Chapter 15- Metabolism: Basic Concepts and Themes

Metabolism is composed of many interconnected reactions

• Energy is required for mechanical work (muscle contraction and cell movement), active transport, and biosynthesis.

• phototrophs = capture energy from sunlight

  • example: all photosynthetic organisms

• chemotrophs = capture energy through the oxidation of chemicals

  • example: all animals

  • have to oxidize chemical fuel to gain energy

Metabolism

Highly integrated network of chemical reactions that carry out energy extraction and synthesis of new material

Cellular processes of extracting energy and synthesizing new material are carried out by metabolism

Metabolic pathway

a series of linked reactions by which fuels are degraded and large molecules are constructed

Some reactions are not metabolically favorable

example: glycolysis is a 10-step metabolic pathway converting glucose to pyruvate

Themes common to all metabolic reactions

• Metabolism is a coherent network containing many common motifs.

• Adenosine triphosphate (ATP) is used as an energy currency to link energy-releasing (exergonic) and energy- requiring (endergonic) pathways.

• Either sunlight or the oxidation of chemical fuels powers ATP formation.

• ~100 molecules serve as activated intermediates.

• Metabolism uses only a few types of mechanisms that are relatively simple.

• Metabolic reactions are highly regulated because metabolic pathways are interdependent.

• Many of the enzymes involved in metabolism are organized into large complexes

  • increases speed and efficiency

  • allows efficient processing of unstable or toxic intermediates

Catabolism

Reactions that break down complex molecules into simpler ones to capture energy in useful forms (oxidizes)

Purpose is to generate ATP

Anabolism

Reations that construct a more complex molecule from simpler molecules by using energy

Amphibolic pathways

Pathways that can be either anabolic or catabolic depending on cellular energy conditions

A metabolic pathway must meet two criteria:

1. individual reactions must be specific

2. each of the reactions in the pathway must be thermodynamically favored under real condition

A reaction can occur spontaneously only if ∆G, the
change in free energy, is negative.

Overall free-energy change for a chemically coupled series of reactions

Equals the sum of the free-energy changes of the individual steps

• allows for the coupling of thermodynamically unfavorable and favorable reactions in enzyme active sites

ATP

A nucleotide consisting of adenine, a ribose, and a triphosphate unit

• active in complex with Mg²⁺ or Mn²⁺

Free energy derived from oxidation of food and from light is transformed into ATP

ATP acts as the free-energy donor in most energy- requiring processes

Energy-rich because its triphosphate unit contains two phsophanhydride linkages

Primary Energy Carrier

• All nucleoside triphosphates are energetically equivalent

• Two important electron carriers (NAD⁺ and FAD) and the acyl group carrier, coenzyme A, are derivatives of ATP

Is ATP hydrolysis exergonic or endergonic?

Exergonic

How does free energy get released by ATP hydrolysis?

• formation of new covalent bonds.

• formation of noncovalent interactions with water.

• increase in entropy.

• ∆G for ATP hydrolysis under typical cellular conditions is approximately −50 kJ mol-1.

Enzymes catalyze the exchange of phosphoryl groups from one nucleotide to another

• Some reactions are driven by GTP, UTP, and CTP.

• nucleoside monophosphate kinases = enzymes that phosphorylate nucleoside monophosphates

• nucleoside diphosphate kinase = enzymes that phosphorylate nucleoside diphosphates

  • has broad specificity

How does ATP Hydrolysis drive metabolism?

The unfavorable conversion of the compound A into compound B can be made possible by coupling to ATP hydrolysis

• Renders the formation of product exergonic

• Coupling these reactions under standard conditions changes the equilibrium ratio of B to A

• Negative free energy

Phosphoryl Potential

Tendency of an organic molecule to transfer its terminal phosphoryl group to water

• a means of comparing the tendency of organic molecules to transfer a phosphoryl group to an acceptor molecule

• ex. ATP has a higher phorphoryl-transfer potential than glycerol 3-phosphate

  • The high phosphoryl-transfer potential of ATP can be explained by its structure

• Some compounds have higher phosphoryl-transfer potential than ATP

  • examples: phosphoenolpyruvate (PEP) 1,3- bisphosphoglycerate (1,3-BPG), and creatine phosphate

  • These compounds can transfer their phosphoryl group to ADP to form ATP.

