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FREE ENERGY
It is the portion of the total energy change in a system that is available for doing work at constant temperature and pressure; it is represented as ΔG.Reactions involving free energy:
1. Exergonic2. Endergonic
EXERGONIC REACTIONS
Reactions in which the free energy of the final state is less than the free energy of the initial state.This represents energy that can be used to do biological workReaction is spontaneous or favorable.ΔG is - or <0
ENDERGONIC REACTIONSReactions in which the free energy of the initial state is less than the free energy of the final state.ΔG is + or >0Reaction is nonspontaneous or unfavorableConsiderable amount of energy must be imparted to the system
COUPLED REACTIONS: 2 TYPES
1. Coupling involves a common obligatory intermediate (I)A+C I B+D
2. Synthesizing a compound of high-energy potential in the exergonic reaction and incorporate this new compound into endergonic reaction.
AH2
A Carrier-H2
Carrier
B
BH2
The overall free energy change for the reaction is negative (ΔG < 0)
HIGH ENERGY PHOSPHATES
High energy phosphates play central role in energy capture & transfer.
E
1
2
3
4
EXERGONIC
SYNTHESIS
MUSCULAR CONTRACTION
NERVOUS EXCITATION
ACTIVE TRANSPORT
HIGH ENERGY COMPOUNDSCompound ΔG (Kcal/mol)
Phosphoenolpyruvate -14.81,3 bisphosphoglycerate -11.8Phosphocreatine -10.3ATP( ADP+Pi) -7.3AMP(Adenosine+Pi) -3.4PPi( 2Pi) -4.0Glucose-1-phosphate -5.0Fructose-6-phosphate -3.8Glucose-6-phosphate -3.3
ENERGY CURRENCY OF CELL
High energy phosphates act as energy currency of cell.3 major sources of high energy phosphates takingpart in energy conservation or energy capture.
1. Oxidative phosphorylation: Free energy to drive this process comes from Respiratory chain oxidation using molecular O2 in mitochondria.
ROLE OF ATP/ADP CYCLE IN TRANSFER OF HIGH ENERGY
PHOSPHATES
P CREATINE- P
CREATINE
store of P
SUCCINYL Co-A
PEP1,3 BPG
OXIDATIVE PHOSPHORYLATION
ATP
ADP
P
Gl 1,6 BPG6PGlycerol3P
OtherPhosphorylations
BIOMEDICAL IMPORTANCE
Respiration
Xenobiotics (metabolism by Cytochrome P450 system).
Hyperbaric oxygen therapy in patients with respiratory or circular failure.
May result oxygen toxicity.
ENZYMES INVOLVED IN OXIDATION & REDUCTION:
OXIDOREDUCTASES
Oxidases Dehydrogenases Hydroperoxidases Oxygenases
OXIDASESCatalyse the removal of hydrogen from
a subtrate using oxygen as a hydrogen acceptor.
A
AH2
AH2
A
1/2 O2
H2O2
H2O
O2
e.g.1. Cyt. Oxidase
2. L-AA oxidase
3. Xanthine oxidase
4. Glucose oxidase
DEHYDROGENASESTransfer of hydrogen from one substrate to another in a
coupled oxidation - reduction reaction. Can’t use O2 as H2acceptor.
AH2
A Carrier -H2
Carrier BH2
B
Depend on:
1. Nicotinamide coenzymes2. Flavin coenzymes3. Cytochromes
OXYGENASES
Catalyze direct incorporation of oxygen into a substrate. Takes place in 2 steps:
1. O2 binding to the enzyme at active site, &
2. The reaction in which bound O2 is reduced/transferred to substrate.
2 subgroup of oxygenases:
i. Dioxygenases
ii. Monooxygenases
Dioxygenases: Incorporate both atoms of molecular oxygen into the substrate.
A+O2→AO2
e.g.i. Homogentisate oxidaseii. L-tryptophan dioxygenaseiii. 3-hydroxyanthranilate dioxygenase
Monooxygenases: Incorporate only one atom of molecular oxygen into the substrate.
May be Microsomal or Mitochondrial.A-H + O2 + ZH2 →A-OH + H2O + Z
DRUG-H + O2 + 2Fe2+ + 2H+ →DRUG-OH + H2O + 2Fe3+
Hydroxylase
Respiratory chain oxidizes reducing equivalents and acts as a proton pump.Oxidative phosphorylation is the process by which liberated free energy is trapped as high-energy phosphate.
ELECTRON TRANSPORT CHAIN
4 sequential complexes found in the inner side of inner mitochondrial membrane.
They accept e- from e- donors such as NADH or succinate, shuttle these e- across the membrane creating an electrical & chemical gradient (+1.1V).
Through the proton driven chemistry of the ATP synthase, generate ATP.
Complex I -NADH dehydrogenase/ NADH Coenzyme Q reductase.
