What is KREB’S Cycle ? Citric Acid Cycle

Also known as cit­ric acid cycle/tricarboxylic acid cycle. It is com­mon path­way for com­plete oxi­da­tion of acetyl coA into CO2 and H2O. This path­way is also called a cycle because its end prod­uct oxaloac­etate is reused to start anoth­er cycle. This is a cen­tral path­way con­nect­ing all the meta­bol­ic Path­ways direct­ly or indirectly.

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High­lights of cit­ric acid cycle

• The cycle is also called tri­car­boxylic acid cycle (TCA cycle) as tri­car­boxylic acid Name­ly cit­rate, cis aconi­tate and isoc­i­trate par­tic­i­pate at the out­set of the cycle
• This path­way should not be viewed as closed cycle since many com­pounds enter and leaves this pathway
• This path­way is both ana­bol­ic and cata­bol­ic in nature hence it is also regard­ed as amphi­bol­ic pathway.
• Although there is no direct par­tic­i­pa­tion of oxy­gen in the cycle but still this process takes please under aer­o­bic conditions.This is due to the fact that NAD⁺ and FAD required to oper­ate this cycle are regen­er­at­ed only in the pres­ence of oxygen.

The steps in the cit­ric acid cycle are described below:

1. In the first reac­tion acid acetyl CoA (2C) con­dens­es with oxaloac­etate 4C in the pres­ence of cit­rate syn­thase to form cit­ric acid (hence the name of the cycle)
2. Cit­rate is iso­mer­ized to isoc­i­trate in a two step reac­tion of dehy­dra­tion fol­lowed by hydra­tion. This reac­tion is cat­alyzed by Fe²⁺ acti­vat­ed enzyme aconi­tase and involves and inter­me­di­ate cis — aconi­tate (not shown)
3. Isoc­itric dehy­dro­ge­nase con­verts isoc­i­trate (6C) into alpha ketog­lu­tarate (5C) by oxida­tive decraboxy­la­tion. For­ma­tion of NADH and Co2 occurs dur­ing this reaction.
4. Alpha ketog­lu­tarate (5C) gets con­vert­ed to suc­cinyl CoA (4C) again bu oxida­tive decar­boxy­la­tion. In this reac­tion , NADH and Co2 are lib­er­at­ed . alpha ketog­lu­tarate dehy­dro­ge­nase catalysing this reac­tion requires five cofac­tor as in pyru­vate dehy­dro­ge­nase com­plex. These include three prothet­ic groups (TPP, lipoamide and FAD) and two coen­zyme (CoA and NADH).
5. Suc­cinyl CoA is con­vert­ed to Suc­ci­nate by Suc­ci­nate thiok­i­nase. This reac­tion is cou­pled with the phos­pho­ry­la­tion if GDP ro GTP (Sub­strate lev­el Phosphorylation)
6. Suc­ci­nate is oxi­dised to fumarate by Suc­ci­nate Dehy­dro­ge­nase in a reac­tion which results in the for­ma­tion of FADH₂ and FAD.
7. Fumarase con­verts fumarate to malate with addi­tion of H₂O.
8. An Oxi­da­tion reac­tion con­verts malate into oxaloac­etate. The reac­tion cat­alyzed by Malate dehy­dro­ge­nase results in the Syn­the­sise of NADH.

Oxaloac­etate regen­er­at­ed in the cycle is again avail­able to com­bine with anoth­er mol­e­cule of acetyl CoA to start anoth­er cycle.

Over­all reaction:

Acetyl CoA + 3NAD⁺ + FAD + GDP + Pi +2H₂O ———> 2CO₂ + 3NADH + 3H ⁺ + FADH₂ + GTP + CoA

Ener­get­ics of cit­ric acid cycle

Let us cal­cu­late how much ener­gy ATP is extract­ed from glu­cose break­down under aer­o­bic condition:

• The degra­da­tion of glu­cose to 2 pyru­vate by gly­col­y­sis yields 2 ATP and 2 NADH + 2H⁺
• The oxida­tive Decar­boxy­la­tion. Of 2 pyru­vate to acetyl CoA gen­er­ates 2 NADH + 2H⁺
• Oxi­da­tion of each acetyl CoA via Cit­ric acid cycle pro­duce 3 NADH, 1 FADH₂ and 1GTP. There­fore , two acetyl CoA will pro­duce dou­ble the num­ber of reduc­ing equiv­a­lents and GTP.
• Oxi­da­tion of NADH and FADH₂ by ETC is cou­pled to oxida­tive phos­pho­ry­la­tion. Each NADH pro­duces 2.5 ATP where­as FADH₂ pro­duces 1.5 ATP.
• The final count of ATP is : 10× 2.5+ 2×1.5 +4 = 32 

The num­ber of ATP pro­duced varies from 30–32 , depend­ing on the shut­tle oper­a­tive in a giv­en cell.

Reg­u­la­tion of Cit­ric Acid Cycle

Three enzymes name­ly cit­rate syn­thase, isoc­i­trate dehy­dro­ge­nase and alpha ketog­lu­tarate dehy­dro­ge­nase reg­u­late cit­ric acid cycle.

1. Cit­rate syn­thase activ­i­ty is inhib­it­ed by ATP, NADH, acetyl CoA and Suc­cinyl CoA
2. Isoc­i­trate dehy­dro­ge­nase activ­i­ty is acti­vat­ed by ADP And inhib­it­ed by ATP and NADH.
3. Alpha ketog­lu­tarate dehy­dro­ge­nase activ­i­ty is inhib­it­ed by Suc­cinyl CoA and NADH.

It is impor­tant to under­stand that avail­abil­i­ty of ADP is very cru­cial for the con­tin­u­ous oper­a­tion of cit­ric acid cycle.If ADP lev­els are low oxi­da­tion of NADH in FADH₂ through elec­tron trans­port chain will stop. Accu­mu­la­tion of NADH and FADH₂ inhib­it­ed the above stat­ed enzymes.