View Full Version : Metabolism 3: The Kreb's Cycle Trifecta

19th August 09, 09:26 AM
At the end of glycolysis a 3 carbon compound called pyruvate is released. This compound still contains a large portion of the useful chemical energy from glucose. This will be extracted in the next chapter of metabolism: the Kreb’s Cycle. (http://en.wikipedia.org/wiki/Krebs_cycle) Kreb’s cycle was discovered in 1937 by Hans Krebs. It is also known as the citric acid cycle by those jealous bastards who don’t want to give him props (respect Y’all! Dolla, Dolla bill yo!). It is a multistage enzymatic reaction, occurring exclusively in the mitochondria. It produces more ATP and yields more high energy Hydrogen/2 electron sets for the electron transport chain than glycolysis.

The first step starts with the humble pyruvate leftovers, which must be prepared to enter the cycle with the help of a few good enzymes. The whole cycle (and just about every other bodily function) relies heavily on enzymes. We should take the time here to mention some of the more important points here. Enzymes (Enzymes http://en.wikipedia.org/wiki/Enzyme) are proteins (1) that are biological catalysts, which lower the activation energy of a particular reaction making them easier to run, facilitating their completion. “It takes money to make money” is an idea that should be closely considered. All reactions require energy to start and finish. Some require very little and run almost spontaneously; others require a great deal to complete. A general rule of thumb is if the products of a given reaction are more complex than the reactants, then the reaction will require more energy input to make it go. Catalysts, however, lower this energy without being used up or otherwise changed, making the reaction easier to start and finish.


Typically, catalysts accomplish this by bringing two molecules close enough and in a specific position to where they can bond, or by holding and then stretching a bond to make it easier to break so that other, new bonds can form. In industry, transition metals, like vanadium, iron, copper, and rhodium (2) are used to great effect in this role and are irreplaceable in obtaining cheap products. The older, purely synthetic methods often cannot compete cost-wise. Catalytic reduction (http://en.wikipedia.org/wiki/Catalyst), where platinum metal is used to break double or triple bonds in compounds and replace them with hydrogen is a famous example of this. The platinum metal has an extra group of electrons called d-electrons. This extra set hangs around the outside of the atom and acts like hooks that can snag other loitering atoms. Those with double and triple bonds are especially prone to this attack because they are linear and the electrons are present in clouds above and below the plane of the molecule. Once snagged the molecule is held in place giving the hydrogen an easy target to attack. The result is the loss of the double/triple bonds and their replacement with hydrogen atoms. Singly bonded atoms are less favorable targets for the platinum and are let go while the platinum is otherwise unchanged. The fact that its unchanged is important in that you can reuse it lowering costs overall (3).

Enzymes also work in a similar fashion. Take for instance carbonic anhydrase (http://en.wikipedia.org/wiki/Carbonic_anhydrase), which is responsible for taking H2O and CO2 and making carbonic acid (H2CO3) in our cells [H2O + CO2 ------> H2CO3]. The active site on the enzyme is made up of 3 amino acids called histidine, each connected to a single zinc atom. With three bonds the zinc atom has a +2 positive charge. Next to this structure there is a group of amino acids that attract and bond CO2 molecules. The positive charge on zinc attracts the electronegative oxygen atom in water. When both pieces are in place they are pulled close enough and in just the right position to bond together. Ordinarily, this reaction isn’t one that happens easily and freely, but with the enzyme setting more friendly conditions the rate in our cells is estimated to be 10 million times that of the non-catalyzed reaction.

Often groups of enzymes are built together in to a tiny factory-like structure where chains of reactions can be accomplished with little interference. Generally, the product of the first reactions is handed off to the next enzyme in the complex and the products of these active the next and so on until the desired effect or product is achieved. This kind of system allows for greater control and unwanted reactions are almost eliminated.

