

2-trifluoroethoxy)methyl]-imidazole-1-ethanol), 363–364

treatment response, 66–67, 72f, 335–336, 361,362f, 364f, 367, 474–475, 525, 527f

triacylglycerols (TAGs), 342f, 341–342, 343f,343

tumor suppressors, 339–340, 436VAPOR water suppression, 356, 358–360variability in, 512–513variable projection program (VARPRO),

366in vivo models

choline kinase targeting, 345f, 361–3621H MRS, MRSI quantification, 364–366labeled substrates, 363methods, 359f, 357–359, 360f, 361overview, 357pH measurement, 363, 364f, 365ftreatment efficacy detection, 361,

362ftumor oxygen tension, 363–364

water suppression, 356xenografts

breast cancer, 363mouse models, 357, 359ftCho detection, 361–362treatment efficacy detection, 361, 364fin vivo MRS, 357–358

Cannabinoids, 207tCapillary electrophoresis (CE)

cell metabolite detection, identification, 120,122, 150

history of, 6Capillary electrophoresis-electrospray

ionization-mass spectrometry. SeeCE-ESI-MS

Carbohydratescomplexity in spectra, reduction, 1991H NMR, 258–259IMMS studies, 200isolating lipids from, 71in metabolic profiles, 80overview, 3in plant metabolic profiles, 91–92in rat brain, 198in saliva, diurnal variations, 275 (See also

Saliva)in spina bifida, 290ttargeted metabolite profiling, 217–218trend lines, 185, 196–197, 197f




592 Index

Carbonin acyl chains, 35aromatic, 577–578brain metabolism, intermediary, 418f, 433–436carbon-by-carbon ‘degradation, 416–419carbon-carbon (13C-13C) coupling, 419,

420–422, 446–447, 563–564, 573–574carbon-3 pyranose rings, 310–311, 311fcitric acid cycle (See Krebs cycle)in culture media, 81–83decarboxylation, 424–426, 429f, 437–438elemental mass calculation, 166–167in fatty acids, 380f, 381–382flux, 166, 213–214in glioblastoma, 437gluconeogenesis, 417t, 421–422, 423t, 429f,

428–429, 430f, 432f, 433, 434fglutamine multiplets, 423t, 432f, 439fin isotopomers, 420–421, 423–424methine in sugars, 573quaternary, 573–574radiotracers, 415relative isotopic abundances, 167, 168,

173ntracers, 415, 425f, 424–425, 427

Carbon-13. See 13C NMR studiesCarboxylation, 418f, 429f, 428–429, 430f, 433–434,

579f, 580Carboxyl groups, 319–320Carboxylic acid, 211–212, 213, 214, 233, 350,

466–467dicarboxylic acid, 258–259tricarboxylic acid (TCA) (See Krebs cycle)

Carboxypeptidase G2, 457–458Cardiolipin

31P NMR studies, 380f, 379–380, 381, 389t, 391t,394t

shotgun lipidomics studies, 43–46CARMeN project, 497Carr-Purcell-Meiboom-Gill. See CPMG

(Carr-Purcell-Meiboom-Gill)CCT(CTP:phosphocholine cytidylyltransferase),

337f, 338CDTA (cyclohexanediaminetetraacetic acid)

in cancer studies, 352chemical shift effects, 390f, 392f, 394t, 393–394,

395f, 396, 403–405linewidth effects, 390f, 392f, 394t, 393–394, 395f,

396, 403–405in phospholipidomics 31P NMR studies, 390f,

392f, 394t, 393–394, 395f, 396, 403–405solvents, 318, 387f, 390f, 392f, 393f, 395f,

393–395, 396, 397f, 403–405CE-ESI-MS (cell analysis)

analysis technique, 128–129applications, 121, 135, 150fragmentation, 124, 130instrumentation, setup, 121f, 124, 126–128overview, timing of, 121–122results, data analysis, 130, 131–132, 132f

sample preparation, mammalian, 123, 125–126solvents, 126–128time of flight (TOF), 124, 126–128

Cell cultureadvantages of, 33–34applications of, 32–33buffers, 101–102, 348–349cancer, 346, 348, 355f, 354–355, 357clinical, mammalian-based sample preparation,

101–102, 104f, 105contamination of, 33–34, 35–36dual phase extraction, 350, 351fextracts, concentrating, 529gene expression modulation, 54, 55, 56–59growth, harvesting, 348–350medium, 56–59, 348–349, 354–357oxygen in, 83, 355f, 354–355, 356perfused, 355f, 354–355, 357reproducibility, 83, 121sample preparation (See Culture methods

sample preparation)SNR (signal-to-noise ratio) in, 529solvents, 101–102

Cell deathapoptosis, 329assaying, 66–67, 69, 329cancer, 361triacylglycerols (TAGs), 341–343

Cell extractioncancer

cell culture growth, harvesting, 348–349dual phase extraction, 350, 351fethanol/water extraction, 352metabolite quantification, 353overview, 348perchloric acid extraction, 12, 208, 300, 350,

351f, 385, 418f, 422, 574sample preparation, 352spectrum acquisition, 353tissue harvesting, 349

dual phase, 350, 351fethanol/water extraction, 352perchloric acid extraction, 12, 208, 300, 350,

351f, 385, 418f, 422, 574single cell metabolite detection, identification,

122Cell membrane transport, 261, 338, 340f, 339–340,

427–428, 457–458. See also specificsubstance by name

Cell metabolite detection, identification. See alsoSingle-cell analysis

acetylcholine, 131f, 133–134analysis, 121f, 131–132Aplysia californica, 120–121benefits of, 119capillary electrophoresis (CE), 120, 122,

150CE-ESI-MS (See CE-ESI-MS)DHB (2, 5-dihydroxybenzoic acid), 121–122,

128, 133f, 133–134




Index 593

electrochemical detection, 119–120, 149electrospray ionization (ESI), 122extraction, 122fluorescence detection, 119–120, 150, 151fionization techniques, 120–121 (See also specific

techniques)MALDI (See MALDI)microanalysis, 131–132neurons

left pleural # 1 (LP1), 131f, 130–131, 133f,135

metacerebral cell (MCC), 131f, 130–131,133f, 135

R2, 131f, 130–131, 132f, 133f, 135sample preparation, mammalian, 123, 125–126,

135serotonin, 131f, 133–134subcellular analysis, 131f, 133f, 132–133, 135

Cell perfusioncancer, 343–344, 348co-polarization strategy, 455–456HR-MAS studies, human tissue, 497–499ischemia, reperfusion effects, 428MRS studies, 355f, 354–355, 357multiband spectral-spatial RF excitation,

462real time measurement, 446, 452–453saturation kinetics, 464–465steady state achievement, 421

Cells. See also Cell cultures; Cell death; Cellextraction; Cell metabolite detection,identification; Cell perfusion; Single-cellanalysis; specific cell types

density, 348–349, 353–354lines, 55, 60, 95–97, 99, 101, 103, 193–194, 347f,

348–349pellets, 37–38, 60–61, 67–69, 71, 343–344,

348–349, 353–354, 385, 405–406proliferation, 66–67, 69, 218–220, 329, 361–362,

436, 437–438, 457recognition, 377, 566–567survival, 66–67, 69, 457suspensions, 60–61, 101, 343–344, 348–349,

353–354, 383–384Cell suspensions, 353–354Centrifugation

amniotic fluid, 283–287biological samples, 161–163, 176blood, 206–207, 300CE-ESI-MS, 128–129 (See also CE-ESI-MS

(cell analysis))ChoK� assay protocol, 68f, 67–68, 69CSF, 300culture quenching, 84–85, 101–102gene expression analysis, 60–61HILIC, 177–178particulate removal, 12, 16, 72fpostextraction processing, 105protein removal, 101, 208serum/plasma, 100–101, 300

ultracentrifugation, 57–58urinalysis, 99–100, 300

Ceramides, 39Cerebrospinal fluid (CSF) 1H NMR studies

N-acetylaspartate, 261–263, 264–265N-acetylaspartylglutamate, 260–261, 311–312N-acetylneuraminic acid (free sialic acid), 303,

