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TCA Cycle

Note: Interchangeable with Krebs Cycle
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Pyruvate -> Acetyl CoA

  • Pyruvate dehydrogenase (PDH)

    • links glycolysis with the TCA cycle​

    • involves

      • oxidative decarboxylation - removes CO2​

      • dehydration removes H+ and e- and forms NADH + H

      • Acetyl group attached to coenzyme A to form acetyl coenzyme A (acetyl CoA)

    • also uses other coenzymes

      • TPP​

      • α-lipoic acid

      • FADH2

PDH Complex
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  • As pyruvate enters the mitochondrion, PDH modifies pyruvate to acetyl CoA which enters the Krebs cycle in the matrix

    • a carboxyl group is removed as CO2​

    • a pair of electrons is transferred from the remaining two-carbon fragment to NAD+ to form NADH

    • the oxidized fragment, acetate, combines with coenzyme A  to form acetyl CoA

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SIGNIFICANCE

  • first release of CO2

  • make more NADH which goes to ETC for ATP

  • pyruvate has left glycolysis

  • now energy from pyruvate can go into TCA as acetyl-CoA

Aerobic Oxidation of Glucose

  • begins with anaerobic steps of glycolysis in the cytoplasm

  • glucose only partially oxidized in glycolysis

    • C6 -> C3 vs C1 in CO2

    • more energy to release

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Krebs Cycle

  • Takes place in mitochondria ​

  • aerobic, but no O2 directly involved

  • cycle vs linear pathway

    • glucose is linear​

      • glucose -> pyruvate​

    • TCA is circular

      • regenerates the starting compound after each turn of the cycle​

  • TCA = the hub of metabolism

    • meeting place of catabolic processes of CHO, fat and protein metabolism​

    • starting point of many biosynthetic reactions

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GOAL​

  • uses up (oxidizes) acetyl CoA from glucose and FAs

  • makes reduced coenzymes for respiratory chain (ETC)

  • makes ATP via substrate level phosphorylation

  • regenerates oxaloacetate (OAA)​

  • releases CO2

    • oxidative decarboxylation ​

    • what we eventually breathe out

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Step 1: OAA + Acetyl CoA -> Citrate

  • OAA is a keto acid with 4 carbons

  • OAA binds with Acetyl-CoA to form citrate

  • citrate has 3 carboxyl groups

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Step 2: Citrate -> Isocitrate

  • citrate rearranges to form isocitrate

  • there is an intermediate step during isomerization reaction which forms a compound called cis-sconitate (not shown) before you get isocitrate

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Step 3: Isocitrate -> α-ketoglutarate

  • Complex step - very important

    • dehydrogenation (loss of e- and H+)​

      • NAD -> NADH + H​

      • these carry the H and the e- to the ETC so ATP can be made by oxidative phosphorylation

    • decarboxylation (remove CO2)

      • one of the CO2 that OAA contributed, not from acetyl CoA​

      • C6 -> C5

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Step 4: α-ketoglutarate -> Succinyl-CoA

  • Similar to last step but more complex

    • Dehydration​

      • more NAD+ -> NADH + H​

    • Decarboxylation

      • lose another CO2​

      • one of the CO2 that OAA contributed, not from acetyl CoA​

      • C5 -> C4

    • Add CoASH

      • CoASH puts high energy into the system​

      • this energy will be used to make ATP via substrate level phosphorylation, similar to step 5 of glycolysis 

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CoASH

  • when acetyl CoA is not attached to a acyl group = CoASH

  • -SH can form a thioester linkage

  • acyl-CoA carry high - carry high energy bond in the form of a thioester linkage

  • thioester bond has higher energy (less stable - wants to hydrolyze) and will drive the next reaction forward

Step 5: Succinyl-CoA -> Succinate

  • use the energy from breaking the thioester bond to form GTP from GDP + Pi

    • GTP is similar to ATP, except made with guanine instead of adenine​

    • GTP can easily be converted to ATP so we say that we made ATP in this reaction

  • still stay at C4

  • lose the CoASH

    • just used to provide energy for substrate level phosphorylation​

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Step 6: Succinate -> Fumarate

  • third dehydrogenation step

    • uses FAD -> FADH2​

    • not removing H from OH, but removing two H to form double bond

      • CH2-CH2 -> CH=CH​

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Step 7: Fumarate -> Malate

  • hydration step

  • hydration of the C=C bond

  • setting up for one more dehydration step

  • both compounds still C4

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Step 8: Malate -> OAA

  • This is the last step

  • the next step would be to start the cycle over again​

    • dehydration step​

    • NAD -> NADH + H (more reducing equivalents to the ETC)

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ATP Yield in TCA cycle

  • 2X/glucose (1 glucose -> 2 pyruvate)

    • once for each pyruvate​

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©2023 by Syracuse University Dr.Margaret Voss

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