No title available 1998 Metabolic Engineering

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INDEX 
, 
A 
Acetate 
excretion, 260-261 
labeled, T CA cycle metabolite isotopomers, 
377-382 
utilization in Escherichia coli, 394-396 
Acetolactate synthase, in Bacillus subtilis, 
261-262 
Acetone, industrial fermentation,, 220-222 
Acetyl-CoA 
formation, 48-51 
metabolism, label distribution, 364-367 
Actinomycetes, as polyketide source, 237-238 
Actinorhodin, production, 236 
Active transport 
ATP consumption, 36-37 
group translocation, 35-36 
role of permeases, 34 
via ATPase, 34-35 
Alanine 
metabolic pathway synthesis algorithm, 
299-300 
synthesis in Zymomonas mobilis, 215 
Alcohol 
fermentation pathway, 46-48 
passive diffusion, 28-29 
Alcohol dehydrogenase, catalyzed reaction, 
AG O ', 662 
Aldehyde dehydrogenase, in alcohol fermenta- 
tion, 47 
Algorithms 
Gibbs free energy change for reaction, 
641-645 
metabolic flux, optimization, 610-613 
metabolic pathway synthesis 
alanine synthesis, 299-300 
analysis, 307-308 
execution, 288-295 
lysine biosynthesis, 300-303 
alternatives, 304-306 
maximum yield restrictions, 306-307 
role of oxalacetate, 303 
overview, 295-297 
serine synthesis, 297-298 
Allosteric enzymes 
application of Hill equation, 172-173 
cooperative binding, 170-172 
cooperativity, 168-169 
noncooperative sites, 169-170 
Amine group, in AG O' determination, 651 
Amino acids 
aromatic, biosynthesis 
independent pathways, 557-563 
model, 554.557, 
biosynthesis, 58-61 
catabolism, 55-57 
in AG O' determination, 651 
from metabolic pathway manipulation 
alanine, 215 
for amino acid production, 212-214 
isoleucine, 219-220 
threonine, 215-219 
tryptophan, 214-215 
707 
708 Index 
production by glutamic acid bacteria, 
413-414 
theoretical yields, 419-425 
Aminocarbohydrates, polymerization, 66-71 
Ammonia 
ammonium, uptake, 415 
in lysine biosynthesis, 300-303 
passive diffusion, 28-29 
Anaplerotic pathways, TCA cycle, 53-55 
Antibiotics, production by metabolic path- 
ways, 235-237 
Aspartate, pathway, feedback control, 165-168 
Aspergillus nidulans, PP pathway, 43 
Aspergillus niger, in antibiotic production, 236 
Assembly reactions, in cellular metabolism, 
22-23 
Atom mapping matrix, in isotope distribution 
modeling, 405-409 
ATP 
as branch point in metabolic network model, 
566-573, 593-596 
consumption for active transport, 36-37 
consumption for maintenance, 72-73 
effect of organic acids, 29-31 
in Escherichia coli metabolism, 344-345 
formation, Gibbs free energy, 659-660 
in pathway integration, 24 
production and consumption, balance, 105 
ATPase 
as active transport system, 34-35 
FoFI-, proton export, 37 
B 
Bacillus subtilis, acetolactate synthase, 
261-262 
Bacteria 
glutamic acid 
amino acid production, 413-414, 
419-425 
biochemistry and regulation, 414-419 
glyoxylate shunt pathway, 396-397 
lactic acid, heterofermentative metabolism, 
MFA, 330-333 
TCA cycle, 396-397 
Benzene-toluene-p-xylene mixture 
degradation with pWWO, 269-271 
as pollutant, 267-268 
simultaneous biodegradation, 271-273 
Benzoic acid, effect on respiration in yeast, 
29-31 
Biocatalysts, production, 12-13 
Biochemical pathways 
identification, 311-312 
metabolite participation, 295-297 
Biochemical systems theory, modeling com- 
plex systems, 463-464 
Biochemistry 
glutamic acid bacteria, 414-419 
role in M CA, 8-9 
Biodegradation, BTX mixtures, 269-271 
Biofuel, ethanol as, 205 
Biomass 
cell 
in black box model, 117-118 
dry weight, 22 
constituents 
in cellular reactions, 83 
in dynamic mass balance, 98 
Biopolymers, production by organisms, 
243-244 
Bioreactor control equivalents, in MCA, 8 
Bioreactors 
batch type, 94 
continuous type, 95 
dynamics, 93-94 
fed-batch type, 95 
Biosynthetic reactions 
amino acids, 58-61 
aromatic amino acids 
independent pathways, 557-563 
model, 554-557 
in cellular metabolism, 23-24, 57-58 
control by enzyme activity, 165-168 
deoxyribonucleotides, 62 
fatty acids, 62-64 
lipids, 62-64 
lysine 
alternatives, 304-306 
bypass pathway flux, 359-364 
from glucose and ammonia, 300-303 
group FCC in, 589-590 
maximum yield restriction, 306-307 
metabolic fluxes, 317-320 
Index 7 0 9 
MFA 
description, 426-427 
perturbations at Glc6P branch point, 
429-436 
perturbations at PEP-pyruvate branch 
point, 436-438 
principal node identification, 428-429 
role of oxaloacetate, 303 
nucleotides, 62 
penicillin 
application of M CA with thermokinetics, 
690-692 
MCA, 494-499 
storage carbohydrate, 64-65 
Biotin, production, 242-243 
Black box model 
cell biomass, 117-118 
simple 
carbon balance, 120-121 
description, 118 
elemental balances, 123 
generalized degree of reduction balance, 
124-125 
metabolic, 85-86, 106 
variables, 119-120 
Bottom-up approach 
control coefficients in metabolic networks, 
582-585 
for group control coefficient determination 
ATP branch point, 593-596 
FDP//GAP branch point, 598 
glucose-6-phosphate branch point, 
597-598 
PPH branch point, 600-601 
X5P 4- CHR branch point, 599-600 
Branch points 
ATP, group control coefficients, 593-596 
classification in metabolic networks, 
193-196 
control in cellular pathways, 311 
FDP//GAP, group control coefficients, 598 
Glc6P, metabolic flux perturbations, 
429-436 
glucose-6-phosphate, group control coeffi- 
cients, 597-598 
MCA 
applications, 499-506 
gluconeogenesis, 506-510 
glycolysis, 506-510 
oxidative phosphorylation, 510-513 
in metabolic networks, 522-525 
ATP, 566-573 
chorismate, 576-577 
fructose-l,6-diphosphate, 574-576 
glucose-6-phosphate, 573-574 
glyceraldehyde-3-phosphate, 574-576 
link metabolites and group flux, 563-566 
prephenate, 578-580 
xylulose-5-phosphate, 576-577 
multiple, overlapping reaction groups, 
605-607 
PEP-pyruvate, flux perturbations, 436-438 
PPH, group control coefficients, 600-601 
prephenate, application of group FCC con- 
sistency tests, 623-625 
single, flux distribution, control, 539-545 
X5P 4- CHR, group control coefficients, 
599-600 