310–311, 311facute meningitis, 265–266adenylosuccinate lyase (ADSL) deficiency, 264Alzheimer’s disease, 266amyotrophic lateral sclerosis, 266antipsychotic medications, 266D-arabinitol, 259–260arabitol, 259–260, 261–263arginine:glycine amidinotransferase (AGAT)

deficiency, 263–264�-hydroxyisobutyrate (BHIB), 265–266brain magnetic resonance spectroscopy,

259–260CAFSA (cerebellar ataxia with elevated

cerebrospinal free sialic acid), 260, 308t,311f, 310–311

Canavan disease, 261–263collection, sample preparation, 257–258connexin, 261contamination, 257–258creatine deficiency syndromes, 263–264creatine transporter (CrT1) defect, 263–264described, benefits of studying, 257dimethylsulfone, 258–259erythritol, 259–260fatty aldehyde dehydrogenase (FALDH)

deficiency, 264–265free sialic acid storage disease (SASD),

260–261GABA (� -aminobutyric acid) accumulation,

263–264GJC2 gene, 261, 262fguanidinoacetate methyltransferase (GAMT)

deficiency, 263–2643-hydroxyisobutyric aciduria, 265–266hypoacetylaspartia, 264–265hypomyelination, 261, 311f, 311–312idiopathic polyneuropathy, 265–266inborn errors of metabolism (See Inborn errors

of metabolism)initial prodromal state of psychosis (IPS), 266lactate, 261–263, 265–266medications interfering with, 258–259metabolites detected by, 258–2593-methylglutaconic aciduria type 1, 263–264methylsulfonylmethane, 258–259multiple sclerosis, 265–266non-ketotic hyperglycinemia, 260Pelizaeus-Merzbacher disease, 261, 262f, 312phenylketonuria, 263–264PLP1 gene, 261, 262fpolyols, 258–260, 261–263ribitol, 259–260, 261–263




594 Index

Cerebrospinal fluid (CSF) 1H NMR (cont.)Salla disease, 260schizophrenia, 266sialin, 261Sjögren-Larsson syndrome (SLS), 264–265SLC17A5 gene, 260–261succinic semialdehyde dehydrogenase

(SSADH) deficiency, 263–264transaldolase deficiency, 259–260

Cervical cancer, 488f, 487–488CHD (coronary heart disease), 317, 327, 328fChelating agents, 350, 352, 383–384, 385–386,

401Chelating organic acids, 562Chelex, 350, 568fChemical bond, 31–32, 210–211, 211f, 214–215,

306–307, 319–320, 325, 338–339, 340–341,347f, 379, 465, 472–473, 564–577

Chemical derivatization, 213f, 211–213, 214f, 215f,215

Chemical exchange. See also specific substances byname or abbreviation

activation energy of, 398–399brain metabolic compartmentation, 434–435flux vs., 453ion, 210–211, 229–230, 237–239, 239t, 284–285,

286f, 396–399, 450, 464–465, 526–528in isotopomers, 424–426ligand, 383, 398–399in phosphate linewidths, 382, 402–403process, 383, 396–399, 434frate, 396–399strong acids, 239t, 239strong bases, 239t, 237–239two-site, 453, 461–462weak acids, 239t, 239–240weak bases, 239t, 239

Chemical formula. See Formula (chemical)Chemically selective saturation (CHESS),

358–360Chemical shift (31P NMR studies)

CDTA concentration effects, 390f, 392f, 394t,393–394, 395f, 396, 403–405

combined factor effects, 396–399crossing temperature, 386–389described, 379–381downfield, 324–325, 358–360, 379–382, 396,

423t, 562lipid extract concentration effects, 391–393pH effects, 396, 397frange, 563–564, 572–573solvents, 318, 387f, 390f, 392f, 393f, 395f,

393–395, 396, 397f, 403–405temperature effects, 386–389upfield, 324–325, 358–360, 423t

Chemical-shift anisotropy (CSA), 399Chemical shift imaging (CSI)

cancer, 335–336, 357–358, 363–364IDEAL spiral CSI, 460t, 461–462spiral CSI, 458–459, 460t

Chemical shifts in resonance assignment,529–562

Chemometricsalkaptonuria, 248f, 249f, 248–249bucketing, 246, 248f, 248–249, 249f, 252f, 252,

509–510class labels, 250–251creatinine, 253dimension reduction, 250f, 251discriminant analysis, 250f, 249–250,

251homogentisic acid, 248f, 249f, 248–249loading plots, 247f, 248f, 249f, 248–249mean-centering, 253methylmalonic aciduria, 248f, 249f, 248–249,

253overfitting, 254f, 253–254,

255overview, 244partial least squares discriminant analysis

(PLSDA), 250f, 249–250, 251preprocessing, 252f, 251–252principal component analysis (PCA), 246f,

245–246, 247f, 248f, 249 (See also Principalcomponent analysis (PCA))

scaling, 250f, 253, 254fscore plots, 245–246, 247f, 249f, 248–249scree plots, 247f, 247, 248software, 255time warping, 252validation (cross validation), 254f, 253–254,

255Chemostat approach, 84Chenomx, 13, 14CHESS water suppression, 356, 358–360Chloroform/methanol/water solvent extraction,

384–386, 406Chloroform purification, 92ChoK� assay

overview, 66–67protocol, 68f, 67–68, 69

ChoK� downregulation, 69–70ChoK� inhibitors, 66–67, 69–70Cholesterol, 323f, 324t, 324, 327, 328fCholine

choline kinase targeting, 345f, 361–36213C NMR studies, 435f, 433–435, 436human tissues (HR-MAS studies), 497, 498f,

514–515thyperpolarized NMR spectroscopy,

448tisotopomers, 418f, 420–421phospholipid metabolism in cancer, 337f,

336–337, 339, 345f, 344–345, 437–438total (tCho), 336–337, 344–345, 345f, 357–358,

359f, 361–362, 362f, 364–366, 476f, 483,486–487, 488–489

Choline-esterase, 282Choline transporter-like protein-1 (CTL1), 337f,

338




Index 595

ChromaTOF, 18Chromatographic assays, 66Citrate

13C NMR studies, 417thuman tissues (HR-MAS studies), 508serum, plasma sample preparation, 100–101

Citrate synthase, 423–426, 429f, 430, 431Citric acid (See Krebs cycle)Clinical applications

blood (See Serum, plasma (blood))compressed sensing, 460t, 461LC-MS, 216–217 (See also LC-MS)metabolomic strategy, 217–218overview, 205urine (See Urinalysis)in vivo MR spectra, 357–358

Closterium acerosum, 150–151CMP (cytidine monophosphate), 337f,

338Coffee, 276–277Coherence (of spins), 274–275, 382, 465Coil (in NMR), 228, 287, 321–322, 336, 360–361,

364t, 366, 403, 459t, 462, 464, 475–477,504–506

Collision induced dissociation (CID), 178f, 180,199

Colon cancer, 361–362Colorectal adenocarcinoma, 218–220,

220fCombination (of detection technology), 24. See

also specific technologiesComparison

CPMG, 480GC-MS technology, 7t, 23–24histology, 477LC-MS technology, 7t, 23–24LC-NMR vs, LC-SPE-NMR, 237, 240fmetabolite quantification, 481metabolome, 194–196MRS method, cancer, 366–367NMR spectroscopy technology, 7t, 23–24range of nuclei, 481reproducibility of methods, 7tsalts, analytic method comparison, 7tsample preparation, size, stability, 477spectral resolution, 477targeting, 477

Compartment (brain), 433–434Complementarity, 47, 54, 59f, 61–63, 119, 121,

131–132, 205, 227, 415–416, 474–475Compressed sensing, 460t, 461Condensation, 167–168, 424–426, 439fCongenital adrenal hyperplasia, 220–221Congestive heart failure, 427–428Conjugated metabolite hydrolysis, 209f, 208–209,

209f, 210Connectivity

chemical, 196–197, 564–566covalent, 564–566, 567, 578short-range, 564–566, 567

Connexin, 261Contamination

bacterial, 11, 84biofluids, 12biopsy samples, 502–504buffers, 11of cancer sample, 490f, 511–512of cell cultures, 33–34, 35–36CSF, 257–258ethanol, 510, 511–512human tissues (in vivo MRS studies), 477,

482–483human tissues (HR-MAS studies), 502isopropyl alcohol, 12loop storage, 231of media, 84NMR spectroscopy, 12of organelles, 37–38of plant material, 90–91prevention of (quality control), 37–38,

