Introduction to metabolism
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Introduction to Metabolism. A hummingbird has a rapid rate of metabolism, but its basic metabolic reactions are the same as those in many diverse organisms. Autotrophs – use CO 2 as sole carbon source (plants, photosynthetic bacteria, etc.) Heterotrophs-obtain carbon from their environment

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Introduction to metabolism
Introduction to Metabolism

  • A hummingbird has a rapid rate of metabolism, but its basic metabolic reactions are the same as those in many diverse organisms

  • Autotrophs – use CO2 as sole carbon source (plants, photosynthetic bacteria, etc.)

  • Heterotrophs-obtain carbon from their environment

  • Constant cycling of material between autotrophs and heterotrophs

Chapter 10

Metabolism is the sum of cellular reactions
Metabolism Is the Sum of Cellular Reactions

  • Metabolism - the entire network of chemicalreactions carried out by living cells

  • Metabolites - small molecule intermediates in the degradation and synthesis of polymers

  • Catabolic reactions - degrademolecules to create smaller molecules and energy

  • Anabolic reactions - synthesize molecules for cell maintenance, growth and reproduction

Metabolic reactions
Metabolic Reactions

  • Metabolism includes allenzymecatalyzed reactions

  • The metabolism of the four major groups of biomolecules will be considered: Carbohydrates Lipids Amino Acids Nucleotides

Organization of metabolic reactions
Organization of Metabolic Reactions

  • Occur via pathways – series of organized reaction steps

  • Compartmentalized – certain reactions occur in particular cells, organelles or other specific sites

  • Pathways are regulated – controlled

    • to keep anabolism and catabolism reactions separate (some use the same enzymes)

    • Timing to produce products only when necessary

    • At least one step in a pathway needs to be irreversible (exergonic, -G)

Chapter 10

Types of pathways
Types of pathways

  • Individual reaction series

    • Linear (can branch out)

    • Cyclic

    • Spiral

  • Connecting pathways

    • Converging (metabolic)

    • Diverging (anabolic)

Chapter 10

Forms of metabolic pathways
Forms of metabolic pathways

  • Linear (b) Cyclic

  • or branched

Metabolism proceeds by discrete steps
Metabolism Proceeds by Discrete Steps

  • Multiple-steppathways permit control of energy input and output

  • Catabolic multi-step pathways provide energy in smallerstepwiseamounts)

  • Each enzyme in a multi-step pathway usually catalyzes only one single step in the pathway

  • Controlpoints occur in multistep pathways

Metabolic pathways are regulated
Metabolic Pathways Are Regulated

  • Regulation permits response to changing conditions

  • Common ways to regulate

  • (1) Supply of substrates(concentration) (2) Removal of products (3) Pathway enzyme activities

    • Allosteric regulation

    • Covalent modification

Feedback inhibition
Feedback inhibition

  • Product of a pathway controls the rate of its own synthesis by inhibiting an early step (usually the first “committed” step (unique to the pathway)

Feed forward activation
Feed-forward activation

  • Metabolite early in the pathway activates an enzyme further down the pathway

Covalent modification for enzyme regulation
Covalent modification for enzyme regulation

  • Interconvertible enzyme activity can be rapidly and reversibly altered by covalentmodification

  • Protein kinases phosphorylate enzymes (+ ATP)

  • Protein phosphatases remove phosphoryl groups

  • The initial signal may be amplified by the “cascade” nature of this signaling

Reaction types in pathways
Reaction Types in Pathways

  • Oxidation-Reduction (Redox)

  • Making or breaking C-C bonds

  • Internal rearrangements, isomerizations or eliminations

  • Group transfers

  • Free radical reactions

Chapter 10

Redox reactions
Redox reactions

  • Oxidation – loss of electrons, gain of oxygen, loss of hydrogen

    • Hydrogenases

    • Oxidases

  • Note the different oxidation states of carbon

Chapter 10

Carbon carbon bonds
Carbon-Carbon Bonds

  • Bond cleavage

    • Homolytic (1 electron for each atom)

    • Heterolytic (both electrons to one atom)

    • Recall

      • Nucleophiles (attracted to + charges)

      • Electrophiles (attracted to – charges)