BTX mixture, see Benzene-toluene-p-xylene 
mixture 
Butanol, industrial fermentation, 220-222 
C 
Calorimeter, for heat measurement, 129 
Candida lipolytica, fermentation of citric acid, 
MFA, 320-325 
Candida shehatae, as pentose fermentor, 208 
Carbohydrates 
aminocarbohydrates, 66-71 
polymerization, 66-71 
storage, synthesis, 64-65 
worldwide production, 11-12 
Carbon 
balance in simple black box model, 120-121 
direct balance, 397-405 
in T CA cycle, 50 
Carbon dioxide 
passive diffusion, 28-29 
in PP pathway, 40-42 
Carbonyl cyanide p-trifluoro-metho- 
xyphenylhydrazone, effect on proton-mo- 
tive force, 511 
Carboxylation, pyruvate, compensation by 
PPC, 441-442 
Carboxylic acids, in AG ~ determination, 651 
Carrier-substrate complex, in 
Michaelis-Menten reaction, 32-34 
Catabolism, fats, organic acids and amino 
acids, 55-57 
710 Index 
CCC, see Concentration control coefficients 
Cell biomass 
in black box model, 117-118 
dry cell weight, 22 
Cell cultures 
mammalian, MFA 
description, 445-446 
intracellular fluxes, 446-452 
isotope labeling studies, 452-457 
media design, application of MFA, 457-458 
Cell growth 
effect of organic acids, 260 
nonequilibrium thermodynamic descrip- 
tion, 679-682 
Cell physiology 
in reaction pathway analysis, 3 
role of metabolic flux, 4-5 
Cells 
liver, rat, gluconeogenesis and glycolysis, 
506-510 
whole, global control 
definition, 180-183 
signal transduction by phosphorylation, 
183-188 
Cellular engineering 
for cellular properties, 256-257 
maintenance of genetic stability, 263-266 
nitrogen metabolism alteration, 257 
overflow metabolism prevention,259-262 
for oxygen utilization, 257-259 
substrate uptake alteration, 262-263 
Cellular metabolism 
analysis with metabolic engineering, 11 
assembly reactions, 22-23 
biosynthetic reactions, 23-24 
dry cell weight biomass, 22 
fueling reactions, 24 
pathway integration, 24 
polymerization reactions, 23 
relaxation time, 25-27 
role of NADH and NADPH, 44-45 
Cellular pathways 
branch point control, 311 
dynamic mass balances, 93-94 
linear rate equations, 102-105 
metabolic model, 85-86 
metabolites, dilution effect, 314-316 
mixed acid fermentation in Escherichia coli 
rates, 90-92 
specific rates, 92-93 
nonequilibrium thermodynamics, 663 
stoichiometry 
biomass constituents, 83 
intracellular metabolites, 83 
metabolic product, 82-83 
substrate, 82 
yield coefficients, 102-105 
Cellular synthesis, biosynthetic reactions, 
57-58 
Cellulose-hemicellulose depolymerization, 
229-230 
Cephalosporin C, production, 236 
Cephalosporium acremonium, antibiotic pro- 
duction, 236 
Chemical engineering, role in metabolic engi- 
neering, 10 
Chemical reactions 
alcohol dehydrogenase-catalyzed, AG O ', 662 
Gibbs free energy, algorithm, 641-645 
group contributions, in Gibbs free energy 
determination, 649-654 
thermodynamic feasibility, 639-641 
Chlamydomonas reinhardtii, in hydrogen pro- 
duction, 255 
Cholesterol, synthesis and elimination, 
179-180 
Chorismate 
in aromatic amino acid biosynthesis, 557 
as branch point in metabolic network model, 
576-577, 599-600 
CHR, see Chorismate 
Citrate, in TCA cycle, 50 
Citrate synthase, in T CA cycle, 50 
Citric acid, fermentation, MFA, 320-325 
C-mole basis, and yield calculation, 122 
Coefficients 
concentration control, 526-527 
control, 582-585, 613-616 
elasticity 
calculation from kinetic models, 487-488 
gluconeogenesis, 508-509 
in MCA, 470-473 
flux control, see Flux control coefficients 
for MCA, 513-514 
yield 
in black box model, 119-120 
calculation, 122 
cellular reactions, 102-105 
Coenzymes, in biosynthetic reactions, 23-24 
Competitive inhibition, characteristics, 
159-161 
Index 711 
Computer programs, MATLAB, MATHCAD, 
and MATHEMATICA, 135 
Concentration 
change prediction with CCC, 526-527 
nutrient, role in flux changes, 527-529 
Concentration control coefficients 
group 
determination, 591-592 
from flux measurements, 585-586 
in metabolic networks, 582-585 
in prediction of concentration changes, 
526-527 
Concentration gradient, maintenance, 72 
Condition number, calculation, 349 
Connectivity theorem, in MCA, 470-473 
Consistency tests, for group FCCs 
application to prephenate branch point, 
623-625 
characteristics, 616-618 
development, 618-623 
Control coefficients 
group, see Group control coefficients 
in metabolic networks, 582-585 
for Saccharomyces cerevisiae flux optimiza- 
tion, 613-616 
Control equivalents, in MCA 
bioreactor control equivalents, 8 
group control equivalents, 8 
Copolymers, production, 247-248 
Corynebacterium glutamicum 
in amino acid production, 212-214 
deletion mutants, MFA, 439-441 
transhydrogenase discovery, 442-445 
isoleucine synthesis, 219-220 
lysine biosynthesis, MFA 
description, 426-427 
perturbations at Glc6P branch point, 
429-436 
perturbations at PEP-pyruvate branch 
point, 436-438 
principal node identification, 428-429 
lysine production, 43 
pyruvate carboxylation, compensation by 
PPC, 441-442 
threonine synthesis, 215-219 
Cost, ethanol production, 206-208 
D 
Data consistency, in anaerobic yeast cultiva- 
tion, 125-126 
Degradation 
biodegradation, BTX mixtures, 269-271 
xenobiotic degradation, 266 
Delgado-Liao approach, extension, 689-690 
3-Deoxy-D-arabino-heptulosonate-7-phos- 
phate, in aromatic amino acid biosynthe- 
sis, 557 
Deoxyribonucleic acid 
polymerization, 66-71 
recombination, in metabolic pathway ma- 
nipulation, 1-2 
Deoxyribonucleotides, biosynthesis, 62 ' 
Depolymerization, cellulose--hemicellulose, 
229-230 
Deviation theory, large 
basis, 514-517 
in FCC determination, 519-520 
for role of nutrient concentration in flux 
change, 527-529 
Diffusion 
facilitated 
definition, 31 
saturation kinetics, 32-34 
free, in passive transport, 28 
Diisopropyl phosphofluoridate, as irreversible 
inhibitor, 163 
1,3-Diphosphoglycerate, in EMP pathway, 40 
Dissipation function, in nonequilibrium ther- 
modynamics, 664-665 
DNA, see Deoxyribonucleic acid 
Dynamic mass balance 
