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Biochemistry 3511Introduction to Metabolism (Chapter 14, Sections 1-3)
1. Overview of Metabolism• Metabolic pathways consist of a series of enzymatic
reactions• Thermodynamics dictates the direction and regulatory
capacity of metabolic flux• Metabolic flux must be controlled
2.“High Energy” Compounds (ATP)• Phosphoryl group-transfer potential and how it can be
coupled to drive endergonic reactions
3.Oxidation-Reduction Reactions (NAD+, NADH, FAD, FADH2)• NAD+ and FAD are electron carriers• Nernst equation describes oxidation-reduction reactions• Favorableness of a reaction can be determined by
measuring reduction potential differences
MetabolismSeries of biochemical reactions
by which material substance(food) is broken down into simpleproducts, which are then used for
the synthesis of complexcompounds (e.g. DNA).
Metabolism
MetabolismSeries of biochemical reactions
by which material substance(food) is broken down into simpleproducts, which are then used for
the synthesis of complexcompounds (e.g. DNA).
Metabolism
Approximately 4,000 knownreactions, and thus 4,000
known enzymes!
The overall process through which living organisms acquire free energy (fromfood) and utilize the free energy to construct complex molecules (e.g. DNA).
Living organisms do not operate at equilibrium but require a constant influx of nutrients.
Degradation of compounds intocommon building blocks
Construction of complexmolecules required for life
Metabolism: Catabolism & Anabolism
Metabolism: Nutrition
• Autotrophs– Chemolithotrophs– Photoautotrophs
• Heterotrophs
• Anaerobes– Obligate anaerobes– Facultative anaerobes
• Aerobes– We are obligate aerobes!
CatabolismFood is converted into common
intermediates (glucose, pyruvate,Acetyl-CoA, NH3, CO2) via two
processes: glycolysis and the citricacid cycle.
Catabolism
Glycolysis and the Citric Acid Cycleconvert:
1. ADP → ATP2. NAD+ → NADH3. FAD → FADH2
•Catabolism will use the free energygenerated by the breakdown of foodinto driving ATP generation (ourenergy currency).
•Catabolism will store the electronsreleased by the breakdown of food inNADH and FADH2 (electroncarriers).
Catabolism
Obtain free energy from food (sugar) by carrying out its stepwise oxidation andtransferring the released energy and electrons to carrier molecules (ATP, NADH, etc.).
Catabolism
The final step in catabolism involvesconverting the electron carriers(NADH, FADH2) into our energy
currency (ATP) via oxidativephosphorylation.
The final electron acceptor is oxygenwhich is converted into water.
Catabolism
Catabolism
Catabolismfull catabolic pathway
Catabolism (degradation) generates NADPH (in addition to NADH, FADH2), ATP andsimple products.
Anabolism uses the NADPH, ATP and simple products to generate complexmetabolites, NADP+ and ADP.
Catabolism & Anabolism:Connected Pathways
Vitamins: present functionality lacking in an organism’s proteins/enzymes,and cannot be synthesized by that organism. Most water-soluble vitamins
are converted to coenzymes.
Rickets
Many Metabolic Reactions Require Vitamins
Vitamins: present functionality lacking in an organism’s proteins, andcannot be synthesized by that organism. Most water-soluble vitamins are
converted to coenzymes.
Rickets
Many Metabolic Reactions Require Vitamins
Pellagra Symptoms1. Diarrhea2. Dermatitis3. Dementia
Vitamins: how to get functionality not present in proteins, and not able to be synthesized by the organism.
Vitamins: Niacin
Obtained by eating fish, chicken, turkey,pork, peanuts, avocados, mushrooms...
Vitamins: how to get functionality not present in proteins, and not able tobe synthesized by the organism.→ Are incorporated in the biosynthesis of key metabolites.
pantothenic acid“vitamin B5”
Obtained by eatingmushrooms,cheese, oily fish,avocados...
Vitamins: Pantothenic Acid
cobalamin“vitamin B12”
vitamin B12 deficiency → vitiligo, psoriasis
Vitamins: Cobalamin (B12)Vitamins: how to get functionality not present in proteins, and not able to be synthesized by the organism.
Obtain by eating shellfish, oily fish, cereals,soy products, beef, milk, cheese, eggs...
Minerals also Assist Metabolic Reactions
Minerals also Assist Metabolic Reactions
(signal transduction,bones, teeth)
(reactions involving ATPand other nucleotides,in synthesis of DNA, RNA,and proteins)
(hemes)
(enzymatic cofactors)
MetabolismWith up to 4,000 possible
reactions in a host of pathways,how does the cell manage all of
these processes???
Metabolism
MetabolismWith up to 4,000 possible
reactions in a host of pathways,how does the cell manage all of
these processes???
Compartmentation!
Metabolism
Different Metabolic Pathways Occur inDifferent Cellular Compartments
Compartmentation in multicellular organisms also occurs on the tissue and organ levels.
Directing Metabolic Information Flow (Flux)
• The majority of metabolicreactions are near-equilibrium.
∆G ≈ 0 Reactions can be easily
reversed by changing thesubstrate/product ratio.
• Some reactions are far fromequilibrium.
∆G << 0 Reactions difficult to reverse
by changing thesubstrate/product ratio.
• How does metabolism controlwhat path a compound shouldtake?
Metabolism: Routing Information Flow (Flux)
S P1
P2
P3
Metabolic flux: the rate of flow of metabolites through a series oftransformations (metabolic pathway).
