Chapter 10: Introduction to MetabolismChapter 10: Introduction to Metabolism
Metabolites: small molecules that are intermediates in the degradation or synthesis of biopolymers.
Anabolic reactions: Synthesis of molecules necessary for the life of the cell.
Catabolic reactions: Degradation of molecules to smaller molecules and to produce energy.
The entire network of chemical reactions carried out by the cell
AA, carb, nucleotides, fatty acids
Animals need food for organic molProvided by biosyn pathway in another species
4 major groups of biomolecules:
Metabolic PathwaysMetabolic Pathways
Pathways are sequences of reactions:
Linear pathwayCyclic pathway
(citric acid cycle)
Spiral pathway(fatty acid synthesis)
Series of independent enzymes Intermediates are regenerated every turn
(Very few are cyclic pathways)
Same set of enzymes are used repeatedly
Product is sub for next rxnPolymerization rxns
Major Metabolic PathwaysMajor Metabolic Pathways
Catabolic Pathways
Reactions and pathways can be linked to form extended metabolic routes
Major Metabolic PathwaysMajor Metabolic Pathways
Autotrophs: can utilize inorganic sources of essential elements.
Anabolic Pathways (biosynthesis)
PhotoautotrophsChemoautotrophs
Large mol from smaller molBy adding C and N
Energy provided byLight orBreakdown of organic mol from other autotrophs
Heterotrophs: need mol such as glucose
Most biochemically complex organisms?? Autotrophs
Catabolic PathwaysNot simply reverse of anabolic rxns
AA, nucleotides, monosacc,FA are formed by hydrolysis
Then degraded in oxidative rxns and energy conserved in ATP and red coenzymes (NADH)
Eliminate unwanted mol and generate energy
CAC: main source of energy to drive ATP syn
But also important in anabolic pathways: source of precurcors for AA syn
Main role:
Metabolism Proceeds in Discrete StepsMetabolism Proceeds in Discrete Steps
Narrow conditions of the cell (pH, temperature, pressure, concentrations) require specific and efficient enzymes.
Limited reaction specificity of enzymes requires multiple steps.
Multiple steps required to control energy input and output.
Allow sharing of intermediates.
Allow more control pointsto regulate biochem process.
But why are there so manydistinct rxns involved ??
Energy carriers (ATP/NADH) are in all life forms
Metabolic Pathways are RegulatedMetabolic Pathways are Regulated
Organisms react to changing environmental conditions (avail. of nutrients) and genetically programmed instructions (during development)
Regulate synthesis/degradation of biomol and generation/ use of energy
Most pathways:
Go in single direction (in physiological conditions)Without backing up and wasting energy etc
Flux = flow through a pathway.
Flow will continue as long as A is high and P is removed
Intermediates are in steady state (B,C,D,E do not change much)
Special regulatory controls that affect particular enzymes in pathwayUsually there are multiple control points
“regulatory enzymes”
Regulation of Metabolic PathwaysRegulation of Metabolic Pathways
Feedback inhibition.
Feed-forward activation.
Controls the first committed step (the first rxn unique to pathway)
Prevent unnecessary accumulation of metabolic intermediates
Inc in metabolite B increases flux thru the pathway
Two patterns of metabolic regulation
Allosteric modulation
Regulation of GlycolysisRegulation of Glycolysis
Signals adequatesupply of energy
Intermediate of CAC
Glycolysis activity dec when its products are no longer reguired
First committed step of glycolysis
High AMPindicatesdec. ATP
Phosphofructokinase-1Phosphofructokinase-1
ATP: allosteric inhibitor
AMP: allosteric activator
It is an allosteric enzyme and a regulatory step for glycolysis
Metabolically irreversible rxn.
[ATP] > ADP / AMP
Regulation of Metabolic PathwaysRegulation of Metabolic Pathways
Regulation of pathway occurs through allosteric modulators (inhibitors and activators),
and by covalent modification (protein kinases,phosphatases).
Amplification of original signal
Kinases with multiple specificities:
Coordinated reg of many pathyways
Slow process : relative to allosteric/covalent
Anabolic pathways: phosp-inactive
Rapid and reversible
Catabolic pathways: phosp-active
Regulated rate of enzyme syn/ degradation
phosphorylated protein is active or inactive
A + B C + D
Keq = [C][D]
[A][B]
G = 0 at equilibrium, no net synthesis of products
Greaction = Go’ + RTln [C][D]
[A][B]
When Greaction > 0, the reaction is unfavorable, energy needed to make G neg..When Greaction << 0, the reaction is favorable, spontaneous and irreversible
(no external source of energy needed).
