Lecture 1- Metabolism: Basic Concepts and Design

Chem 454: Regulatory Mechanisms in Biochemistry

University of Wisconsin-Eau Claire

Chem 454: Regulatory Mechanisms in Biochemistry

University of Wisconsin-Eau Claire

Lecture 1- Metabolism: Basic Concepts and Design

Lecture 1- Metabolism: Basic Concepts and Design

22

Questions we will focus on this semester:

How does a cell extract energy and reducing power from its environment?

How does a cell synthesize the building blocks of its macromolecules and the then the macromolecules themselves?

How are these processes integrated and regulated?

Questions we will focus on this semester:

How does a cell extract energy and reducing power from its environment?

How does a cell synthesize the building blocks of its macromolecules and the then the macromolecules themselves?

How are these processes integrated and regulated?

IntroductionIntroduction

33

Living organisms require an input of free energy to meet various needs:

For mechanical work

For active transport of molecules and ions

For synthesis of biomolecules

Living organisms require an input of free energy to meet various needs:

For mechanical work

For active transport of molecules and ions

For synthesis of biomolecules


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Living organisms require an input of free energy

Phototrophs

Use energy from the sun to convert energy-poor molecules into energy rich molecules

Chemotrophs

Obtain energy by oxidizing the energy-rich molecules made by the phototrophs

Living organisms require an input of free energy

Phototrophs

Use energy from the sun to convert energy-poor molecules into energy rich molecules

Chemotrophs

Obtain energy by oxidizing the energy-rich molecules made by the phototrophs


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Reduced molecules are energy-richOxidized molecules are energy-poor

Reduced molecules are energy-richOxidized molecules are energy-poor


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Energy from photosynthesis or the oxidation of fuels can be transformed into an unequal distribution of ions across a biological membrane.

The ion gradient can be used for

Oxidative phosphorylation to make ATP

Active transport across membranes

Nerve transmission

Energy from photosynthesis or the oxidation of fuels can be transformed into an unequal distribution of ions across a biological membrane.

The ion gradient can be used for

Oxidative phosphorylation to make ATP

Active transport across membranes

Nerve transmission


77

Ion gradients:Ion gradients:

IntroductionsIntroductions

See Chapter 2.3.3See Chapter 2.3.3

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Metabolism is composed of many coupled interconnecting reactions

Metabolism is composed of many coupled interconnecting reactions

MetabolismMetabolism

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1010

Classes of metabolic pathways:Catabolic pathwaysThose that convert energy into biologically useful

forms

Anabolic pathwaysThose that require an input of energy

Classes of metabolic pathways:Catabolic pathwaysThose that convert energy into biologically useful

forms

Anabolic pathwaysThose that require an input of energy


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Basic concepts of metabolism include:

Thermodynamically unfavorable reactions can be driven by favorable reactions.

ATP is the universal currency of free energy.

ATP hydrolysis drives metabolism by shifting the equilibrium constant of coupled reactions.

There is a structural basis for the high phosphoryl transfer potential of ATP.

The phosphoryl transfer potential is an important form of cellular energy transformation.

Basic concepts of metabolism include:

Thermodynamically unfavorable reactions can be driven by favorable reactions.

ATP is the universal currency of free energy.

ATP hydrolysis drives metabolism by shifting the equilibrium constant of coupled reactions.

There is a structural basis for the high phosphoryl transfer potential of ATP.

The phosphoryl transfer potential is an important form of cellular energy transformation.


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Thermodynamically unfavorable reactions can be driven by favorable reactions.Free energy change for a reactions:

Thermodynamically unfavorable reactions can be driven by favorable reactions.Free energy change for a reactions:

ThermodynamicsThermodynamics

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Coupling unfavorable reactions with favorable ones

Coupling unfavorable reactions with favorable ones

ThermodyamicsThermodyamics

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ATP is the universal currency of free energy

ATP is the universal currency of free energy

ATPATP

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Hydrolysis of ATP:Hydrolysis of ATP:

ATPATP

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ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions

ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions

ATP HydrolysisATP Hydrolysis

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Problem:Under standard conditions, the free energy

for the hydrolysis of L-glycerol phosphate to form glycerol and inorganic phosphate is -2.2 kcal/mol. Calculate the factor by which the equilibrium ratio for the concentration of L-glycerol phosphate to glycerol is increased when ATP is used as the phosphoryl donor for the formation L-glycerol phosphate in place of inorganic phosphate.