  • Phosphoryl transfer potential is intermediate among phosphorylated molecules → effiicent carrier

    
    

Features of the ATP structure

• ATP has a high phosphoryl-transfer potential because of:

  • orthophosphate (Pi) has greater resonance stabilization than any of the ATP phosphoryl groups

  • electrostatic repulsion of the triphosphate unit

    • negative charges repel one another because they’re close in proximity

  • the entropy of the products of ATP hydrolysis is greater

  • ADP and Pi are stabilized due to hydration.

Creatine Phosphate

• Serves as a reservoir of high potential phosphoryl groups

• ATP in muscles sustains contractile activity for < 1 second

• creatine kinase = catalyzes the regeneration of ATP from creatine phosphate and ADP

• Negative free energy

How do the sources of ATP change as exercise duration increases?

Oxidation of carbon fuels

• an important source of cellular energy

• ATP is the principal immediate donor of free energy for biological activities, but it is limited

• ATP must constantly be regenerated from ADP

• Takes place one carbon at a time

• carbon atoms in fuels are oxidized to yield CO₂

  • the more reduced a carbon atom is, the more free energy is released upon oxidation

• electrons are ultimately accepted by oxygen to form H₂O

Are fats or carbohydrates a more efficient fuel source?

Fats- the carbon in fats is more reduced

But carbohydrates gives you the fastest energy

Glyceraldehyde 3-phosphate

A metabolite of glucose formed during glucose oxidation

• the C-1 carbon is at the aldehyde-oxidation level and is not in its most oxidized state

• Compounds with high phosphoryl-transfer potential can couple carbon oxidation to ATP synthesis

• Oxidation of glyceraldehyde 3-phosphate does not occur directly

  • Carbon oxidation generates 1,3 bisphosphoglycerate (1,3-BPG), and the electrons released are captured by NAD+ to form NADH.

  • 1,3-BPG has high phosphoryl-transfer potential, and its hydrolysis can be coupled to the synthesis of ATP

How do proton gradients power ATP synthesis

• Ion gradients provide an important form of cellular energy that can be coupled to ATP synthesis

• oxidation produces electrochemical potentials of ion gradients across

  • serves as a means of coupling thermodynamically unfavorable and favorable reactions

• In animals, 90% of ATP is generated when the energy of a proton gradient is coupled with ATP synthesis

  • this process is called oxidative phosphorylation

• Proton gradients formed using the energy from either sunlight or chemical oxidation can power ATP synthesis

Phosphates

Play a prominent role in biochemical processes

• Phosphate esters are thermodynamically unstable yet kinetically stable in water.

  • Kinetic stability is due to the negative charges that resist hydrolysis in the absence of enzymes.

  • Their energy release can be manipulated by enzymes.

• The addition of a phosphate group changes molecule
  conformation and behavior.

• No other ions have the chemical characteristics of
  phosphate
  

Stages of energy being extracted from food

Stage 1: Large molecules in food are broken down into smaller units (digestion)

Stage 2: Small molecules are degraded to a few simple units that play a central role in metabolism

Stage 3: ATP is produced from the complete oxidation of the acetyl unit of acetyl CoA

Activated carriers

Small molecules to which a chemical group or electrons have been added, which can then be donated to another molecule

• frequently act as coenzymes or cosubstrates

• example: ATP is an activated carrier of phosphoryl groups

NADH

• an activated carrier of electrons for fuel oxidation

• Fuel molecules transfer electrons to carriers, which then transfer their high-potential electrons to O2.