105–106reference standards, 322by salts, 35–36solvents, 35–36, 230in statistical analysis, 509–510of tissues, 103

Continuous culture, 82t, 84Conversion rate, 452–453, 461–462, 464–465Coronary heart disease (CHD), 317, 327, 328fCorrelations

bucket plots, 246cancer, 326, 483, 484f, 487–488chemical shifts, 389t, 389f, 391t, 392f, 394t, 395f,

396, 397f, 398–400dipolar, 274–275, 565–566dipoles, 565–566heteronuclear, 567–577hyperpolarized agents, 448IEM diagnosis, 285f, 289, 293–295, 301,

307fIMMS measurement of, 192–194linear, 144–145, 386–389PCA measurement of (mobility-mass),

194–197position determination, 235prenatal disorders, 285f, 289, 293–295rotational, 382–383, 399sensory perceptions, 276–277time, 382–383tissue profiling, 516–518

Correlation spectroscopy (COSY)genetic metabolic diseases, 301heteronuclear, 409–410resonance assignment, 566f, 564–566, 570f,

578Corticoids, 207tCorticosteriods, LC-ESI-MS/MS chromatograms,

216fCorynebacterium jeikeium, 86–87COSY. See Correlation spectroscopy (COSY)




596 Index

Couplingcarbon-carbon (13C-13C), 419, 420–422,

563–564, 573–574doublet, 303f, 302–303, 304, 306–307, 307f,

312–313, 346, 419, 420–421, 423t, 426–427,430, 434f, 435–436, 438, 439f, 504–506, 507,529, 562–563, 573

DTIMS, 189first order, 562–563heteronuclear, 419, 420–421, 423t, 435f,

436–437, 439fhomonuclear, 564–567HSQC, 572–573IMMS, 185–186, 192–194LAESI, 146, 152–153LC, 174long-range, 419multiplet, 262f, 303f, 307f, 311f, 312–313,

322–323, 418f, 419–421, 422, 423t, 426–427,430f, 430, 431, 432f, 437, 562–563

quartet, 273f, 301, 303f, 303, 420–421, 423t,426–427, 438, 439f, 562–563

quintet, 489–490, 562–563scalar, 302f, 419, 423t, 564–566, 567, 568–570,

571–576, 577triplet, 273f, 301, 303f, 306–307, 423t, 438, 439f,

489–490, 562–563, 573Coupling constants, 419, 420–421, 422, 423t, 572CPMG (Carr-Purcell-Meiboom-Gill)

acquisition, processing parameters, 482–483,505t

adenocarcinoma, 517famniotic fluid, 284f, 291f, 291–292applications of, 272–274, 283–284, 291–292biopsy samples, 498f, 504–506, 507, 511f,

511–512, 513f, 517fcancer, 482–483, 488f, 489f, 490fcomparison, 477data analysis, 507data processing, 507epilepsy, 510fetal malformations, 284f, 291f, 291–292oligodendroglioma, 497, 498fpulse train, 504–507, 508quantification of, 508–509renal cell carcinoma, 511–512, 513f, 517fsaliva, 272–274signal assignment, 507–508statistical analysis, 509–510tissue samples, 504–506

Creatinebreast cancer, 566fin cancer, 473f, 476f, 483, 484f, 485f, 486f, 487f,

490f, 491f, 497, 514–515tdual phase extraction of, 350human tissues (HR-MAS studies), 477, 497,

498f, 514–515tMR spin peak areas, 473in T lymphocytes, 145f

Creatine deficiency syndromes, 263–264Creatine kinase, 304

Creatine transporter (CrT1) defect, 263–264Creatinine

in amniotic fluid, 284f, 290tin genetic metabolic diseases, 305fin urine, 99–100

Cross peakscovalently linked, 564–566, 568f, 570fHACACO, 576f, 576–577, 578HCCH-TOCSY, 566f, 575f, 574–575, 576isotopomers, 566–567off-diagonal, 574–576one-bond connectivity, 567in resonance assignment, 572, 573urine, 302f

Cryo probe (cryogenic probe), 228, 235, 236f, 242CSI (See Chemical-shift imaging)CTP:phosphocholine cytidylyltransferase (CCT),

337f, 338Culture methods sample preparation

batch growth, 82t, 81–82, 83chemostat approach, 84continuous culture, 82t, 84media selection, 84overview, 81permittistat, 84

Cyberlipids, 47Cyclohexanediaminetetraacetic acid (CDTA), 352Cystic fibrosis, 282, 289Cytidine monophosphate (CMP), 337f, 338Cytosolic PC-PLA2 (cPC-PLA2), 337f, 338–339

DAG. See DiacylglycerolData acquisition, 408f, 408–409

human tissues (HR-MAS studies), 505t,504–505, 507

lipidomics, 46–49Data dependent fragmentation, 182Decarboxylation, 424–426, 429f, 437–438Decay rate, 452–453Deconvolution

blood, 143–145cancer, 218–220described, 13, 14f, 14–17, 17f, 18global, 528f, 563in LC-MS, 19–20 (See also LC-MS)Lorentzian/Gaussian, 408–409peak intensity quantification, 528f, 563software, 13, 14–18, 409

Dedicated ontology plant reference standards,89–90

Degradationcarbon-by-carbon, 416–419KEGG database, 47–49lipid, 71, 321metabolic products, 90–92, 122, 415–416mRNA, 55–56, 59f, 59–60, 62f, 91–92, 217–218,

336–337oxidative, 321pyrimidine, 305–307of samples, 80, 126, 210, 319, 477, 491f, 497–500,

500f, 501, 502–504, 506–507




Index 597

of tissues, 319, 477, 491f, 500f, 499–500, 501,502–504, 506–507

Derivatizationacylation, 213–214chemical, 213f, 211–213, 214f, 215f, 215extractable alkyloxycarbonylation, 214–215GC-MS, 16, 18–19, 38, 214–215HPLC, 39IMMS, 192–194LC-MS, 211–212in metabolomics generally, 140sample preparation, 16, 22–23shotgun lipidomics, 43–46silylation, 212–213

De-shielding, 379–381Detection threshold, 391–393, 508Diabetes, 427–428Diacylglycerol

in cancer cells, 210, 623, 342f, 341–342, 343f, 34331P NMR studies, 380f, 379–380, 381

Diagnosisdifferential, 377–378, 474–475histopathological, 497–499of inborn errors of metabolism, 285f, 289,

293–295, 299, 301, 305f, 307fDicarboxylic acid, 258–259Dichloroacetate, 427–428Dictionary of Natural Products, 174–175, 182,

183nDiet. See Saliva metabonomicsDifferentiation, 66–67, 135, 326, 327, 341–343Diffusion ordered spectroscopy (DOSY), 284–285Dihydroxyphenylacetic acid (DOPAC), 1983, 5-Diluorobenzoyl-L-glutamic acid (3,

5-DFBGlu), 457–458Dimension reduction, 250f, 251Dimethylglycine dehydrogenase deficiency,

304–305, 306f, 308tN,N-Dimetylglycine, 303–304, 305f, 306f, 308tDI nESI FT-ICR MS, 163Diophantine equations, 166–168Diphosphodiester (DPDE), 345f, 346–347Dipole

correlations, 565–566dipole-dipole relaxation, 383interactions, 210–211, 383, 466, 482–483,

565–566magnetic dipole moment, 383, 472–473

Direct injection mass spectrometry (DIMS)history of, 6reference protocols, plant-based, 92, 93f

Discriminant analysis, 250f, 249–250, 251Disease progression, 448, 455–456Dissolution, 447, 459tDithioerythreitol in silylation, 212–213DNA

amplification, 55–56, 61–63cDNA, 60–61, 63in cell cultures, 348–349gene overexpression induction, 55gene transduction, 58f, 56–58, 59

gene transfection, 56f, 55–56in plasmid vectors, 55–56, 56freplication, 55–56SYBR R© Green method, 63TaqMan R© method, 61, 62fin viral vectors, 58f, 56–58, 59

Docetaxel, 361, 362f, 486f, 487fDopamine, 198Doping agents, 207tDOSY (diffusion ordered spectroscopy), 284–285Dotarem R© (gadoterate meglumine), 449Double spin-echo (DSE), 462–463Drift tube ion mobility time-of-flight mass

spectrometer (DTIMMS), 186–187, 188f,189

DrugBank, 3–4DSS (2, 2-dimethyl-2-silapentane-5-sulfonic acid),

529DTIMMS, 186–187, 188f, 189DTIMS, 189Dual phase extraction, 350, 351fDuchenne muscular dystrophy (DMD), 327Dynamic nuclear polarization (DNP), 446–447,