Problem:Under standard conditions, the free energy

for the hydrolysis of L-glycerol phosphate to form glycerol and inorganic phosphate is -2.2 kcal/mol. Calculate the factor by which the equilibrium ratio for the concentration of L-glycerol phosphate to glycerol is increased when ATP is used as the phosphoryl donor for the formation L-glycerol phosphate in place of inorganic phosphate.

ATP Hydrolysis ATP Hydrolysis

Do this calculation for liver where the concentrations for ATP, ADP and Pi are 3.5 mM, 1.8 mM and 5.0 mM, respectively.

Do this calculation for liver where the concentrations for ATP, ADP and Pi are 3.5 mM, 1.8 mM and 5.0 mM, respectively.

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Phosphoryl transfer is a common means of energy coupling

Molecular motors

Muscle contraction

Ion pumps

Phosphoryl transfer is a common means of energy coupling

Molecular motors

Muscle contraction

Ion pumps

ATP HydrolysisATP Hydrolysis

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Structural basis for high transfer potentialCompare:

Structural basis for high transfer potentialCompare:

Phosphoryl TransferPhosphoryl Transfer

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Phosphate ester vs Phosphate anhydride

Phosphate ester vs Phosphate anhydride


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Stabilization of orthophosphate

resonance stabilization

electrostatic repulsion

hydration

Stabilization of orthophosphate

resonance stabilization

electrostatic repulsion

hydration


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Resonance stabilizationResonance stabilization

Stabilization of OrthophosphateStabilization of Orthophosphate

OrthophosphateOrthophosphate

PyrophosphatePyrophosphate

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There are other molelcules with favorable phosphoryl transferase energies

There are other molelcules with favorable phosphoryl transferase energies

Phosphoryl Transfer and Energy Transfer

Phosphoryl Transfer and Energy Transfer

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In terms of energy for phosphoryl transfer, ATP is intermediate:

In terms of energy for phosphoryl transfer, ATP is intermediate:


2525

Question:What information do the ∆Go’ data given in

Table 14.1 provide about the relative rates of hydrolysis of pyrophospate and acetyl phosphate?

Question:What information do the ∆Go’ data given in

Table 14.1 provide about the relative rates of hydrolysis of pyrophospate and acetyl phosphate?


2626

Creatine phosphate is used to generate ATP in the short term:

Creatine phosphate is used to generate ATP in the short term:


2727

The oxidation of Carbon fuels is an important source of cellular energy


Cellular EnergyCellular Energy

2828




2929

High phosphoryl transfer potential compounds can couple carbon oxidation to ATP synthesis.Ion gradients across membranes provide an important form of cellular energyThe extraction of energy from foodstuffs occurs in stages.

High phosphoryl transfer potential compounds can couple carbon oxidation to ATP synthesis.Ion gradients across membranes provide an important form of cellular energyThe extraction of energy from foodstuffs occurs in stages.


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High phosphoryl transfer potential compounds can couple carbon oxidation to ATP synthesis.

Example from glycolysis:

High phosphoryl transfer potential compounds can couple carbon oxidation to ATP synthesis.

Example from glycolysis:

Coupling oxidation to ATP synthesisCoupling oxidation to ATP synthesis

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In the next step ATP is harvested from the high energy phosphate intermediate.

In the next step ATP is harvested from the high energy phosphate intermediate.

