Biosynthetic Use of ATP

The input of energy in the form of the hydrolysis of ATP to either ADP and P_i or to adenosine monophosphate (AMP) and pyrophosphate powers the synthesis of biological molecules, including, as we have seen, carbohydrates in photosynthesis, proteins, DNA, RNA, and fatty acids. To delve into the role of ATP in biosynthesis in depth is not possible in this brief article. Aspects of fatty acid biosynthesis, however, reveal interesting principles of the energetics of biosynthetic pathways.

Fatty acids are oxidized completely to CO₂ and water by β-oxidation and the citric acid cycle. Acetyl CoA is the end product of β-oxidation of fatty acids and is the source of carbon for fatty acid biosynthesis. Yet, the pathways for fatty acid degradation and synthesis are so very different that they even occur within different compartments within cells. Fatty acid synthesis takes place in the cytoplasm of animal cells and in the plastids of plant cells, whereas β- oxidation is located in mitochondria in both animal and plant cells.

Often, the pathway for the synthesis of a compound differs significantly from that for its degradation. Among the reasons that the separation of synthetic and degradative pathways evolved are energetics and regulation. The oxidation of fatty acids to acetyl CoA is very exergonic. It is not feasible on energetic grounds to make fatty acids from acetyl CoA by reversing β-oxidation. Metabolism of carbohydrates and fats is regulated in mammals by a number of hormones, including insulin, glucagon, and epinephrine (adrenaline). Having separate pathways for the degradation and the biosynthesis makes it possible to turn off one pathway while up-regulating another. For example, glucagon and epinephrine selectively stimulate the breakdown of fats and fatty acids, whereas insulin has the opposite effect. The fine control of fatty acid metabolism that has evolved would clearly not be possible without the existence of separate pathways for biosynthesis and catabolism.

CO₂ is required for the synthesis of fatty acids. Yet, when fatty acid synthesis is carried out in the presence of radioactive CO₂, the fatty acid made is devoid of radioactivity. ATP is used to add CO₂ to a precursor, and in a subsequent step in the pathway of fatty acid biosynthesis, this same CO₂ is released. This seemingly perplexing phenomenon may readily be explained on an energetic basis.

Acetyl CoA is carboxylated by using bicarbonate as the source of CO₂ andATP hydrolysis as the source of energy:

⇒ Equation [12]

acetyl CoA + ATP + HCO3− ↔ malonyl CoA +ADP + Pi.

The enzyme that catalyzes this reaction, acetyl CoA carboxylase, contains biotin, one of the B vitamins. Several other vitamins, including niacin (part of NAD⁺ and NADP⁺) and riboflavin (part of FAD), are essential players in metabolism.

The carboxylation of acetyl CoA without the hydrolysis of ATP is energetically unfavorable. The exergonic hydrolysis of ATP pulls the reaction toward malonyl CoA synthesis. But why bother to carboxylate acetyl CoA?

All the carbon atoms in synthesized fatty acids are derived from the acetyl group of acetyl CoA. In principle, fatty acids could be made by condensation of acetyl units and subsequent reduction. However, the condensation of two acetyl CoA molecules is energetically unfavorable. The release of CO₂ as part of a reaction helps to drive a reaction to completion. The oxidative decarboxylation reactions of the citric acid cycle illustrate this fact. The loss of CO₂ from the malonyl group as it condenses with the acetyl group bound to the fatty acid synthetase drives the condensation reaction. The resulting β-keto compound is reduced to the level of a hydrocarbon by NADPH.

ATP hydrolysis provided the energy for the carboxylation of acetyl CoA. The immediate energy source for the condensation reaction was the loss of the same CO₂ molecule added to the acetyl CoA. It is clear that CO₂ plays a catalytic but essential role in fatty acid biosynthesis