455–456Dynamic series, 449

Echo-planar spectroscopic imaging (EPSI), 458,460t

Echo time (TE), 359f, 365f, 366, 461–462, 476f,482–483, 485f, 486f, 488f, 489f, 490f, 508

EDTAcancer, 352hyperpolarized NMR spectroscopy, 447serum, plasma sample preparation, 100–101

EGTA (ethylene glycol tetraacetate), 37, 562Eigenstates, 466–467El (electron impact), 211–212Electrochemical detection, 119–120, 149Electron density, 379Electronic reference to access In vivo

concentrations (ERETIC)amniotic fluid, 286–287human tissues (HR-MAS studies), 508

Electron paramagnetic agent (EPA), 447Electrophoresis

capillary electrophoresis (CE), 120, 122, 150capillary electrophoresis-electrospray

ionization-mass spectrometry (SeeCE-ESI-MS)

history of, 6separation, 64f

Electroporation, 59–60Electrospray ionization (ESI)

cell metabolite detection, identification, 122fragmentation in, 38lipidomics, 32, 35–36, 38–41sensitivity, 38solvents, 122, 124, 152fstructural elucidation, 174

Electrospray ionization mass spectrometry(ES-MS), 378




598 Index

Endometabolome measurement (metabolicfingerprinting), 81, 83, 87f

Energetics, 422, 436–437, 474tEnergy metabolism, 417t, 421–422, 423tEnergy source, 426–427Environment

hospital, 100–101, 496–497, 501f, 518–519magnetic, 379, 416–419

Enzyme assay, 63–69Enzymes

activation, 54, 338, 340factivity profiles in metabolic pathways,

215–217enzymatic reaction, 122, 170, 340–341, 457enzyme assay (See also GC-MS; LC-MS)

continuous, 66discontinuous, 66

gene overexpression, silencing validation,63–69

metabolic, flux, 54, 84–85treatment, 121f, 125–126, 207–208

Ependymoma, 485fEpilepsy, 510, 511f, 512fEPSI (See Echo-planar Spectroscopic Imaging

(EPSI)Equilibrium

dynamic, 489–490non-equilibrium spin polarization, 465solid-state, 449thermal, 451–452, 453–455, 465time, 216–217, 448

ERETIC studies, 286–287, 508Ernst equation, 400–402Erythritol, 259–260Erythronic acid, 308t, 312–313Escherichia coli, 209–210ESI. See Electrospray ionization (ESI)ES-MS, 378Esterification in silyation, 213Estriadol, 214f, 211–214, 215Estrogens, 207tEthanol

13C NMR studies, 417tin extraction, 208sample preparation clinical, mammalian based,

208Ethanolamine, 380f, 379–380, 381Ethanol/water extraction, 352Ether bond, 34, 212–213, 214, 325, 381–382Ether-linked alkenes, 381–382Ethylenediaminetetraacetate (EDTA)

cancer, 352hyperpolarized NMR spectroscopy, 447serum, plasma sample preparation, 100–101

Ethylene glycol tetraacetate (EGTA), 37, 562Ethylpyruvate, 448tEvaporative light scattering detection (ELSD),

377Evolution period, 573Exchange (chemical). See Chemical exchange

Exchange limited relaxation, 398–399Excitation pulse, 357–358, 382, 400–402, 453, 462Exometabolome measurement (metabolic

footprint), 81, 84, 101, 102Extracellular

exometabolome measurement (metabolicfootprint), 81, 84, 101, 102

organic compound removal, 121pH, 354–356, 365f

Extractable alkyloxycarbonylation, 214–215Extracts, extraction

cancer (See under Cancer)cell (See Cell extraction)chloroform/methanol/water solvent, 384–386,

406detergent-containing aqueous solvent, 383–384lipid profiling, 317, 319–321 (See also Lipid

extraction)optimization, 391t, 392f, 391–392, 393f, 393plant sample preparation, 91–92 (See also

Plants)tissue, 383–385, 405–406 (See also Tissue

extracts)Ex vivo analysis, 477, 489–490, 491f

19F (fluorine), 230–231, 335–336, 355f, 354–355,356, 363–364, 472–473, 474t, 474–475, 477

Fatty acids (FA)13C NMR studies, 426f, 426–427derivatives sensitivity, 212fragmentation, 212human tissues (HR-MAS studies), 511–512,

513f, 514–515thydrolysis, 31–32, 338–339, 381–382lipidomics studies, 31–32, 37lipid profiling, 324t, 325long chain, 421, 426f, 426–427, 428monounsaturated fatty acids, 325oxygen in oxidation of, 40531P NMR studies, 380f, 379–380, 382polyunsaturated fatty acids (PUFAs), 325, 329sample preparation clinical, mammalian based,

212saturated fatty acids, 325

Fatty aldehyde dehydrogenase (FALDH)deficiency, 264–265

�-Fetoprotein, 282FID (free induction decay), 322, 408f, 422, 563,

570–571Field-frequency lock, 13, 272–274, 300, 422Field of view (FOV), 359f, 362f, 363–364, 365f,

459t, 458–459, 460t, 462, 488fFirst order coupling, 562–563Flash-freezing, 348–349Flip angle, 400–402, 422, 458–462, 464, 482–483Flow cytometry, 149. See also Flow NMRFlow NMR

capillary, 231cryogenic probe heads, 228detection limits, 230–231




Index 599

directly coupled, 230loop storage, 231solid phase extraction as interface, 231–232,

232f, 233fstop-flow, 231

Fluid dynamics, 447Fluorescence microscopy, 55–56Fluorine (See 19F)Flux

absolute, 431, 452–453analysis, 80–81, 360–361, 421, 466–467, 525–526anaplerosis, 428–433, 437brain metabolism, 433–436cancer metabolism, 438cardiac metabolism, 427–428enzymes, metabolic, 54, 84–85exchange vs., 453intracellular measurements, 81–83lipid, 47–49placental, 289–290relative, 419–420, 421, 455–456in subcellular organelles, 36–38

Flux-based measurements, agar plates in, 81–83Food. See SalivaFooDB, 3–4Formula (chemical)

calculation, 21compound sum formula, 227, 230, 287Diophantine equations, 166–168elemental, 174–175, 180empirical formulae assignments, 161, 166–168,

173n, 182t, 182molecular, 174–175, 177f, 178f, 180, 181fpeak assignment, 161relative isotopic abundances, 167, 168, 173nstructural elucidation (See Structural

elucidation)Fosfomycin, 180, 181fFourier transform infrared (FT-IR) spectroscopy,

378Fourier transform ion cyclotron resonance

(FT-ICR)accuracy, 150, 287, 175tbioinformatics, 159–161, 162, 163tmetabolite identification, 235resonance assignment, 578

Fourier transform mass spectrometry (FTMS),174–175, 178–180

FOV (field of view), 359f, 362f, 363–364, 365f,459t, 458–459, 460t, 462, 488f

Fragmentationacylation, 213–214application of, 168CE-ESI-MS, 124, 130 (See also CE-ESI-MS)chemical derivatization, 213f, 211–213, 214f,

215f, 215collision induced dissociation (CID), 178f, 180,

199data dependent, 182differential kinetics, 41–43

in ESI-MS, 38 (See also Electrospray ionization(ESI))

fatty acids, 212in GC-MS, 16 (See also GC-MS)IMMS, 200, 201f (See also Ion mobility mass

spectrometry (IMMS))induction of, 187, 189isomeric species identification, 39in LC-MS, 20 (See also LC-MS)MALDI, 130–131, 134f, 134–135 (See also

MALDI (cell analysis))molecular fragments, 577–578neutral loss, 42patterns, 182pulsed Q dissociation (PQD), 180, 181fresources, 47, 130–131tandem MS, 161, 174–175, 200targeted, 180–181unknown metabolites, 15, 22, 142, 577–578

Fragmentation methods (structural elucidation)data dependent, 182overview, 180patterns, 182targeted, 180–181