in cellular reactions, 93-94 
derivation, 95-96, 99-102 
biomass constituents, 98 
substrates, 97-98 
E 
ED pathway, see Entner-Doudoroff pathway 
Effector amplification factor, in nutrient con- 
centration calculations, 528 
Elasticity coefficients 
calculation from kinetic models, 487-488 
gluconeogenesis, 508-509 
Electrical potential, gradient, maintenance, 72 
Electrolysis, in hydrogen production, 253 
Electron transport, NADH to oxygen, 51-53 
Elemental balance 
generalized degree of reduction balance, 
124-125 
in simple black box,model, 123 
7 1 2 Index 
Embden-Meyerhof-Pamas pathway 
control points, 44 
in glycolysis, 38 
hexokinase reaction, nonequilibrium ther- 
modynamics, 665 
intermediates, 42-44 
reactions, 40 
thermodynamic feasibility analysis, 
645-649 
EMP pathway, see Embden-Meyerhof-Parnas 
pathway 
Energetics, Saccharomyces cerevisiae, 110-114 
Energy 
free, see Free energy 
generation, decoupling, 29-31 
transduction, definition, 663 
Enolase, elasticity coefficient, 509 
Entner-Doudoroff pathway 
in glycolysis, 38 
reactions, 42 
Enumeration, complete, metabolite iso- 
topomers, 367-370 
Enzyme I, in active transport, 36 
Enzyme II, in active transport, 36 
Enzymes 
activity in Escherichia coli, regulation, 150, 
152 
allosteric 
application of Hill equation, 172-173 
cooperative binding, 170-172 
cooperativity, 168-169 
noncooperative sites, 169-170 
change, in determination of flux change, 
521-522 
control of biosynthetic network, 165-168 
genetic alteration, 478, 480-481 
in hydrogen production, 253 
kinetics, 152-153 
purified, in titration, in FCC, 481-482 
transcriptional control, 173-177 
translational control, 178-180 
Equations 
Hill, application to allosteric enzymes, 
172-173 
linear rate, cellular reactions, 102-105 
phenomenological, nonequilibrium thermo- 
dynamics, 666-667 
Equilibrium, rapid, in substrate inhibition, 
155-156 
Errors 
diagnosis in yeast cultivation measurement, 
144-146 
in gross measurement, 130-131 
in metabolic flux measurement, 625-626 
in variance-covariance matrix calculations, 
142-143 
Erwinia carotovora, for cellulose-hemicellu- 
lose depolymerization, 229-230 
Erwinia chrysanthemi, for cellulose-hemicel- 
lulose depolymerization, 229-230 
Erythromycin, production by Saccha- 
ropolyspora erythrea, 238-241 
Erythrose-4-phosphate, in aromatic amino acid 
biosynthesis, 556-557 
Escherichia coli 
acetate utilization, 394-396 
enzymatic activity, regulation, 150, 152 
in ethanol production, 210-211 
fermentative pathway, 46 
growth, 413 
indigo production, 250-252 
metabolism, stoichiometry, 344-347 
mixed acid fermentation 
rates, 86-90 
specific rates, 92-93 
overflow metabolism, prevention, 259-262 
Pho regulon, 187-188 
promoters, transcription initiation, 174-175 
1,3-propanediol synthesis, 222-223 
tryptophan synthesis, 214-215 
Ethanol 
aerobic yeast cultivation without formation, 
136-140, 143 
as biofuel, 205 
from fermentative metabolism, 208-209 
from glucose conversion, 47-48 
-glucose mixtures, yeast growth, 413 
industrial fermentation, 220-222 
production, 206-208 
from Escherichia cali, 210-211 
from pdc and adh genes, 211-212 
pentose metabolism for, 224 
from pyruvatedecarboxylase, 209 
from Saccharomyces cerevisiae, 208 
by yeast, 225-227 
by Zymomonas mobilis, 227-228 
Index 7 1 3 
Eukaryotes, metabolic network regulation, 
190-192 
Excretion, acetate, 260-261 
F 
Facilitated diffusion 
definition, 31 
saturation kinetics, 32-34 
Fats, catabolism, 55-57 
Fatty acids 
biosynthesis, 62-64 
passive diffusion, 28-29 
FCC, see Flux control coefficients 
FDP, see Fructose-l,6-diphosphate 
Feedback 
control in aspartate pathway, 165-168 
inhibition and activation, modes, 151 
Fermentation 
alcohol, 46-48 
citric acid, MFA, 320-325 
in hydrogen production, 253 
industrial, solvents, 220-222 
mixed acid in Escherichia coli 
rates, 86-90 
specific rates, 92-93 
pentose, by microorganisms, 208 
pyruvate conversion to lactic acid, 45-46 
First Law of Thermodynamics, definition, 631 
Flow-force relations, in nonequilibrium ther- 
modynamics, 668-669 
Flux control coefficients 
change prediction, 520-521,525-526 
determination, 475-478 
double modulation, 484-485 
elasticity coefficients, 487-488 
from enzyme change, 521-522 
expressions for estimation, 517-519 
genetic alteration of expressed enzyme, 478, 
480-481 
group 
definition, 538-539, 546-547 
kernel determination via matrix algebra, 
551-553 
SIMS matrix analysis, 549 
kinetic models, 491-492 
from large deviations, 519-520 
matrix, 500 
in MCA, 465-469 
nonlinear function determination, 476 
single modulation, 486 
titration with purified enzyme, 481-482 
titration with specific inhibitors, 482-483 
top-down approach, 486-487 
transient metabolite measurement, 488-491 
Force ratio, in nonequilibrium thermodynam- 
ics, 671 
Fossil fuel, ethanol as, 205 
Free energy 
Gibbs, see Gibbs Free energy 
glycolytic reactions, 637-638 
standard 
glucose oxidation, 680 
hexokinase reaction in EMP pathway, 665 
nomenclature, 635 
oxidative phosphorylation, 674 
reaction, 636-637 
Fructan, production, 249-250 
Fructose, phosphorylation, 39 
Fructose- 1,6-diphosphate 
in aromatic amino acid biosynthesis, 556 
as branch point in metabolic network model, 
574-576, 598 
Fructose-6-phosphate 
in EMP pathway, 40 
in glycolysis, 39 
Fueling reactions 
in cellular metabolism, 24 
purpose, 38 
G 
GAP, see Glyceraldehyde-3-phosphate 
Genes 
enzyme, alteration, 478, 480-481 
hemoglobin, cloning, 258-259 
pdc and adh, in ethanol production, 
211-212 
pentose metabolism for ethanol production, 
224 
stability, maintenance, 263-266 
Genetic engineering, in metabolic pathway 
manipulation, 1-2 
Genetic regulatory network, cholesterol syn- 
thesis and elimination, 179-180 
Genetics, role in MCA, 8-9 
Gibbs free energy 
alcohol dehydrogenase-catalyzed reaction, 
662 
714 Index 
ATP formation, 659-660 
determination, 631-634 
glutamate' formation, 654, 659 
from group contributions, 649-654 