Chapter 10

Common reaction types
Common Reaction Types

  • Many use the carbonyl group C=O

  • + on Carbon; - on Oxygen

    • Reactive group in

      • Aldol condensations

      • Claisen condensations

      • Decarboxylations

Chapter 10

Internal reactions
Internal Reactions

  • Rearrangements, isomerizations, eliminations

    • Groups

    • Bonds

    • Atoms

Chapter 10

Group transfers
Group Transfers

  • There are many groups to transfer

    • Acyl

    • Glycosyl

    • Phosphoryl

  • Phosphate = Pi

  • Pyrophosphate = PPi

Chapter 10

Free radicals
Free Radicals

  • Unpaired electrons

  • More common than previously thought

Chapter 10

10 3 major pathways in cells
10.3 Major Pathways in Cells

  • Metabolic fuels

  • Three major nutrients consumed by mammals: (1) Carbohydrates - provide energy(2) Proteins - provide amino acids for protein synthesis and some energy(3) Fats - triacylglycerols provide energy and also lipids for membrane synthesis

Fig 10 5
Fig 10.5

  • Overview of catabolic pathways

Catabolism produces compounds for energy utilization
Catabolism produces compounds for energy utilization

  • Three types of compounds are produced that mediate the release of energy

  • (1) Acetyl CoA

  • (2) Nucleoside triphosphates (e.g. ATP)

  • (3) Reduced coenzymes (NADH, FADH2, QH2)

Reducing power

Reducing Power

10 4 compartmentation and interorgan metabolism
10.4 Compartmentation and Interorgan Metabolism

  • Compartmentation of metabolic processes permits:

  • - separate pools of metabolites within a cell

  • - simultaneous operation of opposing metabolic paths

  • - high local concentrations of metabolites

  • - coordinated regulation of enzymes

  • Example: fatty acid synthesis enzymes (cytosol), fatty acid breakdown enzymes (mitochondria)

Fig 10 6 compartmentation of metabolic processes
Fig. 10.6 Compartmentation of metabolic processes

10 5 thermodynamics and metabolism
10.5 Thermodynamics and Metabolism

A. Free-Energy Change

  • Free-energy change(DG) is a measure of the chemicalenergyavailablefromareaction

  • DG = Gproducts - Greactants

  • DH = change in enthalpy

  • DS = change in entropy

Relationship between energy and entropy

  • Both entropy and enthalpy contribute to DG

  • DG = DH - TDS

  • (T = degrees Kelvin)

  • -DG = a spontaneous reaction in the direction written

  • +DG= the reaction is not spontaneous

  • DG= 0 the reaction is at equilibrium

Relationship between energy and entropy

The standard state d g o conditions
The Standard State (DGo) Conditions

  • Reaction free-energy depends upon conditions

  • Standard state(DGo)- defined reference conditions

  • Standard Temperature = 298K (25oC)

  • Standard Pressure = 1 atmosphere

  • Standard Solute Concentration = 1.0M

  • Biological standard state =DGo’

  • Standard H+ concentration = 10-7 (pH = 7.0) rather than 1.0M (pH = 1.0)

B equilibrium constants and standard free energy change

B. Equilibrium Constants and Standard Free-Energy Change

DGreaction = DGo’reaction + RT ln([C][D]/[A][B])

  • At equilibrium: Keq = [C][D]/[A][B] and DGreaction = 0, so that:

DGo’reaction = -RT ln Keq

C actual free energy change determines spontaneity of cellular reactions
C. Actual Free-Energy Change Determines Spontaneity of Cellular Reactions

  • When a reaction is not at equilibrium, the actual free energy change (DG) depends upon the ratio of products to substrates

  • Q = the mass action ratio

DG = DGo’ + RT ln Q

Where Q = [C]’[D]’ / [A]’[B]’

10 6 the free energy of atp
10.6 Cellular Reactions The Free Energy of ATP

  • Energy from oxidation of metabolic fuels is largely recovered in the form of ATP

Table 10 1
Table 10.1 Cellular Reactions

Fig 10 7
Fig 10.7 Cellular Reactions

  • Hydrolysis of ATP

Atp is an energy rich compound
ATP is an Cellular Reactions“energy-rich” compound

  • A large amount of energy is released in the hydrolysis of the phosphoanhydridebonds of ATP (and UTP, GTP, CTP)

  • All nucleoside phosphates have nearly equal standard free energies of hydrolysis

Energy of phosphoanhydrides
Energy of phosphoanhydrides Cellular Reactions

(1) Electrostaticrepulsion among negatively charged oxygens of phosphoanhydrides of ATP

(2) Solvationofproducts (ADP and Pi) or (AMP and PPi) is better than solvation of reactant ATP

(3) Productsaremorestablethanreactants There are more delocalized electrons on ADP, Pi or AMP, PPi than on ATP