Free induction decay (FID), 322, 408f, 422, 563,570–571

Free sialic acid. See N-acetylneuraminic acidFree sialic acid storage disease (SASD), 260–261Freeze-clamping, 34, 90, 405–406, 432fFreeze-drying, 71, 91, 105, 285fFreezer, 126, 161–162, 497–499, 501–504French marigold (Tagetes patula), 144f, 143–144Fruits, 89–90FSE-EPSI, 459t, 463–464Fumarate

13C NMR studies, 417t, 424f, 425f, 424–425, 426,436

hyperpolarized NMR spectroscopy, 448t,455–456

Fumarate hydratase, 429f, 436Function

brain, 433–436cardiac, 427–428cellular, 66–67cellular lipids, 30, 31–32chemical, 196–197, 213, 378, 529–562, 573citric acid cycle (See Krebs cycle)correlation (spectral density), 382–383delta, 17–18exponential weighting, 322, 477, 507Gaussian weighting, 566f, 569fgene, 55, 79–80, 217–218, 261Hanning window, 164lipid extraction, 34, 37, 49loss of, 212, 261–263, 285, 310membranes, 30, 31–32, 377metabolic pathways, 54, 215–217mitochondrial, 437, 438molecular structure, 378networks, 47–49




600 Index

Function (cont.)phospholipids, 377, 381–382point spread, 477renal, 291–292, 328–329reporter probes, 457resolution enhancement, 563strong bases, 237–239, 239ttiters, 58T-wave device, 191vector, functional, 220

Functional markers, 525. See also Biomarkers

GABA (� -aminobutyric acid)13C NMR studies, 417t, 423t, 435f, 433–435, 436CSF 1H-NMR studies, 263–264human tissues (HR-MAS studies), 497, 498f,

508resonance assignment, 573–574

Gabapentin, 258–259Gadolinium (ProHance R©), 449Gadoterate meglumine (Dotarem R©), 449Gas chromatography-mass spectrometry. See

GC-MSGaussian parameter (GB), 408–409GC column. See GC-MSGC-MS (gas chromatography-mass spectrometry)

acylation, 213–214advantages, disadvantages of, 7t, 6–7, 8, 16,

23–24AMDIS, 18AnalyzerPro, 18batch growth culture, 81–83cell metabolite detection, identification,

120–121ChromaTOF, 18clinical samples, chromatographic separation,

215–216, 216fcompound identification, quantification, 8f, 9t,

16–17, 17f, 18databases, 18derivatization, 16, 18–19, 38, 214–215detection rates, 18–19extraction, plant-based, 91–92fragmentation in, 16history of, 6match factor (MF), 17–18monitoring, 6NIST database, 18plant-based reference protocols, 93f, 92–93, 94f,

95, 103postextraction processing, analysis, 105reference protocols, plant-based, 92–95reproducibility, 7t, 16retention indices (RI), 17–18S. cerevisiae ion chromatograms, 87f, 86–87sample preparation, 16sensitivity, 7t, 23–24serum, plasma, 101silylation, 212f, 212–213, 213fsoftware, 18technology comparison, 7t, 23–24

time of flight (TOF), 16, 18urine samples, 98–100

Gene overexpressionChoK� assay, 66–67ChoK� assay protocol, 68f, 67–68, 69chromatographic assays, 66gene expression analysis, 60–61Molecular Beacon method, 61–63multiplicity of infection (MOI), 58native expression, 457–458phosphatidylinositol 3-kinase (PI3K) assay, 67phospholipase D (PLD) assay, 66–67, 69plasmid vectors (gene transfection), 55–56, 56fradiometric assays, 66RT-PCR, 62f, 61–62, 63SYBR R© Green method, 63TaqMan R© method, 61, 62futility of as tool, 55validation of by enzyme assay, 63–69validation of by mRNA, 60–63validation of by protein level analysis, 64f,

63–64, 66viral vectors (gene transduction), 58f, 56–58, 59Western blotting (See Western blotting)

Gene silencingChoK� assay, 66–67ChoK� assay protocol, 68f, 67–68, 69chromatographic assays, 66microRNAs (miRNAs), 60Molecular Beacon method, 61–63phosphatidylinositol 3-kinase (PI3K) assay,

67phospholipase D (PLD) assay, 66–67, 69radiometric assays, 66RT-PCR, 62f, 61–62, 63shRNAs, 60, 62f, 68f, 70f, 361–362siRNAs, 59–60, 62fSYBR R© Green method, 63TaqMan R© method, 61, 62futility of as tool, 59f, 59–60validation of by enzyme assay, 63–69validation of by mRNA, 60–63validation of by protein level analysis, 64f,

63–64, 66Western blotting (See Western blotting)

Genetic metabolic diseases. See also Inborn errorsof metabolism

N-acetylaspartylglutamate, 311–312N-acetylated amino acids, 306f, 308t, 309–310N-acetylglutamylneuraminic acid, 303N-acetylneuraminic acid (free sialic acid), 303,

310–311, 311faminoacylase 1 deficiency, 305f, 306f, 308t,

309–310arabitol, 305f, 306f, 308tbetaine, 303–304, 305f, 308tbiomarkers (See Biomarkers)body fluids, 299, 302–304CAFSA (cerebellar ataxia with elevated

cerebrospinal free sialic acid), 260, 308t,311f, 310–311




Index 601

correlation spectroscopy (COSY), 301creatinine, 305fCSF, 300–301dimethylglycine dehydrogenase deficiency,

304–305, 306f, 308tN,N-dimetylglycine, 303–304, 305f, 306f, 308terythronic acid, 308t, 312–313hypomyelination, 261, 311f, 311–312inborn errors of metabolism (See Inborn errors

of metabolism)leukodystrophies, 260–261, 312metabolite quantification, 301, 306f, 308tmethylcitric acid, 3013-methylglutaconic aciduria, 308t, 313methylmalonic acid, 301methylmalonic aciduria, 301, 302fpropionylcarnitine, 301ribitol, 305f, 306f, 308tribose-5-phosphate isomerase deficiency, 305f,

306f, 308t, 307–308, 309sample preparation, 300–301serum, plasma, 300–301transaldolase deficiency, 308t, 312–3133-ureidoisobutyric acid, 305f, 306f, 307f, 308t3-ureidopropionase deficiency, 305f, 306f,

305–306, 307f, 307, 308t3-ureidopropionic acid, 305f, 306f, 305–306, 307,

308turine, 300–301, 303furocanic aciduria, 308t, 312

Gene transcription, 54, 57Gene transduction (viral vectors), 58f, 56–58,

59Gene transfection (plasmid vectors), 55–56,

56fGene translation, 54, 55–56, 59f, 59–60, 336–337Genome, genomics, 83

amniotic fluid, 281 (See also Amniotic fluid)cancer, 336 (See also Cancer)databases, 47–49, 142, 299overview, 3single-peak search, 169–170vectors, 55, 57, 58, 59–60

Gestational age, 287, 289–290Gestational diabetes, 291–292GFP (green fluorescent protein), 55–56, 58, 150,

359fGJC2 gene, 261, 262fGlass (amorphous), 448Glassware, 35–36, 406Glia, 433–436Glioblastoma, 437, 484f, 517f, 516–517, 518f,

518Glioma

glutamine import by, 437low-grade, 436

Gluconeogenesis, 417t, 421–422, 423t, 429f,428–429, 430f, 432f, 433, 434f

Glucose[1–13C], 43713C NMR studies, 417t, 431, 432f

human tissues (HR-MAS studies), 499–500,500f, 501, 514–515t

resonance assignment, 529transport, 340f, 339–340, 427–428[U-13C], 418f, 420–421, 426f, 433, 438, 439f,

563–564, 579f�-Glucuronidase, 209–210�-Glucuronidase/arylsulfatase, 209–210Glucuronide, 210, 235, 432–433Glutamate

13C NMR studies, 417t, 421–422, 423t, 424f,425f, 424–425, 426f, 427, 429f, 428–429,430f, 432f, 433, 434f, 437

isotopomers, 418f, 420–421Glutamine, 417t, 437Glutaminolysis, 436Glutathione (GSH), 145f, 433, 434f, 437, 527f,

562–563, 566f, 566–567, 574–576Glycerol, 84–85, 380f, 379–380, 381Glycerol 3-phosphate (G3P), 341–343, 405–406,

574–576Glycerol-saline in culture quenching, 84–85Glycerophosphocholine (GPC), 336–337, 337f,

345f, 344–345, 346–347Glycerophosphoethanolamine (GPE), 345f,

346–347Glycerophosphoglycerol (GPG), 405–406Glycerophosphoinositol (GPI), 405–406Glycerophospholipids, 22–23, 47, 73, 379, 380f,

577Glycogen, 422–423, 431Glycogenolysis, 431Glycolipids, 326Glycolysis

anaerobic, 265–266, 339–340, 483, 497–499in cancer, 340f, 339–340, 360f, 360–361

Glycoproteins, 284f, 291–292, 377GOI (gene of interest), 55–56, 56f, 57, 58f, 59–60.