in growth energetics, 71 
reactions, algorithm, 641-645 
relationship to thermodynamic feasibility, 
639-641 
in substrates, 126-127 
Glc6P, see Glucose-6-phosphate 
Global control, at whole cell level 
definition, 180-183 
signal transduction by phosphorylation, 
183-188 
Gluconeogenesis, rat liver cells, 506-510 
Glucose 
conversion to ethanol, 47-48 
-ethanol mixtures, yeast growth, 413 
facilitated diffusion, 31-32 
in lysine biosynthesis, 300-303 
oxidation, standard free energy, 680 
phosphorylation, 39 
transport, 415 
uptake by phosphotransferase system, 
83-84 
Glucose dehydrogenase, in hydrogen produc- 
tion, 253-255 
Glucose-l-phosphate, in glycolysis, 38-39 
Glucose-6-phosphate 
in aromatic amino acid biosynthesis, 556 
branch point, metabolic flux perturbations, 
429-436 
as branch point in metabolic network model, 
573-574, 597-598 
in glycolysis, 38-39 
in PP pathway, 40-42 
Glutamate, formation, Gibbs free energy, 654, 
659 
Glutamate dehydrogenase, production, 257 
Glutamic acid, bacteria 
amino acid production, 413-414, 419-425 
biochemistry and regulation, 414-419 
Glyceraldehyde-3-phosphate 
in aromatic amino acid biosynthesis, 556 
as branch point in metabolic network model, 
574-576, 598 
in ED pathway, 42 
in EMP pathway, 40 
Glyceraldehyde-3-phosphate dehydrogenase, 
elasticity coefficient, 509 
Glycerol, in aromatic amino acid biosynthesis, 
556 
Glycolysis 
definition, 38 
free energy, 637-638 
Leloir pathway, 39-40 
rat liver cells, 506-510 
sugars, 38-39 
Glyoxylate, shunt pathway, in bacteria, 
396-397 
Gradients 
concentration, maintenance, 72 
proton, in Penicillium chrysogenum, 29-31 
Group concentration control coefficients 
determination, 591-592 
from flux measurements, 585-586 
in metabolic networks, 582-585 
Group contribution method, in Gibbs free en- 
ergy determination, 649-654 
Group control coefficients, metabolic network 
model 
ATP branch point, 593-596 
FDP/GAP branch point, 598 
glucose-6-phosphate branch point, 597-598 
PPH branch point, 600-601 
X5P + CHR branch point, 599-600 
Group control equivalents, in MCA, 8 
Group flux control coefficients 
from characterized perturbations, 590-591 
consistency test and experimental valida- 
tion, 616-618 
experimental determination, 601-604 
graphical representation, 619-621 
intermetabolite links, 607-609 
for lysine biosynthesis, 589-590 
measurement error effects, 625-626 
from three perturbations, 586-590 
Group translocation, in active transport, 
35-36 
Growth 
cell 
effect of organic acids, 260 
nonequilibrium thermodynamic descrip- 
tion, 679-682 
energetics, definition, 71 
Escherichia coli, 413 
Penicillium chrysogenum, rate, 104-105 
Saccharomyces cerevisiae 
anaerobic growth, 413 
on glucose-ethanol mixtures, 413 
Index 7 1 5 
yeast, heat generation 
aerobic growth, 127-129 
anaerobic growth, 127-129 
H 
Heat 
balance, 126-127 
generation at anaerobic and aerobic growth, 
127-129 
Hemicellulose-cellulose depolymerization, 
229-230 
Hemoglobin, gene cloning, 258-259 
Hexokinase, reaction in EMP pathway, 665 
Hexose monophosphate, in glycolysis, 38-39 
Hill equation, application to allosteric en- 
zymes, 172-173 
Histidine protein, in active transport, 36 
Hydrogen, production, 253-255 
Hydrogenase, in hydrogen production, 
253-255 
3-Hydroxybutyrate, in copolymer production, 
247-248 
3-Hydroxyvalerate, in copolymer production, 
247-248 
I 
Indigo, production, 250-252 
Inhibition systems 
competitive, characteristics, 159-161 
irreversible 
biosynthetic network control, 165-168 
molecules, 163-165 
noncompetitive, characteristics, 161-163 
simple reversible, substrate inhibition, 153, 
157-159 
substrate 
competitive inhibition, 159-161 
noncompetitive inhibition, 161-163 
rapid equilibrium, 155-156 
as simple reversible inhibition system, 
153, 157-159 
steady-state approach, 156-157 
uncompetitive inhibition, 163 
titration, in FCC, 482-483 
uncompetitive, characteristics, 163 
Intensity, transient, in metabolic flux determi- 
nation, 356-357 
Intermetabolite links, group FCCs, 607-609 
Intracellular metabolites, in cellular reactions, 
83 
Irreversible inhibition 
biosynthetic network control, 165-168 
molecules, 163-165 
Isoleucine, synthesis in Corynebacterium glu- 
tamicum, 219-220 
Isotope labeling analysis 
acetate, 377-382 
acetate utilization in Escherichia coli, 
394-396 
acetyl-CoA metabolism, 364-367 
in complete enumeration of metabolite iso- 
topomers, 367-370 
distribution, modeling with atom mapping 
matrix, 405-409 
flux in mammalian cell cultures, 452-457 
glyoxylate shunt pathway in bacteria, 
396-397 
metabolite carbon atoms, NMR analysis, 
382-390 
pyruvate, 371-377 
pyruvate utilization in mammal, 390-394 
steady state experiments, 357-359 
TCA cycle inbacteria, 396-397 
Isotopomers, metabolite 
complete enumeration, 367-370 
direct carbon balances, 397-405 
T CA cycle, distribution 
from labeled acetate, 377-382 
from labeled pyruvate, 371-377 
K 
Kernel, determination via matrix algebra, 
551-553 
2-Keto-3-deoxy-6-phosphogluconate, in ED 
pathway, 42 
2-Keto-3-deoxy-6-phosphogluconate aldolase, 
in ED pathway, 42 
2-Keto-L-gluconic acid, commercial produc- 
tion, 241-242 
a-Ketoglutarate, in TCA cycle, 53-55 
a-Ketoglutarate dehydrogenase, in T CA cycle, 
50 
716 Index 
Kinetic models 
dynamic mass balance, 100 
elasticity coefficient calculation, 487-488 
enzyme, 152-153 
for FCC, 491-492 
Saccharomyces cerevisiae, 601-604 
saturation, facilitated diffusion, 32-34 
L 
Labeling, see Isotope labeling analysis 
Lac operon, transcriptional control, 175-177 
Lactate dehydrogenase, conversion of pyru- 
vate to lactic acid, 45-46 
Lactic acid 
bacteria, heterofermentative metabolism, 
MFA, 330-333 
from pyruvate, 45-46 
Lactose, utilization, 230-233 
Large deviation theory 
basis, 514-517 
in FCC determination, 519-520 
for role of nutrient concentration in flux 
change, 527-529 
Leloir pathway, in glycolysis, 39-40 
Level flow, in nonequilibrium thermodynam- 
ics, 672 