Coupling oxidation to ATP synthesisCoupling oxidation to ATP synthesis

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Ion gradients across membranes provide an important form of cellular energy

Ion gradients across membranes provide an important form of cellular energy

Ion GradientsIon Gradients

3333

Ion gradients across membranes can be used to synthesize ATP

Ion gradients across membranes can be used to synthesize ATP


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Extraction of energy from foodstuffs is carried out in stages:

Extraction of energy from foodstuffs is carried out in stages:


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Activated carriers exemplify the modular design and economy of metabolism.

Key reactions are reiterated throughout metabolism.

Metabolic processes are regulated in three principle way.

Activated carriers exemplify the modular design and economy of metabolism.

Key reactions are reiterated throughout metabolism.

Metabolic processes are regulated in three principle way.

Recurring Motifs in MetabolismRecurring Motifs in Metabolism

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ATP is an activated carrier of phosphate groups

Other examples include:

Activated carriers of electrons in oxidation reactions

Activated carriers of electrons in reductive biosynthesis

Activated carriers of two-carbon fragments

ATP is an activated carrier of phosphate groups

Other examples include:

Activated carriers of electrons in oxidation reactions

Activated carriers of electrons in reductive biosynthesis

Activated carriers of two-carbon fragments

Activated CarriersActivated Carriers

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NAD+

(Nicotinamide Adenine Dinucleotide)

NAD+

(Nicotinamide Adenine Dinucleotide)

Activated carriers of electrons in catabolism


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FAD(Flavin Adenine Dinucleotide)

FAD(Flavin Adenine Dinucleotide)



3939

Reduction of isoalloxazine ring of FADReduction of isoalloxazine ring of FAD



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NADPH(Nicotinamide Adenine Dinucleotide Phosphate)

NADPH(Nicotinamide Adenine Dinucleotide Phosphate)

Activated carriers of electrons in biosynthesis

Activated carriers of electrons in biosynthesis

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Coenzyme A is a carrier of Acyl groups

Coenzyme A is a carrier of Acyl groups

Activated carriers of acyl groupsActivated carriers of acyl groups

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Other common activated carriers:Other common activated carriers:

Activated CarriersActivated Carriers

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There are six basic reactions in metabolism:There are six basic reactions in metabolism:

Key ReactionsKey Reactions

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Metabolic motifsMetabolic motifs

Key ReactionsKey Reactions

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Metabolic processes are regulated in different ways:

Enzyme levels

Enzyme activity

Accessiblity of substrates to the enzyme

Metabolic processes are regulated in different ways:

Enzyme levels

Enzyme activity

Accessiblity of substrates to the enzyme

Metabolic RegulationMetabolic Regulation

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Degradative and biosynthesis pathways are usually distinct

Compartmentalization

Allosteric control

Degradative and biosynthesis pathways are usually distinct

Compartmentalization

Allosteric control


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The energy chargeThe energy charge


4848

The structures

of ATP,

CoEnzyme A

NADH and FADH2 belie

their “RNA

world” origin.

The structures

of ATP,

CoEnzyme A

NADH and FADH2 belie

their “RNA

world” origin.

Evolution of Metabolic Pathways

Evolution of Metabolic Pathways

4949

The pK of an acid is measure of its proton-group-transfer potentiala. Derive a relation between ΔGo’ and pK.b.What is the ΔGo’ for the ionization of

acetic acid, which has a pK of 4.8?

The pK of an acid is measure of its proton-group-transfer potentiala. Derive a relation between ΔGo’ and pK.b.What is the ΔGo’ for the ionization of

acetic acid, which has a pK of 4.8?

ProblemsProblems

5050

Calculate ΔGo’ for the isomerization of glucose 6-phosphate to glucose 1-phosphate. What is the equilibrium ration of glucose 6-phosphate to glucose 1-phosphate at 25°C?

Calculate ΔGo’ for the isomerization of glucose 6-phosphate to glucose 1-phosphate. What is the equilibrium ration of glucose 6-phosphate to glucose 1-phosphate at 25°C?

ProblemsProblems

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Lecture 1- Metabolism: Basic Concepts and Design