See also Gene overexpression; Genesilencing; Vectors

Goodness of fit, 509–510. See also Statisticalanalysis

G3P (See glycerol 3-phosphate)GPC (See glycerophosphocholine), 337f, 336–337,

345f, 344–345, 346–347Gradient

high-speed centrifugation, 37–38linear, 176–178oven, 16–18

Gradient sequencesblip, 461dephasing, 358–360magnetic field, 475–477phase-encoding, 335–336, 357–360, 364fpulsed field, 475–477, 564–566shimming, 518–519spiral readout, 458–459symmetric, 458waveform, 458

� -retroviruses, 58f, 56–58, 59GSH (See glutathione)




602 Index

Guanidinoacetate methyltransferase (GAMT)deficiency, 263–264

Gyromagnetic ratio, 335–336, 348, 416–417,472–473, 474t, 572

1H NMR spectroscopyamniotic fluid, 284f, 282–284, 285f, 286f, 288f,

291f, 292calibration, 227, 504–506CPMG (Carr-Purcell-Meiboom-Gill) (See

CPMG (Carr-Purcell-Meiboom-Gill))isotopic labeling, 465–466lipid profiling (See Lipid profiling)reproducibility, 290–291, 504–506, 510–513,

518–519resonance assignment, 527f, 526–527, 528f,

564–566, 566f, 570f, 573–574saliva, 272–274sensitivity, 282–292, 321–322, 358–360, 436–437

HACACO, 576f, 576–577, 578Hair sample analysis, 207t, 207–208Hanning window function, 164HCCH-TOCSY, 566f, 575f, 574–575, 576Heart

13C NMR studies, 417t, 421–422, 423t, 427–428ischemia, reperfusion effects, 428oxygen in cardiac metabolism, 428pig, 385, 449, 462–463rat, 421, 428

Heat shock protein (hsp90), 361Helium

liquid helium bath, 447, 448resolution, effects on, 186–187

Helix pomatia, 209f, 209, 210Hemodynamic, 428Hepatocellular carcinoma (HCC), 463–464HEPES, 84–85Hermogenes, 5–6HETCOR (heteronuclear correlation), 572Heterogeneity

analysis, 119–120biopsy samples, 496–497cellular, 36–38, 119, 135, 149gene expression, 149MALDI analysis, 129, 150–151mixtures, 384–385plant tissues, 148–149tissue, 33–34, 335–336, 477

Heteronuclearamniotic fluid spectra, 285f13C NMR studies (See 13C NMR studies)correlation spectroscopy (COSY) (See

Correlation spectroscopy (COSY))coupling, 419, 436–4372-D experiments, 566f, 568f, 567–568, 569f,

570f, 571f, 575f, 576f, 577HMBC, 567, 568f, 569f, 578HMQC, 274–275, 567HSQC, 283–284, 566f, 567, 568f, 569f, 572–573,

578

NMR resonance assignment, 2-D experiments,566f, 568f, 567–568, 569f, 570f, 571f, 575f,576f, 577

solid phase extraction system, 231–232Hetero-TOCSY, 568–570Hexamethyldisiloxane (HMDSO), 363–364Hexoses, phosphorylated, 573High mass accuracy/high mass resolution mass

spectrometry, 42–43High-performance liquid chromatography

(HPLC), 377High resolution. See specific process or technique

by nameHigh-resolution magic angle spinning (HR-MAS).

See also 1H NMR spectroscopyamniotic fluid, 287, 290–291human tissues (See Human tissues)in vivo MRS studies vs., 477, 482–483

High Resolution Spectroscopy (HiRes), 217tHigh throughput

LEASI-MS (See Laser ablation electrosprayionization (LAESI))

lipid analysis, 41–42, 82tHILIC (hydrophobic interaction), 177–178, 179f,

184nHILIC-NMR, 241Hippocrates, 5–6Histology

cancer, 476fcomparison, in vivo MRS studies, 474–475,

476f, 477, 490–491sample preparation, 501–504

History of metabolomics, 5–8, 140HMBC, 567, 568f, 569f, 578HMDB, 20–21HMDB server, 15HMQC, 274–275, 567Holistic metabolic profiling, 79Homeostasis, 285, 299, 428–433Homeostatic control, 525–526, 578–580Homogentisic acid, 248f, 248–249, 249fHomonuclear 2-D experiments, 566f, 564–566,

567, 570f, 571fHormones, 488–489, 489f, 490fHospital environment, 100–101, 496–497, 501f,

518–519HPLC, 39–41, 377HR-MAS. See High-resolution magic angle

spinning (HR-MAS)HR-MAS studies. See 1H NMR spectroscopy;

Human tissues (HR-MAS studies)HRQUEST, 287Hsp90, 361, 362fHSQC, 283–284, 566f, 567, 568f, 569f, 572–573,

578HSQC-TOCSY, 567, 570f, 573–574Human metabolome

characterization of, 3–4endogenous vs. exogenous metabolites, 3–4metabotypes, 4–5




Index 603

small molecule metabolites in, 3specialization in, 5variation in, 4f, 4–5

Human Metabolome Database, 3–4, 47, 161,299

Human Metabolome Project, 3–4Human tissues (in vivo MRS studies)

applications, 474–475artifacts, 477brain cancer, 476f, 483, 484f, 485fbreast cancer, 486f, 486–487, 487fcervical cancer, 488f, 487–488concentration, 473–474, 474t, 477contamination, 477, 482–483histology comparison, 477HR-MAS vs., 477, 482–483invasiveness of technique, 477magnetic field strengths, 473metabolite quantification comparison, 477MRS overview, 473f, 472–473, 474t, 474patient management impacts, 477phosphodiesters, 489–490, 491fphosphomonoesters, 489–490, 491f31P HR-MAS spectra, in vivo vs. ex vivo,

489–490, 491fprostate cancer, 488–489, 489f, 490frange of nuclei comparison, 477reference compounds, 472–473, 477relaxation effects, 473f, 477, 485f, 486fsample stability comparison, 477sensitivity, 474t, 473–474, 477, 490–491signal peak areas, 473f, 473SNR (signal-to-noise ratio), 357–358, 473–474spectra acquisition, 476f, 475–476, 477,

488fspectral resolution comparison, 477spectra quantification, 473f, 477, 485f, 486fspin signal frequency, 472–473targeting comparison, 477

Human tissues (HR-MAS studies)acetate, 500f, 499–500, 501, 514–515tN-acetylaspartate, 497, 498f, 508adrenalin, 508alanine, 499–500, 500f, 501, 507, 514–515tascorbic acid (Vitamin C), 258–259, 500f,

499–500, 501, 514–515tbrain cancer, 476f, 483, 484f, 485fbreast cancer, 486f, 486–487, 487fbuffers, 502–504cancer tissues, 497, 498fCARMeN project, 497cervical cancer, 487–488, 488fcholine, 497, 498f, 514–515tcitrate, 508contamination, 477, 502creatine, 477, 497, 498f, 514–515tdata acquisition, 475, 505t, 504–505, 507data analysis, 507–509data processing, 477, 483, 505t, 507effective TE, 508

epilepsy, 510, 511f, 512fEretic, 508fatty acids, 511–512, 513f, 514–515tGABA (� -aminobutyric acid), 497, 498f,

508glioblastoma, 517f, 516–517, 518f, 518glucose, 499–500, 500f, 501, 514–515thistopathological diagnosis, 497–499ischemia, 497–499kidney biopsy, 503f, 511–512, 513f, 514–515t,

516tlactate, 497–499, 507, 514–515tlung, 499–500, 500f, 501metabolic tissue profiling, 517f, 516–517, 518f,