Lignocellulose, in ethanol production, 206 
Linear force relation, in nonequilibrium ther- 
modynamics, 682-686 
Linear programming, undetermined systems, 
341-344 
Linear rate equations, cellular reactions, 
102-105 
Link metabolite 
group CCC, 591-592 
identification, 563-566 
intermetabolite links, group FCCs, 607-609 
Lipids 
biosynthesis, 62-64 
polymerization, 66-71 
Liver cells, rat, gluconeogenesis and glycoly- 
sis, 506-510 
Lysine 
biosynthesis 
alternatives, 304-306 
bypass pathway flux, 359-364 
from glucose and ammonia, 300-303 
group FCC in, 589-590 
maximum yield restriction, 306-307 
metabolic fluxes, 317-320 
MFA 
description, 426-427 
perturbations at Glc6P branch point, 
429-436 
perturbations at PEP-pyruvate branch 
point, 436-438 
principal node identification, 428-429 
role of oxaloacetate, 303 
formation pathway, 415 
M 
Macromolecules 
and assembly reactions, 22-23 
polymerization, 66-71 
turnover, 73 
Malonate, effect on proton-motive force, 511 
Malonic acid, as competitive inhibitor, 159 
Mammals, pyruvate utilization, 390-394 
Maps, metabolic, definition, 9-10 
Mass balance, dynamic 
in cellular reactions, 93-94 
derivation, 95-96, 99-102 
biomass constituents, 98 
substrates, 97-98 
MATHCAD program, for matrix operations, 
135 
MATHEMATICA program, for matrix opera- 
tions, 135 
MATLAB program, for matrix operations, 135 
Matrices 
atom mapping, in isotope distribution mod- 
eling, 405-409 
redundancy, reduced, in overdetermined 
systems, 334 
SIMS 
for aromatic amino acid biosynthesis, 
557-563 
for independent pathway identification, 
549 
in kernel determination, 551-553 
variance-covariance, calculation errors, 
142-143 
Matrix algebra, in kernel determination, 
551-553 
Matrix operations 
basic matrix operations, 132-134 
matrix inverse, 134-135 
matrix transpose, 134 
variance-covariance, calculations errors, 
142-143 
Index 717 
MCA, see Metabolic control analysis 
Medermycin, production, 237 
Media, design for cell culture, application of 
MFA, 457-458 
Medicine, chiral, production via metabolic en- 
gineering, 13 
Metabolic control analysis 
in analysis of flux control, 7-8 
application of thermokinetics, 686-688 
basic assumptions, 464-465 
bioreactor control equivalents, 8 
branched pathways 
applications, 499-506 
gluconeogenesis, 506- 510 
glycolysis, 506-510 
oxidative phosphorylation, 510-513 
coefficients, 513-514 
connectivity theorems, 470-473 
control coefficients, 465-469 
definition, 545 
elasticity coefficients, 470-473 
extension of Delgado-Liao approach, 
689-690 
group control equivalents, 8 
intermetabolite reaction groups 
overlapping groups in multiple branch 
points, 605-607 
perturbation constant, 604-605 
linear pathways, 492-499 
penicillin biosynthesis, 690-692 
role of biochemistry, 8-9 
role of genetics, 8-9 
summation theorems, 465-469 
theory generalization, 473-475 
Metabolic engineering 
in analysis of 
cellular metabolism, 11 
pathways, 10-11 
definition, 2 
in flux control analysis, 7-8 
pentose metabolism for ethanol production, 
224 
petroleum-derived thermoplastic produc- 
tion, 12 
reverse, in pathway characterization, 2 
role 
in biocatalyst production, 12-13 
chemical engineering, 10 
in chiral medicine production, 13 
flux and pathways, 5-7 
in tissue and organ metabolism in vivo, 
14 
Metabolic factors, in biosynthetic reactions, 
23-24 
Metabolic flux 
acetate utilization in Escherichia coli, 
394-396 
bypass pathway, in lysine biosynthesis, 
359-364 
consistency test, 616-618 
application to prephenate branch point, 
623-625 
development, 618-623 
control coefficients 
determination, 475-478 
nonlinear function derivatives, 476 
definition, 3-4 
error measurement effects, 625-626 
experimental validation, 616-618 
group control coefficients from, 585-586 
and isotopic steady state experiments, 
357-359 
optimization 
algorithm, 610-613 
application to Saccharomyces cerevisiae, 
613-616 
phosphofructokinase, amplification, 
609-610 
pyruvate utilization in mammal, 390-394 
relationship to material structure characteri- 
zation, 15 
role 
in cell physiology, 4-5 
in metabolic engineering, 5-7 
nutrient concentration, 527-529 
from transient intensity measurements, 
356-357 
Metabolic flux analysis 
alternative biochemical pathways, 311-312 
application to cell culture media design, 
457-458 
branch point control, 311 
citric acid fermentation, 320-325 
Corynebacterium glutamicum deletion mu- 
tants, 439-441 
transhydrogenase discovery, 442-445 
718 Index 
definition, 10 
dilution effect of pathway metabolites, 
314-316 
Escherichia coli metabolism, 344-347 
extracellular fluxes, 312 
heterofermentative metabolism of lactic acid 
bacteria, 330-333 
linearly dependent reaction stoichiometries, 
326-330 
lysine biosynthesis, 317-320 
description, 426-427 
perturbations at Glc6P branch point, 
429-436 
perturbations at PEP-pyruvate branch 
point, 436-438 
principal node identification, 428-429 
mammalian cell cultures 
description, 445-446 
intracellular fluxes, 446-452 
isotope labeling studies, 452-457 
maximum theoretical yields, 312 
with NMR, 16 
overdetermined systems, 333-340 
and sensitivity analysis, 347-350 
theory, 313 
undetermined systems, 341-344 
Metabolic flux control 
analysis via metabolic engineering, 7-8 
over respiration, 512-513 
at single branch point, 539-545 
structure of pathways, 11 
Metabolic maps, definition, 9-10 
Metabolic models 
equations, 85-86 
Penicillium chrysogenum, 106 
Metabolic networks 
analysis with metabolic engineering, 10-11 
antibiotic production, 235-237 
aromatic amino acid biosynthesis, 555-557, 
557-563 
biopolymer production, 243-244 
biotin production, 242-243 
branched 
branch points, 522-525 
CCC and concentration changes, 
526-527 
flux change prediction, 525-526 
branch point location 
ATP, 566-573 
chorismate, 576-577 
fructose- 1,6-diphosphate, 574-576 
glucose-6-phosphate, 573-574 
glyceraldehyde-3-phosphate, 574-576 
link metabolites and group flux, 563-566 
prephenate, 578-580 