The Free Energy of Metabolic ReactionsThe Free Energy of Metabolic Reactions
Gibbs free energy change: measure of energy available from a rxn
Standard Gibbs free energy: change under standard conditions(1M reactants and products)
Actual Gibbs free energy: depends on real concentrations
G = H - TS chem process)
Measure how far from equilibrium the reacting system is operating
Go’
G
Determine the spontaneity of a rxn and thus its direction
G
A + B C + D
Keq = [C][D]
[A][B]G = 0 at equilibrium, no net synthesis of products
Greaction = Go’ + RTln [C][D]
[A][B]
Gibbs free energy change
Measure how far from equilibrium the reacting system is operating
Near equilibrium rxns: small free energy changes
Rxns are readily reversible
Can accomodate flux in either directionand quickly restore levels of R and P to equil status
(Most metabolic rxns)
Not suitable control points of a pathway
Direction of rxn can be controlled by changes in [S] [P]
G
A + B C + D
Keq = [C][D]
[A][B]G = 0 at equilibrium, no net synthesis of products
Greaction = Go’ + RTln [C][D]
[A][B]
Near equilibrium rxns: small free energy changes
Metabolically irreversible rxns
Rxns are readily reversible
Rxns greatly displaced from equil
Large G
Can accomodate flux in either directionand quickly restore levels of R and P to equil status
Flux is is unaffected by changes in metabolite concthus usually controlled by modulating the enzyme
(Most metabolic rxns)
Gibbs free energy change
Measure how far from equilibrium the reacting system is operating
G
Metabolic Pathways are RegulatedMetabolic Pathways are Regulated
Most pathways:
Go in single directionWithout backing up and wasting energy etc
Regulation of unidirectional rxns (irreversible)
“regulatory enzymes”
[S] and [P] far from equilibrium
Regulatory enzyme controls flux
E6
Reverse reaction need different enzyme…….key regulatory step
unaffected by changes in metabolite conccontrolled by modulating the enzyme
Large G
Metabolically irreversible rxns : need diff enzyme for reverseMetabolically irreversible rxns : need diff enzyme for reverse
Fructose 1,6 bisphosphatase
Inhibited by AMP
Inc in AMP indicatesDec in ATPNeed ATPNeed glycolysisInhibit glc synthesis
The Free Energy of ATPThe Free Energy of ATP
ATP (and PPi) is an energy-rich compound:
Why large amt of energy released during hydrolysis?
Electrostatic repulsion of negative charges on phosphoanhydride bonds is less after hydrolysis.
Products of hydrolysis are better solvated (by H2O) than ATP.
The products of hydrolysis are more stable than ATP.
e- on terminal oxygens more delocalized
Phosphoanhydride vs Phosphoester linkage
Dec the repulsion of P groups drive the rxn
Bridging O two terminal O
The Free Energy of ATPThe Free Energy of ATP
[ATP] >> other NTP but all are called ‘energy rich compounds’
Intracellular [ATP] little fluctuation
Maintained by adenylate kinase AMP + ATP + 2Pi 2 ATP + 2 H20
[ATP] > ADP / AMP small change in [ATP]…large change in [ADP/AMP]
allosteric modulator of some energy yielding processes
Phosphoanhydride higher energy
The Metabolic Roles of ATPThe Metabolic Roles of ATP
Phosphoryl-group transfer:
Glutamate + NH4+ Glutamine; Go’ = +14 kJ mol-1
Rxn not possible (not spontaneous) in living cells:Glutamine steady state levels are highLimiting supply of ammonia
ATP hydrolysis drives the rxn
The Metabolic Roles of ATPThe Metabolic Roles of ATP
Phosphoryl-group transfer:
Glutamate + NH4+ Glutamine; Go’ = +14 kJ mol-1
Glutamate + ATP Glutamyl-P + ADPGlutamyl-P + NH4
+ Glutamine +Pi
Glutamate + NH4+ Glutamine Go’ = +14 kJ mol-1
ATP ADP + PiGo’ = -32 kJ mol-1
Glutamate + NH4+ + ATP Glutamine + ADP + Pi Go’ = -18 kJ mol-1
Carboxyl group Is activated
Coupledrxn
(Glutamine synthetase)
Phosphoryl group-transfer potentialPhosphoryl group-transfer potential
ATP: intermediate phos-group-trans potential and kinetically stable thus mediates most energy transfers
Measure of free energy required for formation of the phosp compound
Production of ATP by phosphoryl group transfer:
Phosphagens
High phosphorylgroup-transfer potential
More stableMetabolically irreversible
Energy storage in muscle
3-4 sec burst of energy
When ATP low
Allows replenishment
The Metabolic Roles of ATPThe Metabolic Roles of ATP
Nucleotidyl group transfer:
ATP AMP + PPi
Acetate + HS-CoA Acetyl-CoA PPi 2Pi
Go’ = -45 kJ mol-1
Go’ = +32 kJ mol-1
Go’ = -29 kJ mol-1
Acetate + ATP + HS-CoA Acetyl-CoA + AMP + 2PiGo’ = -42 kJ mol-1
Removal of (PPi) productdrives the rxn
AMP is transferred
Thioesters have high free energies of hydrolysisThioesters have high free energies of hydrolysis
GTP synthesis by coupling to thioester hydrolysis.
Thioesters less stable than oxygen estersunshared e- of S not effectively delocalized
Energy similar to phosphoanhydride linkage
Substrate level phosphorylation Conserves the energy used in formation
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