!
Flux = J = v f " vr
!
Jeq = 0 so v f = vr
!
When far fromequilibrium... J " v f
S P1
P2
P3
Use an irreversible enzymaticstep to commit the substrate
down a given pathway.
Metabolism:Routing Information Flow (Flux) ⇒ 3 Ways
S P1
P2
P3
Use an irreversible enzymaticstep at the end of the pathway,
making the entire pathwayirreversible.
Metabolism:Routing Information Flow (Flux) ⇒ 3 Ways
S
P2The catabolic and anabolic pathway differ.
Metabolism:Routing Information Flow (Flux) ⇒ 3 Ways
S P1
P2
P3
Use an irreversible enzymaticstep to commit the substrate
down a given pathway.
S P1
P2
P3
Use an irreversible enzymaticstep at the end of the pathway,
making the entire pathwayirreversible.
S
P2The catabolic and anabolic pathway differ.
Metabolism:Routing Information Flow (Flux) ⇒ 3 Ways
Mechanisms to Control Metabolic Flux
Flux Control Mechanisms
1. Allosteric regulation and feedback control
2. Regulation by covalent modification
3. Independent control of interconversions (substrate cycling)
4. Genetic regulation
allosteric regulation and feedback
Metabolic Flux Control:Allosteric Regulation
Effectors are often substrates,products, or cofactors of the pathway.
allosteric regulation and feedback
Metabolic Flux Control:Allosteric Regulation
covalent modification(phosphorylation & dephosphorylation)
“Off” “On”
Metabolic Flux Control:Covalent Modification
covalent modification(phosphorylation & dephosphorylation)
Metabolic Flux Control:Covalent Modification
glycogen phosphorylase
independent control of interconversions
Rates of forward andreverse reactions can bevaried independently.
S
P2
!
Flux = J = v f " vr
Metabolic Flux Control:Independent Control of Interconversions
Metabolic Flux Control:Genetic Regulation
genetic regulation (products stop enzyme transcription)
Reaction Energetics
ΔGo' = +13.8 kJ/mol
Glycolysis
Is this conversionfavorable or unfavorable?
Reaction Energetics
The energy stored inphosphoryl groups is
used to drivethermodynamically
unfavorable reactions.
These phosphatehydrolysis reactions are
thermodynamicallyfavorable reactions,but kinetically stable
(very slow).
Reaction EnergeticsCoupled reactions can drive unfavorable processes!
OHOHO
OH
OH
OH
OHOHO
OH
OH
OP
OOH
OH
ΔGo' = +13.8 kJ/mol
Reaction EnergeticsCoupled reactions can drive unfavorable processes!
OHOHO
OH
OH
OH
OHOHO
OH
OH
OP
OOH
OH
What else can we couple this reaction with?
ΔGo' = +13.8 kJ/mol
Reaction Energetics
Because the phosphate is not coming from ATP,this is called “substrate-level phosphorylation”.
Another example
ΔGo' = +30.5 kJ/mol
Oxidation-Reduction (Redox) Reactions• The reduction potential (E ) describes the tendency for an oxidized compoundto gain electrons (become reduced); these values can be looked up.
• The change in reduction potential (∆E ) for a reaction describes the tendencyfor a given oxidized compound to accept electrons from a given reducedcompound. ∆E is the electromotive force.
• The greater the reduction potential, the more negative the free energyand the more favorable the reaction.
∆G = -nF ∆E
Oxidation-Reduction (Redox) Reactions• Redox reactions generate force/energy.
The more positive the standard reductionpotential, the higher its affinity for
electrons.The more positive the standard reduction
potential, the more negative ∆G.
Arrange the equation to obtain a positivestandard reduction potential.
Fe → Fe2+ + 2e - 0.44 VCu2+ + 2e- → Cu 0.34 V--------------------------------Fe + Cu2+ → Fe2+ + Cu 0.78 V
In this case, the reaction will oxidize Feand reduce Cu2+.
Oxidation-Reduction (Redox) Reactions• Redox reactions generate force/energy.
The more positive the standard reductionpotential, the higher its affinity for
electrons.The more positive the standard reduction
potential, the more negative ∆G.
Arrange the equation to obtain a positivestandard reduction potential.
Fe → Fe2+ + 2e - 0.44 VCu2+ + 2e- → Cu 0.34 V--------------------------------Fe + Cu2+ → Fe2+ + Cu 0.78 V
In this case, the reaction will oxidize Feand reduce Cu.
Which metal will be oxidized,silver or sodium?
Oxidation-Reduction (Redox) Reactions: Alternative Mode of Calculation
∆E = E (e-acceptor) - E (e-
donor )E = standard reduction potential
∆E = 0.34 – (-0.44) = 0.78
⇒ Once you know which metal accepts theelectrons, you can just plug in the standard
reduction potentials.
Remember: you want to have a positivestandard reduction potential (ΔE ) to get a
negative ∆G.
The more positive the standard reductionpotential, the higher its affinity for
electrons.
Oxidation-Reduction (Redox) Reactions
Radicals (species with unpairedelectrons) are stabilized byconjugation with adjacent multiplebonds (resonance forms).Addition of H• is really the paired (orstepwise) addition of an electron anda proton.
• NAD+ and FAD are electron carriers:they accept electrons from metabolitesand transfer them to other compounds.
You can also use half reactions for biological reactions!
Which compoundgets oxidized,
oxygenor lactate?