xylulose-5-phosphate, 576-577 
complex, definition, 536 
control coefficients, 582-585 
copolymer production, 248-249 
ethanol production 
as biofuel, 205 
from Escherichia coli, 210-211 
by fermentative metabolism, 208-209 
from pdc and adh genes, 211-212 
production, 206-208 
from pyruvatedecarboxylase, 209 
from Saccharomyces cerevisiae, 208 
flux control structure, 11 
fructan production, 249-250 
group CCC, 591-592 
group control coefficients, 582-585 
ATP branch point, 593-596 
FDP/GAP branch point, 598 
from flux measurement, 585-586 
glucose-6-phosphate branch point, 
597-598 
PPH branch point, 600-601 
X5P + CHR branch point, 599-600 
group FCC, 547-554 
from characterized perturbations, 
590-591 
experimental determination, 601-604 
from three perturbations, 586-590 
independent pathway identification, 
547-554 
indigo production, 250-252 
kernel determination via matrix algebra, 
551-553 
manipulation 
for amino acid production 
alanine, 215 
commercial use, 212- 214 
isoleucine, 219-220 
threonine, 215-219 
tryptophan, 214-215 
Index 7 1 9 
in microorganisms, 1-2 
for solvent production 
industrial fermenation, 220-222 
1,3-propanediol, 222-223 
nutrient concentration and flux change, 
527-529 
perturbation observability, 592 
plant poly(hydroxyalkanoate)s, 248-249 
poly~hydroxyalkanoate)s production, 
244-247 
regulation 
branch point classification, 193-196 
in eukaryotes, 190-192 
pathways, 188-193 
in prokaryotes, 190-192 
role in metabolic engineering, 5-7 
role of global currency metabolites, 
196-199 
SIMS matrix analysis, 549 
substrate range extension 
cellulose-hemicellulose depolymeriza- 
tion, 229-230 
with ethanol, 227-228 
with lactose and whey, 230-233 
pentose for ethanol production, 224 
yeast, 225-227 
starch-degrading microorganisms, 
233-235 
with sucrose, 233 
unbranched 
basis for large deviation theory, 514-517 
FCC estimation, 517-519 
FCC from large deviations, 519-520 
flux change 
from enzyme change, 521-522 
prediction, 520-521 
flux through, 514 
vitamin A production, 243 
vitamin C production, 241-242 
xanthan gum production, 250 
xenobiotic degradation, 266 
yield and productivity, 205 
Metabolic pathway synthesis 
algorithm, 288-295 
alanine synthesis, 299-300 
analysis, 307-308 
lysine biosynthesis, 300-303 
alternatives, 304-306 
maximum yield restriction, 306-307 
role of oxaloacetate, 303 
overview, 295-297 
serine synthesis, 297-298 
definition, 285-287 
Metabolic products 
in black box model, 119-120 
in cellular reactions, 82-83 
Metabolism 
acetyl-CoA, label distribution, 364-367 
endogenous, in cellular reactions, 103-104 
Escherichia coli, stoichiometry, 344-347 
heterofermentative, lactic acid bacteria, 
330-333 
nitrogen, alteration, 257 
overflow, prevention, 259-262 
in reaction pathway analysis, 3 
Metabolites 
in biochemical pathways, 295-297 
carbon atoms, NMR analysis, 382-390 
global currency, role in metabolic networks, 
196-199 
intermetabolite links, group FCCs, 607-609 
intracellular, in cellular reactions, 83 
isotopomers 
complete enumeration, 367-370 
direct carbon balances, 397-405 
TCA cycle, distribution 
from labeled acetate, 377-382 
from labeled pyruvate, 371-377 
link 
group CCC, 591-592 
identification, 563-566 
intermetabolite links, group FCCs, 
607-609 
pathway, dilution effect, 314-316 
precursor, in biosynthetic reactions, 24 
transient, measurement, in FCC, 488-491 
Methylophilus methylotrophus, single-cell pro- 
tein production, 257 
MFA, see Metabolic flux analysis 
Michaelis-Menten reaction, saturation kinet- 
ics, 32-34 
Microorganisms, in metabolic pathway manip- 
ulation, 1-2, 233-235 
Mitochondria 
inner membrane, 51-53 
oxidative phosphorylation control, 510-513 
Mixed acid, fermentation in Escherichia coli 
rates, 86-90 
specific rates, 92-93 
720 Index 
Mixtures 
benzene-toluene-p-xylene 
degradation with pWW0, 269-271 
as pollutants, 267-268 
simultaneous biodegradation, 271-273 
glucose-ethanol, yeast growth, 413 
Models 
aromatic amino acid biosynthesis, 554-557 
black box 
cell biomass, 117-118 
variables, 119-120 
complex systems, with biochemical systems 
theory, 463-464 
isotope distribution, with atom mapping 
matrix, 405-409 
kinetic 
dynamic mass balance, 100 
elasticity coefficient calculation, 487-488 
enzyme, 152-153 
for FCC, 491-492 
Saccharomyces cerevisiae, 601-604 
saturation, facilitated diffusion, 32-34 
nonequilibrium thermodynamic black box, 
681-682 
simple black box model 
carbon balance, 120-121 
description, 118 
elemental balances, 123 
generalized degree of reduction balance, 
124-125 
Mutants, deletion, Corynebacterium glutam- 
icum, MFA, 439-445 
N 
NAD +, from NADH oxidation, 674 
NADH 
inner mitochondrial membrane permeabil- 
ity, 51-53 
oxidation to NAD +, 674 
in pathway integration, 24 
role in cellular metabolism, 44-45 
NADPH 
in pathway integration, 24 
role in cellular metabolism, 44-45 
Neurospora crassa, in antibiotic production, 
236 
Nitrogen, metabolism, alteration, 257 
NMR, see Nuclear magnetic resonance analy- 
sis 
Noncompetitive inhibition, characteristics, 
161-163 
Nonequilibrium thermodynamics 
cellular growth, 679-682 
cellular systems, 663 
definition, 664 
dissipation function, 664-665 
efficiency, 672-673 
energy transduction, 663 
flow-force relations, 668-669 
force ratio, 671 
goals, 686 
hexokinase reaction in EMP pathway, 665 
independent reactions, 666 
level flow, 672 
linear force relation, 682-686 
Onsager's reciprocal relations, 667 
operational stoichiometry, 671-672 
oxidative phosphorylation, 674-679 
phenomenological equations, 666-667 
phenomenological stoichiometry, 671 
proton-motive force, 675 
reciprocity, 669-670 
static head, 672 
Nonlinear functions, derivatives, 476 
2-Norerythromycin, production, 237 
Nuclear magnetic resonance analysis 
metabolic data, 382-390 
metabolic flux, 16 
Nucleotides, biosynthesis, 62 
Nutrients 
role in flux changes, 527-529 
uptake, 262-263 
0 
Oligomycin, for elasticity coefficient determi- 
