Krebs Cycle - Lecture notes 1 PDF

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Krebs Cycle Lecture...

Description

Kreb’s/Citric Acid/Tricarboxylic Acid Cycle Link Reaction  

Irreversible Pyruvate dehydrogenase (catalyst) is large complex - Mass 4 million to 10 million Daltons - Groups travel from one subunit to another connected to the core by tethers

Co Factors 

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Catalytic cofactors - Thiamine pyrophopshate (TPP) - Lipoic acid Stoichiometric cofactors (is used up) - CoA - NAD+

Pyruvate Dehydrogenase Component (E1) Decarboxylation   

Pyruvate combines with TPP before decarboxylation TPP is the prosthetic group of the enzyme 3C to 2C

Oxidation  

Hydroxyethyl group is oxidised & transferred to lipoamide Forms energy rich thioester bond

Dihydrolipoyl Transacetylase (E2)  

Group transfer – acetyl group - Acetylation Acetyl CoA - Fuel for the TCA

Dihydrolipoyl Dehydrogenase (E3)   

Oxidation of dihydrolipoamide back to lipoamide Must occur before further acetyl CoA can be formed from pyruvate Electrons transferred to FAD then to NAD+

Regulatory Point   

Committed irreversible step – ATP/Lipid/aa formation Pyruvate Dehydrogenase – Selected mechanisms Adenylate control (E1 ): ↑ADP & Pyruvate – PDP ↓ATP – PDK – switches the enzyme of ↓ NADH ↓Acetyl CoA ↑Ca2+

Mercury & Beriberi 

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Mercury - Binds pyruvate dehydrogenase (E3 ) - Inhibits enzyme - Hatters used mercury nitrite - Sulfhydryl treatment - Neurological symptoms due to the inhibition of aerobic metabolism of glucose Beriberi – alcoholics - B1 deficiency (thiamine) - Neurological and cardiovascular symptoms - Raised blood pyruvate levels - Nervous system relies on glucose for energy

Citric Acid Cycle 

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Final common pathway for fuel oxidation - Carbohydrates - Fats - Amino acids Most enter at acetyl coenzyme A (Acetyl CoA) - All enter as components of the TCA

Citrate Synthase   

Aldol condensation followed by hydrolysis 4C (oxaloacetate) + 2C (acetyl CoA) = 6C Entry point for Acetyl CoA

Aconitase   

Isomerisation (dehydration-hydration) Rearranges hydroxyl - Necessary for oxidation step to follow Aconitate intermediate

Isocitrate Dehydrogenase 

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Oxidation - Reduction & Decarboxylation - NAD+ → NADH + H+ - CO2 - Oxidising agent = NAH+ Oxalosuccinate intermediate

Regulatory Point 1 (Of Citric Acid Cycle)  

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The first enzyme to generate high energy e Isocitrate Dehydrogenase - ↑ADP – allosteric - ↓ATP – allosteric - ↓NADH – competitive – product Excess citrate build may inhibit PFK

ɑ-Ketoglutarate Dehydrogenase   

Decarboxylation – Oxidation – Group Transfer An enzyme complex Homologous to pyruvate dehydrogenase

Regulatory Point 2  

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The 2nd enzyme to generate high energy e α-ketoglutarate dehydrogenase - ↓Succinyl CoA – competitive – product - ↓NADH – competitive – product - ↓ATP Excess substrate can be used to make aa’s

Succinyl CoA Synthetase     

Succinyl CoA has a high energy thioester bond Conversion to succinate coupled to GTP formation Nucleoside diphosphokinase GTP + ADP GDP + ATP Group transfer – phosphoryl group

Next Three Steps   

Oxidation – Hydration – Oxidation Reforms oxaloacetate Common series of reactions - Fatty acid oxidation - Fatty acid synthesis - Amino acid breakdown

Succinate Dehydrogenase 

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Hydrogen acceptor is FAD - FAD → FADH2 - Does not dissociate from enzyme - Passed directly to coenzyme Q Forms direct link with electron transport chain

Fumerase  

Addition of H+ and OHRemoval of double bond

Malate Dehydrogenase  

Positive ΔG Driven by product use in ETC & TCA cycle

Biosynthetic Role of the TCA Cycle 

ε∆G is negative

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Reactions will occur spontaneously

The Glyoxylate Cycle       

Carbs from lipids 2x Acetyl CoA Succinate – To TCA Plants – Glyoxomes Some Bacteria Oil rich seeds Only occurs in plants...