Metabolism ConceptsThermodynamics applies to metabolism
DG (but not DGº) must be negative for a process to occur.If DG for a process is (+), then the process will occur in reverse.
DG = DGº + RT ln Q and DGº = -RT ln K
DG = DH - TDS Free energy to drive reactions in living systems is found in a number of “high energy” molecules. ATP or other nucleoside triphosphates (GTP, CTP, TTP, UTP) Reduced ‘coenzymes’ (NADH and FADH2) Thioester coupling (e.g. AcetylCoA , fattyacylCoA)
Living organisms do not violate the 2nd law of thermodynamics
In the process of transforming energy, living organisms must increase the entropy of the universe. Living systems accomplish this by taking “ordered” energy from their surroundings (carbohydrates, lipids, and proteins) and returning disordered energy (heat, CO2, H2O) back to their surroundings.
All reactions/processes that occur in a living organismMetabolism
1. Generate Useable Energy Catabolic/catabolism
Provides cellular energy/ATP
2. Synthesize Molecules/structures Anabolic/anabolism requires energy/ATP
I digestion/hydrolysis Macromolecules → fuels
II Oxidation of fuel Glycolysis – glucose b-oxidation – FAs oxidative deamination - Pro makes NADH/FADH2
III ATP productionKrebs cycle &Oxidative phosphorylation
Stages of Catabolism (and to some degree Anabolism)
triglycerides → glycerol + fatty acids lipase (intestines & adipose)
proteins → peptides various proteases (stomach & intestines) pepsin trypsin and chymotrypsinpeptides → amino acids aminopeptidase and carboxypeptidase
polysaccharides → mono/di saccharides amylase (saliva & intestines) starch → maltose & glucose sucrase/invertase sucrose → fructose & glucose (intestines) lactase (absent in lactose intolerance) lactose → galactose & glucose (intestines)
I digestion/hydrolysis Macromolecules → fuels
All reactions/processes that occur in a living organismMetabolism
PATHWAY
metabolic intermediates — a molecule transiently produced in a pathwayMetabolite — a molecule produced from some ingested/absorbed molecule
A BE1
C D E FE2 E3 E4 E5
Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
C4
ATP
Glycolysis
Bridging Rx.
Oxidative PhosphorylationADP
O2
NAD+/FAD
Metabolic Mainstreet1. Generate Useable Energy (ATP) Catabolic
2. Synthesize Molecular “Parts” Anabolic
NAD+
FAD
Dehydrogenases Oxidative Phosphorylaton
fuel in
SH2 NADH ATP
S NAD+ ADP
work output
ATP uses
Drive anabolic reactions
Mechanical Motion (e.g. Muscles)
Active Transport — maintain membrane gradients
ATP + H2O ADP + Pi DG° = -7.3 kcal/mol
[ATP] + 1/2[ADP] [ATP] + [ADP] + [AMP]
Energy charge
DG = DG + RT ln Q
DG = DH - DS at equilibrium ……DG = 0, Q = Keq & DG = - RT ln Keq
ATP + H2O ADP + Pi DG° = -7.3 kcal/mol
Transition state
Activation energy - related to rate
ATP + H2O
DGº = -7.3 kcal/mol ADP +
Pi
ATP useDrive anabolic reactions
Mechanical Motion (e.g. Muscles)
Active Transport — maintain membrane gradients
ATP + H2O ADP + Pi DG° = -7.3 kcal/mol
PPi + H2O 2Pi DGº′ = -8.0 kcal/mol
ATP + H2O AMP + PPi DG° = -7.3 kcal/mol
ADP + H2O AMP + Pi DG° = -7.3 kcal/mol
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Energy Charge (EC)
Rate
catabolic
anabolic
[ATP] + 1/2[ADP] [ATP] + [ADP] + [AMP]
Energy charge
0 1 with AVG 0.85
EC
ATP, ADP, and AMP are common allosteric enzyme regulators
Cellular ATP concentration is usually far above the equilibrium concentration, making ATP a very potent source of chemical energy.