nation, 512 
Onsager's reciprocal relations 
application to cellular growth, 680 
in nonequilibrium thermodynamics, 667 
Organic acids 
catabolism, 55-57 
effect on ATP, 29-31 
effect on cell growth, 260 
Organs, whole, metabolism in viva, role of 
metabolic engineering, 14 
Overdetermined systems 
analysis, 130-131 
MFA, 333-340 
Index 721 
Oxaloacetate 
role in lysine biosynthesis, 303 
in TCA cycle, 50, 53-55 
Oxidation, pyruvate, 50-51 
Oxidative phosphorylation 
control in mitochondria, 510-513 
nonequilibrium thermodynamics, 674-679 
and TCA cycle, 48-53 
Oxygen 
passive diffusion, 28-29 
utilization, 257-259 
P 
Pachysolen tannophilus, 208 
Passive transport 
compounds, 28-29 
free diffusion, 28 
Penicillin 
biosynthesis 
application of MCA with thermokinetics, 
690-692 
MCA, 494-499 
production, 236, 412-413 
Penicillium chrysogenum 
growth rate, 104-105 
metabolic model, 106 
penicillin production, 412-413 
proton gradient, 29-31 
Pentose 
for ethanol production 
metabolic engineering, 224 
from yeast, 225-227 
fermentation, microorganisms, 208 
production, 256 
Pentose phosphate pathway 
anaplerotic function, 42 
in Aspergillus nidulans, 43 
control points, 44 
in glycolysis, 38 
oxidative function, 42 
reactions, 40-42 
PEP, see Phosphoenolpyruvate 
PEP carboxylase, see Phosphoenolpyruvate 
carboxylase 
Permease, role in active transport, 34 
Perturbation constant, in MCA of inter- 
metabolite reaction groups, 604-605 
Perturbations 
characterized, group FCC from, 590-591 
for group FCC, 592, 607-609 
multiple, in consistency test development, 
618-623 
three, in group FCC determination, 
586-590 
Phenomenological equations, nonequilibrium 
thermodynamics, 666-667 
Phenoxyacetic acid, uncoupling effect, 29-31 
Phenylalanine, in aromatic amino acid biosyn- 
thesis, 557 
Pho regulon, in Escherichiacoli, 187-188 
Phospho enol pyruvate 
in aromatic amino acid biosynthesis, 556 
in group translocation, 35-36 
-pyruvate branch point, flux perturbations, 
436-438 
Phospho enolpyruvate carboxylase 
as anaplerotic reaction, 415 
compensation, 441-442 
Phosphofructokinase, flux amplification, 
609-610 
Phosphoglucomutase, in glycolysis, 39 
6-Phosphogluconate 
in ED pathway, 42 
in PP pathway, 40-42 
6-Phosphogluconate dehydratase, in ED path- 
way, 42 
3-Phosphoglycerate kinase, elasticity coeffi- 
cient, 509 
Phosphoglycerate mutase, elasticity coeffi- 
cient, 509 
Phosphohexoisomerase, in glycolysis, 39 
Phosphorylation 
oxidative 
control in mitochondria, 510-513 
nonequilibrium thermodynamics, 
674-679 
and TCA cycle, 48-53 
in signal transduction, 183-188 
Phosphotransferase 
glucose uptake, 83-84 
in group translocation, 35-36 
Pichia stipitis, 208 
Pigments, biological, production, 250-252 
Plasmids, pWW0, for pollutant degradation, 
269-271 
Pollutants, conversion to nonpollutants, 
267-268 
722 Index 
Polychlorinated biphenyls, metabolic engi- 
neering, 266-267 
Poly(hydroxyalkanoate)s 
plant, production, 248-249 
production, 244-247 
Poly(3-hydroxybutyric acid), production, 
245-247 
Poly (3-hydroxybutyric-co-3-hydroxyvaleric 
acid), production, 247-248 
Polyketides 
source, 237-238 
systems forming, 240-241 
Polymerization 
in cellular metabolism, 23 
depolymerization, cellulose-hemicellulose, 
229-230 
macromolecules, 66-71 
Polysaccharides, in aromatic amino acid 
biosynthesis, 556 
PPC, see Phosphoenolpyruvate carboxylase 
PPH, as branch point in metabolic network 
model, 600-601 
PP pathway, see Pentose phosphate pathway 
Prephenate 
in aromatic amino acid biosynthesis, 557 
branch point 
application of group FCC consistency 
tests, 623-625 
in metabolic network, 578-580 
Prokaryotes, metabolic network regulation, 
190-192 
Promoters, bacterial, transcription initiation, 
174-175 
1,3-Propanediol, synthesis, 222-223 
Proteins, polymerization, 66-71 
Proton gradient, in Penicillium chrysogenum, 
29-31 
Proton-motive force 
mitochondrial, analysis, 511 
in oxidative phosphorylation, 675 
Pseudomonas putida, pWW0, for pollutant 
degradation, 269-271 
Pyrococcus furiosus, in hydrogen production, 
253-255 
Pyruvate 
carboxylation, role in PPC compensation, 
441-442 
complete oxidation, 48-51 
conversion to lactic acid, 45-46 
in ED pathway, 42 
in EMP pathway, 40 
labeled, TCA cycle metabolite isotopomers 
from, distribution, 371-377 
-PEP branch point, flux perturbations, 
436-438 
role in acetate accumulation, 260-261 
utilization in mammal, 390-394 
Pyruvate decarboxylase~' for ethanol produc- 
tion, 209 
Pyruvate dehydrogenase complex, role in 
pyruvate oxidation, 48-51 
R 
Rate equations, linear, cellular reactions, 
102-105 
Reaction groups, intermetabolite, control anal- 
ysis 
overlapping groups in multiple branch 
points, 605-607 
perturbation constant, 604-605 
Reaction rates 
in black box model, 119-120 
mixed acid fermentation in Escherichia coli, 
specific rates, 92-93 
Reactions 
analysis via metabolism and cell physiology, 
3 
assembly, in cellular metabolism, 22-23 
biosynthetic, in cellular metabolism, 23-24, 
57-58 
cellular, see Cellular pathways 
chemical 
alcohol dehydrogenase-catalyzed, AG ~ 
662 
Gibbs free energy, algorithm, 641'645 
group contributions, in Gibbs free energy 
determination, 649-654 
thermodynamic feasibility, 639-641 
coupled, role of global currency metabo- 
lites, 196-199 
fueling 
in cellular metabolism, 24 
purpose, 38 
Index 7 2 3 
glycolytic, free energy, 637-638 
group FCC, 546-547 
grouping, 545 
independent pathway identification, 
547-554 
Michaelis-Menten, saturation kinetics, 
32-34 
polymerization, in cellular metabolism, 23 
SIMS matrix analysis, 549 
standard free energy, 636-637 
Reciprocity, nonequilibrium thermodynamics, 
669-670 
Redundancy matrix, reduced, in overdeter- 
mined systems, 334 
Relaxation time, in cellular metabolism, 25-27 
Respiration 
flux control over, 512-513 
in yeast, effect of benzoic acid, 29-31 
Ribulose-5-phosphate, in PP pathway, 40-42 
RNA 
antisense, function, 265 
polymerization, 66-71 