As well as being one of the largest enzymes known (4), pyruvate dehydrogenase (http://en.wikipedia.org/wiki/Pyruvate_dehydrogenase) is one of these enzyme factories. It affects the oxidation of pyruvate and produces the starting material for Kreb’s cycle. The enzyme smashes pyruvate removing CO2 and leaving a small 2 carbon piece called an acetyl group. This piece is attached to a very important compound called coenzyme A [pyruvate + NAD+ + COA -----------> Acetyl-COA + NADH + CO2] Coenzyme A is unique in that all molecules that are used for energy are catabolized into these 2 carbon acetyl groups and transferred to Coenzyme A making acetyl-COA. Not just sugars, but long fatty acid chains are cleaved into these pieces and transferred to it. Even proteins are deaminated (5) and catabolized in this manner (6). Acetyl COA provides the starting fuel for Kreb’s cycle.

Kreb’s cycle is a series of 9 reactions starting with the ion oxaloacetate. When acetyl COA enters the cycle the acetyl group is transferred to oxaloacetate making a compound called citrate.

Reactions 2 and 3 are reshaping ‘reactions’. They take the citrate and reposition a hydroxyl group (-OH), making cis-aconitate and then isocitrate. Isocitrate is oxidized, removing a high-energy hydrogen/2 electron combo, which is given to a NAD+ ion. The NADH made is used in the electron transport chain, a series of membrane proteins in the mitochondria used to make copious amounts of ATP.

Afterwards in reaction 4, the isocitrate is decarboxylated, meaning that CO2 is taken from it leaving the product a-ketogluterate.

Reaction 5 decaboxylates the a-ketogluterate forming a 3-carbon succinyl group, which combines again with coenzyme A to make succinyl-COA. During this reaction one more hydrogen/2 electron set reduces NAD+ to NADH.

In reaction 6, the succinyl-COA bond is broken and the energy released is used to phosphorylate a molecule called guanosine di-phosphate (GDP) to guanosine tri-phosphate (GTP). GDP is used in substrate level phosphorylation (http://en.wikipedia.org/wiki/Substrate_level_phosphorylation)
to produce a molecule of ATP. After all of this, a 4 carbon piece, succinate is left.

Reaction 7 oxidizes the succinate ion into a a fumarate ion. Energy from this reaction is not sufficient to reduce another molecule of NAD+, so another electron carrier called FAD takes its place and transfers the Hydrogen and electrons to the transport chain.

Reaction 8 adds H2O to fumarate to produce malate.

Finally in reaction 9, malate is oxidized and another hydrogen/2 electron combo is given to NAD and sent on its way. This leaves the final product, oxoacetate, the material the cycle began with.


1. Enzymes aren’t always proteins. RNA is also used to catalyze reactions as well. This adds a bit more weight to the theory that RNA developed before DNA. More evidence is circumstantially supported by the fact that RNA does not use Nitrogen in its structure. The nitrogenous bases (http://en.wikipedia.org/wiki/Nitrogenous_base) in DNA are thought to have become a dominant structural feature after easier access to nitrogen containing compounds was established sometime after nitrogen fixation became widespread.

2. This is not an extensive list by any means. For more information see the below mentioned catalysis book. Vanadium and rhodium catalysts are often used in the manufacture of sulfuric acid, the most widely produced chemical in the world.

1984 M. Hudlicky/Ellis Horwood Limited
British Libiuy Cataloguing in Publication Data
Hudlicky, Milos
Reductions in organic chemistry. -
(Ellis Hotwood series in chemical science)
1. Reduction, Chemical 2. Chemistry, Organic
I. Title
547*.23 QD281.R4
Library of Congress Card No. 84-3768
ISBN 0-85312-345-4 (Ellis Horwood Limited)
ISBN 0-470-20018-9 (Halsted Press)
Printed in Great Britain by Butler & Tanner, Frome, Somerset.

3. These kind of metals are usually fairly expensive, especially platinum, which costs roughly 40$ per gram.

4. It has 60 subunits and can be seen by electron micrograph.

5. Removal of nitrogen containing sections from an amino acid. Amino acids have a basic side containing an amine and an acidic side containing a carboxylic acid and the like.

6. Acetyl COA is used however by only a few processes. When ATP levels are high it is put towards making fatty acids for storage, but when they are low it is put towards the production of ATP in the Kreb’s cycle.

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