• nicotinamide adenine dinucleotide (NAD+) = accepts a proton and two electrons in the oxidation of a substrate to form NADH

  • The reactive part is its nicotinamide ring.

    
    

FADH₂

• An activated carrier of electrons for fuel oxidation

• Flavin adenine dinucleotide (FAD)

  • accepts two protons and two electrons in the oxidation of a substrate to form FADH₂

    • the reactive part is its isoalloxazine ring

NADPH

• Activated carrier of electrons for reductive biosynthesis

• In most biosynthesis, precursors are more oxidized than the products

  • ATP and reducing power are needed

  • ex. four electrons are needed to reduce a keto group to a methylene group

• NADPH is the electron donor in most reductive biosynthesis

Coenzyme A

• Activated Carrier of two carbon fragments

• Carrier of acyl groups that is derived from vitamin B5 (pantothenate)

  • The reactive part is its terminal sulfhydryl group.

  • Acyl groups are linked to CoA by thioester bonds to form an acyl CoA.

  • Acetyl linked to CoA is called called acetyl CoA.

Why is the transfer of the acyl group exergonic?

The thioester is thermodynamically unstable

• The ∆G°′ for the hydrolysis of acetyl CoA has a large negative value.

• Electrons of the C=O bond cannot form resonance structures with the C—S bond that are as stable as those that they can form with the C—O bond
  

What does kinetic stability allow for?

Enzymatic control over the flow of energy

• NADH, NADPH, and FADH2 react slowly with O2 in the absence of a catalyst.

• ATP and acetyl CoA are hydrolyzed slowly in the absence of a catalyst.

What are they key reactions that are reitered throughout metabolism? (there are 6)

Oxidation-Reduction Reactions

Derives useful energy

ex. oxidation-reduction reactions of the citric acid cycle

Group-Transfer reactions

Used to synthesize ATP and in signaling pathways among others

ex. phosphoryl group transfer

Hydrolytic Reactions

Hydrolysis cleaves bonds by the addition of water

• commonly used to degrade large molecules

• (if you see water, it’s very likely hydrolysis)

Carbon Bond Cleavage

Can occur by means other than hydrolysis and oxidation

ex. the conversion of the six-carbon molecule fructose 1,6-biphosphate into two 3-carbon fragments during glycolysis

Dehydration is an important subclass

ex. generation of phosphoenolpyruvate from 2-phosphoglycerate

Isomerization reactions

Rearranges atoms within a molecule

• Typically to prepare the molecule for a subsequent reaction

• example: the conversion of citrate to isocitrate

Ligation Reactions

Forms bonds using free energy from ATP hydrolysis

example: the formation of oxaloacetate from pyruvate and CO₂

Pyruvate + CO₂ + ATP + H₂O → Oxaloacetate + ADP + P_i

3 principal ways metabolic processes are regulated

1. altering the amount of enzymes

   • The amount of a particular enzyme depends on both its rate of synthesis and its rate of degradation.

   • The level of many enzymes is adjusted by a change in the rate of transcription of the genes encoding them.

2. restricting the accessibility of substrates

   • Comparmentalization often segregates opposed restrictions

   • examples: fatty acid oxidation occurs in the mitochondrial matrix, while fatty acid synthesis occurs in the cytoplasm

3. Regulating the catalytic activity of enzymes internally or externally

   • Catalytic activity is regulated allosterically or by covalent modification.

     • Feedback inhibition is an example of allosteric regulation.

     • Concentrations of allosteric activators and inhibitors can be changed.

     • Reversible covalent modification can control catalytic rates of enzymes.

       
       

Energy Charge

Proportional to the mole fraction of ATP plus half the mole fraction of ADP

• Ranges from 0 (all AMP) to 1 (all ATP)

• Cells have to maintain energy charge between two values

• High energy charge → ATP inhibits relative rates of a typical ATP-generating pathway and simulates the typical ATP-utilizing (anabolic) pathway