RNA polymerase, transcriptional control, 
173-177 
S 
Saccharomyces cerevisiae 
anaerobic growth, 413 
aromatic amino acid biosynthesis, model, 
554-557 
cultivation, error diagnosis in measurement, 
144-146 
data consistency, 125-126 
energetics, 110-114 
ethanol production, 208 
flux optimization, 613-616 
glucose 
conversion to ethanol, 47-48 
facilitated diffusion, 31-32 
growth on glucose-ethanol mixtures, 413 
heat generation, 127-129 
kinetic model, 601-604 
prephenate branch point, application of 
group FCC consistency tests, 623-625 
respiration, effect of benzoic acid, 29-31 
simple black box model, 118 
starch degradation, 234-235 
sugar phosphorylation, 39 
Saccharopolyspora erythrea, erythromycin pro- 
duction, 238-241 
Schwanniomyces occidentalis, starch degrada- 
tion, 234-235 
Second Law of Thermodynamics, definition, 
631 
Sensitivity analysis, and MFA, 347-350 
Serine, metabolic pathway synthesis algo- 
rithm, 297-298 
Signal transduction, by phosphorylation, 
183-188 
Simple black box model 
carbon balance, 120-121 
description, 118 
elemental balances, 123 
generalized degree of reduction balance, 
124-125 
metabolic 
equations, 85-86 
Penicillium chrysogenum, 106 
SIMS matrix 
for aromatic amino acid biosynthesis, 
557-563 
for independent pathway identification, 549 
in kernel determination, 551-553 
Single-cell protein, production, 257 
Solvents, industrial fermentation, 220-222 
Standard free energy 
glucose oxidation, 680 
hexokinase reaction in EMP pathway, 665 
nomenclature, 635 
oxidative phosphorylation, 674 
reaction, 636-637 
Standard state, conventions, 635 
Starch, microorganisms degrading, 233-235 
Static head, in nonequilibrium thermodynam- 
ics, 672 
Stoichiometry 
cellular reactions 
biomass constituents, 83 
intracellular metabolites, 83 
metabolic product, 82-83 
substrate, 82 
in Escherichia coli metabolism, 344-347 
operational, in nonequilibrium thermody- 
namics, 671-672 
phenomenological, in nonequilibrium ther- 
modynamics, 671 
reaction, linearly dependent, MFA, 326-330 
724 Index 
Storage carbohydrate, synthesis, role of UDP- 
glucose, 64-65 
Streptomyces coelicitor, in antibiotic produc- 
tion, 236-237 
Streptomyces erythreus, in antibiotic produc- 
tion, 236 
Streptomyces lividans, in antibiotic production, 
236 
Streptomycin, production, 236 
Substrate inhibition 
competitive inhibition, 159-161 
noncompetitive inhibition, 161-163 
rapid equilibrium, 155-156 
as simple reversible inhibition system, 153, 
157-159 
steady-state approach, 156-157 
uncompetitive inhibition, 163 
Substrates 
in cellular reactions, 82 
in dynamic mass balance, 97-98 
Sucrose, utilization, 233 
Summation theory, in MCA, 465-469 
T 
TCA cycle 
anaplerotic pathways, 53-55 
in bacteria, 396-397 
metabolite isotopomers, distribution 
from labeled acetate, 377-382 
from labeled pyruvate, 371-377 
NADH and FADH 2 formation, 107 
and oxidative phosphorylation, 48-53 
regulatory sites, 50 
Tetrahydrodipicolinate, transformation, 
360-361 
Thermodynamic feasibility 
algorithm, 641-645 
chemical reaction, 639-641 
EMP pathway, 645-649 
Gibbs free energy from group contributions, 
649-654 
transport process, 639-641 
Thermodynamics 
first law, 631 
nonequilibrium, see Nonequilibrium ther- 
modynamics 
second law, 631 
Thermokinetics 
application to MCA, 686-688 
extension of Delgado-Liao approach,689-690 
in MCA of penicillin biosynthesis, 690-692 
Thermoplasma acidophilum, in hydrogen pro- 
duction, 253-255 
Thermoplastics, petroleum-derived, metaboli- 
cally engineered, 12 
Threonine, synthesis in Corynebacterium glu- 
tamicum, 215-219 
Tissues, metabolism in vivo, role of metabolic 
engineering, 14 
Titration 
with purified enzyme, in FCC, 481-482 
with specific inhibitors, in FCC, 482-483 
Toluene-benzene-p-xylene mixture 
degradation with pWW0, 269-271 
as pollutant, 267-268 
simultaneous biodegradation, 271-273 
Top-down approach 
experimental determination of group FCC, 
601-604 
group control coefficients from flux mea- 
surement, 585-586 
requirements, 545 
Transcription, control 
bacterial promoters, 173-175 
Lac operon, 175-177 
Transhydrogenase, discovery, 442-445 
Translation, enzymes, control, 178-180 
Translocation, group, in active transport, 
35-36 
Transport 
active 
ATP consumption, 36-37 
group translocation, 35-36 
role of permeases, 34 
via ATPase, 34-35 
electron, NADH to oxygen, 51-53 
glucose, 415 
mechanisms, 27-28 
passive 
compounds, 28-29 
free diffusion, 28 
thermodynamic feasibility, 639-641 
Index 7 2 5 
Tryptophan 
release in Saccharomyces cerevisiae flux, 
613-616 
synthesis in Escherichia coli, 214-215 
Tyrosine, in aromatic amino acid biosynthesis, 
557 
U 
UDP-glucose, in storage carbohydrate synthe- 
sis, 64-65 
Uncompetitive inhibition, characteristics, 163 
Undetermined systems, linear programming, 
341-344 
V 
Variance-covariance matrix, calculation er- 
rors, 142-143 
Velocity, simplified, for allosteric enzymes, 
172-173 
Vitamin A, production, 243 
Vitamin C, production, 241-242 
Vitreoscilla, hemoglobin gene cloning, 
258-259 
W 
Whey, utilization, 230-233 
Whole cells, global control 
definition, 180-183 
signal transduction by phosphorylation, 
183-188 
X 
X5P, see Xylulose-5-phosphate 
Xanthan gum, production, 250 
p-Xylene-benzene-toluene mixture 
degradation with pWWO, 269-271 
as pollutant, 267-268 
simultaneous biodegradation, 271-273 
Xylitol, production, 256 
Xylose, for ethanol production, 227-228 
Xylulose-5-phosphate 
in aromatic amino acid biosynthesis, 556 
as branch point in metabolic network model, 
576-577, 599-600 
Y 
Yeast 
cultivation 
aerobic, without ethanol formation, 
136-140, 143 
anaerobic, data consistency, 125-126 
error diagnosis in measurement, 144-146 
for ethanol production, 225-227 
heat generation, 127-129 
xylitol production, 256 
Yield coefficients 
in black box model, 119-120 
calculation, 122 
cellular reactions, 102-105 
Z 
Zymomonas mobilis 
alanine synthesis, 215 
for ethanol production, 227-228