Average [ ]’s in muscle cells
[ATP] 8mM
[ADP] [AMP] 1mM
[Pi] 8mM
DG = DG + RT ln Q
ATP + H2O ADP + Pi DG = -7.3 kcal/mol
“ An Organism at equilibrium is a dead organism!”“A Cell is always striving to achieve a state of equilibrium, but never succeeding”
Q = [ADP] • [Pi] [ATP]
DG = DH - DS at equilibrium ……DG = 0, Q = Keq & DG = - RT ln Keq
Q = 1x10-3 • 8 x 10-3 = 1 x 10-3. 8 x 10-3
DG = -7.3+ 0.62 ln (0.001) = -11.6 kcal
Enzymatic ATP hydrolysis helps a cell to utilize ATP energy for useful purposes, faster than it will hydrolyze non-enzymatically to generate heat.
Parallel or Kinetic Coupling X + Pi X-P DG = + 5.0
ATP ADP + Pi DG = -7.3
Enzyme = “X” Kinase
X + ATP X-P + ADP DG = -2.3
Series or Thermodynamic CouplingX Y Z
X Y DG˚′ = + 4.0 [Y] << [X]
Y Z DG˚′ = -5.0 [Y] <<< [Z]
X Z DG˚′ = -1.0 [X] < [Z]
Glucose + Pi Glucose-6-P + H2O What is DG°´ for this reaction?
Addition of phosphate is the opposite of hydrolysis....DG°´ = +3.3 kcal/mol
Calculate [G-6-P]/[Glucose] at equilibrium ([Pi] 8mM) DG = - RT ln Keq [G-6-P]/[Glucose] ~ 3.8 x 10-5
DG = - RT ln Keq & [G-6-P]/[Glucose] = 634
Glucose + ATP Glucose-6-P + ADP (assume [ATP] = [ADP]) DG°´ = +3.3 – 7.3 = -4.0
Without coupling[G-6-P]/[Glucose] ~ 3.8 x 10-5
Coupling with ATP hydrolysis shifted equilibrium > 10 million x not a true equilibrium but rather a steady state
Which molecule is more stable …… a) creatine b) creatine phosphate
Which molecule is more stable …… a) 1,3 bisphosphoglycerate b) creatine phosphate
What is DG°′ for the reaction ……. 1,3 bisphosphoglycerate + ADP ↔ 3 BPG + ATP a) -22.1 kcal mol-1 b) -4.5 kcal mol-1 c) +4.5 kcal mol-1 d) none of these
Macromoleculesdigestion/hydrolysis fuels
various catabolic pathways NADH/FADH2
Krebs cycle & oxidative phosphorylation ATP
ATP uses
Drive anabolic reactions
Mechanical Motion (e.g. Muscles)
Active Transport — maintain membrane gradients
ATP + H2O ADP + Pi DG° = -7.3 kcal/mol
[ATP] + 1/2[ADP] [ATP] + [ADP] + [AMP]
Energy charge
DG = DG + RT ln Q
DG = DH - DS at equilibrium ……DG = 0, Q = Keq & DG = - RT ln Keq
Glucose
AcetylCoA
Pyruvate
NADH/FADH2
KrebsCycle
C6
C4
C5
C4
ATP
Glycolysis
Bridging Rx.
OP
ADP O2
NAD+/FAD
Metabolic Mainstreet
PATHWAYS: 4 W’sWhat = Net Reaction
Why = Purpose(s) of Pathway
Where = Organism/Tissue/Organelle
When = Regulation of Pathway
Hydrolysis of ATP is highly favorableunder standard conditions
• Better charge separation in products
• Better solvation of products
• More favorable resonance stabilization of products
Actual DG of ATP hydrolysis differs from DG’
• The actual free-energy change in a process depends on:– The standard free energy– The actual concentrations of reactants and products
• The free-energy change is more favorable if the reactant’s concentration exceeds its equilibrium concentration
• True reactant and the product are Mg-ATP and Mg-ADP, respectively– DG also Mg++ dependent
]MgATP[]P[]MgADP[ln' 2
i-
- DD RTGG
Hydrolysis of Thioesters
Reduction Potential• Reduction potential (E)
– Affinity for electrons; higher E, higher affinity– Electrons transferred from lower to higher E
DE’ = -(RT/nF)ln (Keq) = DG’/nF
∆E’ = E’(e- acceptor) – E’(e- donor)
∆G’ = –nF∆E’For negative DG need positive DE
E(acceptor) > E(donor)
NAD and NADP are common redox cofactors
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