518metabolite quantitation, 507–509OCT medium, 502oligodendroglioma, 497, 498f, 517f, 516–517,

518f, 518overview, 518–519partial least square discriminant analysis

(PLS-DA), 509–510, 517f, 516–517, 518phosphodiesters, 489–490, 491fphosphomonoesters, 489–490, 491f31P HR-MAS spectra, in vivo vs. ex vivo,

489–490, 491fprincipal component analysis (PCA), 510, 511f,

512f, 512–513, 517fprostate cancer, 488–489, 489f, 490fprotocol, 501f, 501–502PULCON, 508renal cell carcinoma, 511–512, 513f, 514–515t,

516treproducibility studies, 510–513sample collection, storage, 500f, 497–500, 501f,

502sample degradation, 499–500, 500f, 501sample preparation, 502–503, 503f, 504sample spinning, 499–500, 500f, 501signal assignment, 507–509statistical analysis, 509–510TSP as reference, 507

Hydrolysisalkaline, 350blood-brain barrier transport analysis, 455in ChoK� analysis, 67–69conjugated metabolite, 209f, 208–209, 209f,

210enzymatic, 207–208, 209f, 209, 210, 211ffatty acid, 31–32, 338–339, 381–382in lipid extraction, 34, 71prevention, tissue extraction, 319triacylglycerols (TAGs), 341–343

Hydrophobic interaction (HILIC), 177–178, 179f,184n

Hydroxyglutaric acid, 4365-Hydroxyindoleacetic acid (5-HIAA), 1983-Hydroxyisobutyric aciduria, 265–266Hypercholesterolemia, 327, 328fHyperlipidemia, 327, 328f




604 Index

Hyperpolarized NMR spectroscopyacetic anhydride, 448t, 453–455N-acetyl-L-methionine, 448t, 457–458agents, correlation of, 448amino acids, 449, 453–455aminoacylase-1, 457–458bicarbonate, 448t, 450, 455–456blood brain barrier, 455BSSFP, 460t13C, 360–361, 438–439, 446, 447, 460tcarboxypeptidase G2, 457–458compressed sensing, 460t, 461co-polarization strategy, 455–4563, 5-difluorobenzoyl-L-glutamic acid (3,

5-DFBGlu), 457–458dissolution process, 447double spin-echo (DSE), 462–463dynamic data analysis, 452–453dynamic nuclear polarization (DNP), 446–447,

455–456echo-planar spectroscopic imaging (EPSI), 458,

460telectron paramagnetic agent (EPA), 447electron spins, 447ethylenediaminetetraacetate (EDTA), 447exchange vs. flux, 453FSE-EPSI, 459t, 463–464fumarate, 448t, 455–456gadolinium (ProHance R©), 449gadoterate meglumine (Dotarem R©), 449hyperpolarization methods, 446–447hyperpolarized agents generally, 448t,

448HyperSenseTM polarizers, 447IDEAL spiral CSI, 460t, 461–462indirect detection, 465kinetic modeling, 453, 464–465lactate, 448t, 449, 451–453, 455, 465–466liquid-state polarization, 451lymphoma, 464–465magnetization transfer, 464–465MENLO, 459t, 463–464metabolite tissue levels, 451–452methionine, 457–458new agent strategy, 451nuclear spin storage, 466–467overview, 446parahydrogen-induced polarization (PHIP),

446–447polarization transfer, 360–361, 446–447, 465,

572proton decoupling, 465–466proton detection, 465pulse sequences, 458pyruvate, 449, 451–453, 455–456, 464–465quantitative metabolic imaging, 451–453rapid encoding, reconstruction strategies, 459t,

458–459, 460t, 462reporter probes, 457–458RF pulse design, 462–463

saturation-recovery metabolic imaging,464–465

secondary labels, 453–455sensitivity, 446, 457Signal Amplification by Reversible Exchange

(SABRE), 446–447spectral-spatial imaging, 460tspiral CSI, 458–459, 460tT2 sampling, 459t, 463–464urea, 448t, 455–456

HyperSenseTM polarizers, 447Hyphenated NMR MS system. See also Flow

NMR; LC-SPE-NMRcryogenic probes, 228detectors, 229HPLC/NMR interface, 230–232integration of mass spectrometry, 227, 229–230,

232fNMR spectrometer, 228, 229–230overview, 227, 242requirements for mass spectrometry, 228–229software, 229

Hypoacetylaspartia, 264–265Hypoxia inducible factor alpha (HIF-1�), 340f,

339–340

ICR-FTMS (ion cyclotron resonance Fouriertransform mass spectrometry), 72f, 72

IDEAL spiral CSI, 460t, 461–462Idiopathic polyneuropathy, 265–266IEPA (imidazol-1-yl)(3-

ethyoxycarbonylpropionic acid), 363,365f

Image contrast, 452–453Imaging

chemical shift imaging (CSI) (See Chemicalshift imaging (CSI))

echo-planar spectroscopic imaging (EPSI) (SeeEcho-planar spectroscopi imaging (EPSI))

magnetic resonance imaging (MRI), 281–282,292–293

magnetic resonance spectroscopic imaging(MRSI), 335–336, 357–358, 364–366, 367

metabolic (See also Chemical-shift imaging,Echo-planar spectroscopic imaging), 147f,145–147, 446, 462–463

spectral-spatial, 460ttissues, 148f, 147–148, 149

Immunodetection, 65–66Immunoprecipitates, 70f, 70Inborn errors of metabolism. See also Genetic

metabolic diseases; specific IEMs by nameadenylosuccinate lyase (ADSL) deficiency,

264aminoacylase 1 deficiency, 305f, 306f, 308t,

309–310arginine:glycine amidinotransferase (AGAT)

deficiency, 263–264biomarkers, 220–221creatine deficiency syndromes, 263–264




Index 605

diagnosis of, 285f, 289, 293–295, 299, 301, 305f,307f

dimethylglycine dehydrogenase deficiency,304–305, 306f, 308t

discovery of, 259–260, 304fatty aldehyde dehydrogenase (FALDH)

deficiency, 264–265guanidinoacetate methyltransferase (GAMT)

deficiency, 263–264hypomyelination, 261, 311f, 311–312lipid profiling, 326–327metabolic profile characterization, 260–261,

262f, 305f, 306f, 308t, 311fnewborn screening programs, 6overview, 299ribose-5-phosphate isomerase deficiency, 305f,

306f, 308t, 307–308, 309succinic semialdehyde dehydrogenase

(SSADH) deficiency, 263–264transaldolase deficiency, 259–260, 308t,

312–3133-Ureidopropionase deficiency, 305f, 306f,

305–306, 307f, 307, 308tIndirect detection, 360–361, 465INEPT (Insensitive Nuclei Enhanced by

Polarization Transfer), 465, 572, 573Inhibitors

ChoK�, 66–67, 69–70choline kinase, 361–362lipid hydrolysis, 71mTOR, 69phosphatase, 63protease, 63, 68–69

Inhomogeneity (magnetic field), 353, 382,465–466, 506

Initial prodromal state of psychosis (IPS), 266Inositol

inositol 1, 4, 5-trisphosphate (IP3), 380f,379–380, 381

myo-inositol, 9t, 260, 290t, 302–304, 379–381,476f, 483, 484f, 485f, 486f, 514–515t

phase separation issues, 403phosphate moieties (See specific substance by

name or abbreviation)phosphatidylinositol (PI), 31–32, 70, 72, 292,

340f, 343f, 341–343, 347f, 379–381, 389fphosphatidylinositol 4, 5-diphosphate (PtdIP2),

380f, 379–380, 381, 389t, 389f, 391t, 394t,396

phosphatidylinositol 3-kinase (PI3K) assay, 67phosphatidylinositol 4-phosphate (PtdIP), 380f,

379–380, 381, 389f, 391t, 394t, 393–394, 396phosphoinositol, 405–406resonance differentiation, 577scyllo-inositol, 476f, 484f, 485f, 486f, 514–515t

Insensitive Nuclei Enhanced by PolarizationTransfer (INEPT), 465, 572, 573

Insulin dependent diabetes mellitus (IDDM),289–290

Integration (peak area), 322, 477, 563

Intensity distortion, 572, 573Intestinal atresia, 289Intracellular

biochemical networks, 578–580endometabolome measurement (metabolic

fingerprinting), 81, 83, 87fflux measurements, 81–83lactate (See Lactate)lipid droplets, 342f, 341–342, 343f, 343, 345–346,