10 7 the metabolic roles of atp
10.7 Cellular Reactions The Metabolic Roles of ATP

  • Energy-rich compounds can drive biosynthetic reactions

  • Reactions can be linked by a common energized intermediate (B-X) below

  • A-X + B A + B-X

  • B-X + C B + C-X

A phosphoryl group transfer
A. Phosphoryl-Group Transfer Cellular Reactions

  • Phosphoryl-group-transfer potential - the ability of a compound to transfer its phosphoryl group

  • Energy-rich or high-energycompounds have group transfer potentials equal to or greater than that of ATP

  • Low-energycompounds have group transfer potentials less than that of ATP

Table 10 3
Table 10.3 Cellular Reactions

B production of atp by phosphoryl group transfer
B. Production of ATP by Cellular ReactionsPhosphoryl-Group Transfer

  • Metabolites with high phosphoryl-group-transfer potentials can donate a phosphoryl group to ADP to form ATP

  • Energy-rich compounds are intermediates in catabolic pathways

  • Energy storage compounds can be energy-rich

Fig 10 10 transfer of the phosphoryl group from pep to adp
Fig 10.10 Transfer of the phosphoryl group from PEP to ADP Cellular Reactions

  • Phosphoenolpyruvate (PEP) (a glycolytic intermediate) has a high P-group transfer potential

  • PEP can donate a P to ADP to form ATP

Phosphagens energy rich storage molecules in animal muscle
Phosphagens Cellular Reactions: Energy-rich storage molecules in animal muscle

  • Phosphocreatine (PC) and phosphoarginine (PA) are phosphoamides

  • Have higher group-transfer potentials than ATP

  • Produced in muscle during times of ample ATP

  • Used to replenish ATP when needed via creatine kinase reaction

C nucleotidyl group transfer
C. Nucleotidyl-Group Transfer Cellular Reactions

  • Transfer of the nucleotidyl group from ATP is another common group-transfer reaction

  • Synthesis of acetyl CoA requires transfer of an AMP moiety to acetate

  • Hydrolysis of pyrophosphate (PPi) product drives reaction to completion

Fig 10 12 synthesis of acetyl coa
Fig 10.12 Synthesis of acetyl CoA Cellular Reactions

(continued next slide)

Fig 10 12 continued
Fig. 10.12 (continued) Cellular Reactions

10 8 thioesters have high free energies of hydrolysis
10.8 Cellular Reactions Thioesters Have High Free Energies of Hydrolysis

  • Thioesters are energy-rich compounds (10.22)

  • Acetyl CoA has a DGo’ = -31 kJ mol-1 (10.23)

10 9 reduced coenzymes conserve energy from biological oxidations

10.9 Reduced Coenzymes Conserve Energy from Biological Oxidations

A free energy change is related to reduction potential

  • The catabolic pathwaysreduction potential of a reducing agent is a measure of its thermodynamic reactivity

  • The electromotive force is the measured potential difference between two half-cells

  • Reference half-cell reaction is for hydrogen:

  • 2H+ + 2e- H2

A. Free-Energy Change Is Related to Reduction Potential

Fig 10 13 diagram of an electrochemical cell
Fig 10.13 Diagram of an electrochemical cell catabolic pathways

  • Electrons flow through external circuit from Zn electrode to the Cu electrode

Standard reduction potentials and free energy
Standard reduction potentials and free energy catabolic pathways

  • Relationship between standard free-energy change and the standard reduction potential:

DGo’ = -nFDEo’

n = # electrons transferred

F = Faraday constant (96.48 kJ V-1)

DEo’= Eo’electron acceptor - Eo’electron donor

Actual reduction potentials d e
Actual reduction potentials ( catabolic pathwaysDE)

  • Under biological conditions, reactants are not present at standard concentrations of 1 M

  • Actual reduction potential (DE) is dependent upon the concentrations of reactants and products

  • DE = DEo’ - (RT/nF) ln ([Aox][Bred] / [Ared][Box])

B electron transfer from nadh provides free energy

B. Electron Transfer from NADH Provides Free Energy

10 10 experimental methods for studying metabolism
10.10 oxidized by the respiratory electron-transport chain Experimental Methods for Studying Metabolism

  • Add labeled substrate to tissues, cells, and follow emergence of intermediates

  • Use sensitive isotopic tracers (3H, 14C etc)

  • Verify pathway steps in vitro by using isolated enzymes and substrates

  • Use metabolic inhibitors to identify individual steps and sequence of enzymes in a pathway