Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
The Citric Acid Cycle
What is the significance of the citric acid cycle?

Now we can ask an important question: why does The oxidation of a simple two-carbon acetyl group actually require such a complex cycle involving the successive formation of six-, five-, and four-carbon intermediates? The answer should be sought in certain fundamental patterns of organic chemistry. Despite its small size and relatively simple Structure, the acetic acid molecule has a distinctive feature: its methyl group is highly resistant to chemical oxidation. The direct oxidation of acetate into two CO₂ molecules requires very harsh conditions, which are completely incompatible with those existing within Cells. Through evolution, living cells have learned to use an alternative, albeit indirect, yet much easier pathway that does not require such high activation Free energy. Cells have learned to attach acetate to another compound (oxaloacetate) and thereby produce a compound (citrate) that undergoes dehydrogenation and decarboxylation much more easily than acetate itself. Although some metabolic reactions, particularly the Krebs cycle, may at first glance seem far more complex than necessary, a closer examination from the perspective of organic reaction mechanisms shows that in each case, the chemically easiest pathway for achieving the given transformation has been selected.