Fp Q
Complex II- Succinate -Coenzyme Q reductase
Complex III -Coenzyme Q -cytochrome c oxidoreductase
Cyt-C
Complex IV -Cytochrome c oxidase.
½ O2 + H+
H2O
COMPLEXES OF ETC
ETC COMPONENTSComplex Components Prosthetic group
I NADH-Q oxidoreductase FMNFe-S
II Succinate Q reductase FADFe-S
III Q-Cytochrome C oxidoreductase
Heme bHHeme bLHeme C1
Fe-s
IV Cytochrome c oxidaseHeme aHeme a3
CuA & CuBATP synthase
H+
H+ H+H+H+
H+H+H+
H+ H+
H+H+
H+H+ H+
H+H+
H+ H+
ATP
Oxidative phosphorylation- Two phases
2. Using the gradient's energy to make ATP
1. Generation of the proton gradient.
TRANSPORT OF REDUCING EQUIVALENTS THROUGH ETC
AH2
A
NAD+
NADH Fp
FpH2 2Fe3+
2Fe2+
H2O
½ O2
H+ 2H+2H+H+
QFp [FMN] FeS
Fp [FAD] FeS
Succinate Choline
NADFp [FAD]
Lipoate
Pyruvate
α - Ketoglutarate
Fp [FAD]
FeS ETF [FAD]
Fp [FAD] FeS
Glycerol 3 phosphate
Acyl - CoASarcosine
Dimethylglycine
Proline3- Hydroxyacyl - CoA
3- HydroxybutyrateGlutamate
MalateIsocitrate
I
II
Q CYCLE
CYTOSOL(OUTSIDE)
MATRIX(INSIDE)
INNER MITOCHONDRIAL MEMBRANE
QH
QH
C1
QH2 H+H+
Q
H+
e-
e-
H+
e-
b566
b562
ATP Synthase
F1 subunit has 5 types ofpolypeptide chains(α3, β3, γ, δ, ε)
F0 contains the proton channelring of 10-14 c subunits
Moving unit (rotor) is c ring & γεRemainder is stationary (stator)‘a’ subunit binds
to outside of ring
Exterior columnhas 1’ a’ subunit2’ b’ subunits, &the δ subunit
P:O RATIO
When substrates oxidized by NAD-dehydrogenase, 3 mol ATP is produced per ½ mol of O2 consumed. P:O= 3.
When substrates oxidized by AFD-dehydrogenase, 2 mol ATP is produced per ½ mol of O2 consumed. P:O= 2.
FMN,FeS Cyt b, FeS, Cyt c1Cyt a Cyt a3Cu Cu
Q Cyt c
FADFeS
Complex IV
Complex III
Complex II
Complex I
Succinate
ADP + Pi ADP + PiADP + PiATPATPATP
O
H2O
NADH
Uncouplers
Oligomycin
Malonate
BALAntimycin A
CN, COAzide, H2S
Piericidine Amobarbital Rotenone
Carboxin TTFA
CHEMIOSMOTIC THEORY (Mitchell)
ATP synthase
ADP+Pi ATP
H+
OLIGOMYCIN
H+
H+
H+
H+
H+
H+
I
Q
III
C
IV
Proton translocation
NADH+H+
NAD+
1/2O2
H2OUncouplers
InnerMitochondrial
membrane
_
+
SHUTTLE PATHWAYS
Two pathways:1. Glycerol Phosphate Shuttle - Muscle & Brain2. Malate-Aspartate Shuttle - Liver, kidney &
heart
They transport the reducing equivalents from cytosol to mitochondria and not vice versa.
Malate aspartate shuttle
Malate Malate
Oxaloacetate
NAD+
NADHH+
Cytosol Mitochondria
+Oxaloacetate
NAD+
NADH+ H+α - KGα - KG
1
Glutamate GlutamateAsp Asp
2
H+ H+
Malate dehydrogenaseMalate dehydrogenase
TransaminaseTransaminase
Liver, kidney & heart
Glycerol 3 phosphate
NADH
H++
Glycerol 3 phosphate
Dihydroxy acetone phosphate
Dihydroxy acetone phosphate
FADH2
FAD
Glycerol 3 PO4 dehydrogenase
Glycerol 3 PO4 dehydrogenase
Cytosol Mitochondria
Resp. chain
Glycerophosphate shuttle
NAD+
Muscle & brain
TRANSPORTER SYSTEMS
1 2 543 6
OUTSIDE
INSIDE
OH-
H2PO4
Pyruvate
H+
HPO4-2
Malate-2
Malate-2
Citrate-3+H+
Malate-2
α-KG-2
ADP3-
ATP4-
1. Phosphate 2. Pyruvate 3. Dicarboxylate 4. Tricarboxylate 5. α-KG 6. Adenine nucleotide
N-Ethylmaleimide
Atractiloside