347fpH, 354–356, 363, 489–490pyruvate (See Pyruvate)salts in intracellular metabolite extraction,

101–102solvents in intracellular metabolite extraction,

86–87water, 356

Intraperitoneal injection, 421in vivo analysis. See Human tissues (in vivo MRS

studies)Iodine in silyation, 212f, 212–213, 213fIodoketones, 212–213. See also KetonesIon cyclotron resonance Fourier transform mass

spectrometry (ICR-FTMS), 72f, 72Ionizable groups, 562, 578Ion mobility mass spectrometry (IMMS)

acetaminophen, 199ambient pressure ion mobility mass

spectrometry (APIMMS), 186–189biofluids, 194f, 192–194, 200fblood, 192–194, 194fBradbury-Nielson (BN) gate, 187caffeine, 200, 201fcollision cross section determination, 187–189,

199–200collision induced dissociation (CID), 191data processing, 189, 191–192dihydroxyphenylacetic acid (DOPAC), 198dopamine, 198drift gases, 186–187drift tube ion mobility time-of-flight mass

spectrometer (DTIMMS), 186–187, 188f,189

E. coli, 194f, 192–194fed-batch culture, 199fragmentation, 200, 201ffragment ion analysis, 191–192, 193fglucose, 197–1985-hydroxyindoleacetic acid (5-HIAA), 198leflunomide, 199Liu Wei Di Huang Wan, 198–199LTQ-Orbitrap, 199mass-mobility correlation curves, 196–197metabolite identification, 193f, 196–197metabolite quantification, 197–198metabolite target analysis, 200f, 198–200metabolome comparison, 194–196metabolome measurement, 194f, 192–194, 195f,

196fmetabolomics applications, 198–200, 200f, 201f




606 Index

Ion mobility mass spectrometry (IMMS) (cont.)metabolomics protocol, 192–198mobility constant, 186–187mobility determination, 187–189, 197fmouse, 198–199oligosaccharides, 199overview, 185–186, 201polyamines, 199principal component (PCA) analysis, 195f,

194–195, 196f, 196quadrupole mass spectrometer (QMS),

190–191rat, 192–194, 194f, 197–198reserpine, 198–199salarins, 199sample introduction, ionization, 190–191signal ion monitoring (SIM), 190–191Synapt High Definition MS system, 189,

199thyroxine, 198–199TOF analysis, 187traveling wave ion guide (TWIG), 190f,

190–191traveling wave ion mobility mass spectrometry

(TWIMMS), 189–192, 198–199traveling wave ion mobility spectrometry

(TWIMS), 191f, 191, 199–200trend lines, 197f, 196–197

Ion suppression, 39–41, 84, 132–135, 213f,227

Ion traps, 175tIschemia, 428, 497–499Isocitrate dehydrogenase, 436Isoelectric focusing, 65Isotopes. See also Isotopic labeling; Isotopomers

in acylation, 213–214bioinformatics (in mass spectrometry), 167,

173n13C NMR studies (See 13C NMR studies)CE-ESI-MS, 130chloride isotope effect, 213–214distribution pattern determination, 142,

185–186empirical formulae assignments filtering via

relative isotopic abundances, 168, 173n1H NMR spectroscopy (See 1H NMR

spectroscopy)IMMS measurement of, 192–194, 196–198isotopomer determination, editing for, 566f,

569f, 570f, 571f, 576f, 571–576, 577laboratory safety, 415–416metabolite quantification via dilution of,

197–19831P NMR (See Phospholipidomics; 31P NMR)pyruvate-lactate isotope exchange, 464–465relative isotopic abundances, 168, 173nsignal identification, 161, 167stable, 415–416, 525steady-state, 80–81, 415–416

Isotopic labelingapplications of generally, 80–81

13C NMR, 339–340, 343–344, 348, 356, 363,418f, 419–420, 421, 423–424, 425f, 426f,426–427, 430f, 428–430, 433, 449, 461–462,465–466, 563–564, 576–577, 578–579, 579f,580 (See also 13C NMR studies)

in exometabolome analyses, 81–83glucose/lactate metabolism, 339–3401H NMR spectroscopy, 339–340, 465–466 (See

also 1H NMR spectroscopy)isotope editing for determination of

isotopomers, 566f, 569f, 570f, 571f, 576f,571–576, 577

isotopomers, 418f, 419–420, 421, 423–424, 425f,426f, 426–427, 430f, 428–430, 433, 525–526,563–564, 577, 578–579, 579f, 580

in LC-MS, 21–23metabolite quantification via, 197–198, 348preclinical model systems, 343–344pyruvate, 449in radiometric assays, 66secondary labels, 453–455stable, 525, 566f, 566–567standards, applications of, 16, 18–19, 22, 103water suppression, 356

Isotopomers. See also Isotopes; Isotopic labelinganalysis sensitivity, 563–56413C analysis of, 418f, 420–421, 423t, 425f,

424–425, 426f, 427chemical exchange in, 424–426cross peaks, 566–567function, 425fisotope editing for determination of, 566f, 569f,

570f, 571f, 576f, 571–576, 577isotopic labeling, 418f, 419–420, 421, 423–424,

425f, 426f, 426–427, 430f, 428–430, 433,525–526, 563–564, 577, 578–579, 579f, 580

isotopomer analysis, 418f, 420–421, 423t, 425f,424–425, 426f, 427, 566f, 566–567

in pathway reconstruction, 566f, 569f, 575f,576f, 578–579, 579f, 580

profiles in metabolic pathways, 566–567,578–580

resonance assignment, 563–564, 566f, 566–567,571f

stable, 566f, 566–567TOCSY analysis of, 566f, 566–567

ISUCA (2-(imidazol-1-yl) succinic acid), 363

Jatropha curcas, 89–90, 94fJerusalem artichokes, 277fJ-resolved NMR, 309, 486t, 486–487, 564–565

KEGG, KEGG Brite (See Kyoto Encyclopedia ofGenes and Genomes)

Kennedy pathway, 66–67, 73, 338�-Ketoglutarate, 424f, 425f, 424–425, 426, 437Ketones

in brain metabolism, 433–436carbonyl ketones, 213in cardiac metabolism, 426f, 4281H NMR studies, 258–259




Index 607

iodoketones, 212–213ketone bodies, 266, 289–290, 423–424, 427oxidation, 428selective labeling of, 22, 423–424, 426–427

Kidney biopsy, 503f, 511–512, 513f, 514–515t, 516tKinetic studies, 415–416KNApSAcK, 161Knockdown, 55, 59–60. See also Gene

overexpression; Gene silencingKrebs cycle, 258–259, 260, 340f, 339–341, 419–420,

421, 423t, 424f, 425f, 426f, 439fKurstakin D, 177f, 176–177, 178f, 182Kyoto Encyclopedia of Genes and Genomes

(KEGG), 47–49, 161, 299

Laboratory safetyblood collection, 98isotopes, 415–416liquid nitrogen, 98–99viruses, 56–57

Lactatein cancer, 34613C NMR studies, 417t, 423t, 435f, 433–435, 436CSF 1H-NMR studies, 261–263, 265–266human tissues (HR-MAS studies), 497–499,

507, 514–515thyperpolarized NMR spectroscopy, 448t, 449,

451–453, 455, 465–466isotopomers, 418f, 420–421resonance assignment, 527f, 528f, 563

Lactate dehydrogenase, 340f, 339–340, 435, 453LAESI. See Laser ablation electrospray ionization

(LAESI)Laser ablation electrospray ionization (LAESI)

ambient mass spectrometry, 141Arabidopsis thaliana, 147atmospheric-pressure mass spectrometry, 141biomarker discovery, 145colocalization maps, 146, 147fdatabases, 142depth profiling of tissues, 148f, 147–148, 149,

151fdirect analysis, 141–142, 146French marigold (Tagetes patula), 143–144,

144fhistamine, 151local analysis, 143–145lymphocytes, 145f, 145metabolic analysis, 143–145, 145fmetabolic imaging, 147f, 145–147metabolite identification, label-free, 142–143mid-infrared laser ablation, 143f, 145–146,

147–148mouse, 144–145neurotransmitters, 146, 147

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