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Mechanism

The two sources of ketone bodies in the body are fatty acids in adipose tissue and ketogenic amino acids. The main formation of ketone bodies is through ketogenesis.

Adipose tissue can be used to store fatty acids for regulating temperature and energy. These fatty acids can be released by hormone signaling of high glucagon and epinephrine levels, which inversely corresponds to low insulin levels. High glucagon and low insulin correspond to times of fasting or to times when blood glucose levels are low. Fatty acids must be metabolized in mitochondria, so coenzyme A is binded to the fatty acid to produce acyl-CoA. The acyl-CoA are able to enter the mitochondria. These fatty acids are used as fuel in cells through β-oxidation, which gives a large energy payout per acyl-CoA molecule that is formed from the β-oxidation of a fatty acid.

As β-oxidation begins, FAD dehydrogenates acyl-CoA to form trans-Δ2-enoyl-CoA and FADH2. Acyl-CoA Dehydrogenase catalyses a double bond in this step. Next, trans-Δ2-enoyl-CoA is hydrogenated by enoyl CoA hydratase to form L-β-hydroxyacyl CoA. NAD+ and the enzyme 3-hydroxyacyl-CoA dehydrogenase oxidize L-β-hydroxyacyl CoA to form β-ketoacyl CoA and NADH. Lastly, the β-ketoacyl CoA is cleaved by a thiol group in CoA to form another acyl-CoA and an acetyl-CoA. This reaction is catalyzed by thiolase. The acyl-CoA will be two carbons shorter than before, so it will enter β-oxidation again until it is all converted into acetyl-CoA.

The acetyl-CoA will enter the citric acid cycle and undergo an aldol condensation with oxaloacetate to form citrate. The citric acid cycle is a key pathway for metabolism which provides precursors of many amino acids as steps in the cycle. It also allows for high energy molecules to form; 3x NADH, FADH2, and GTP/ATP are all produced by one iteration of the cycle. This is equivalent to 10 ATP. Acetyl-CoA will undergo this process in any cell, while liver cells can also undergo a different process: ketogenesis.

In the liver, Acetyl-CoA can undergo ketogenesis to form ketone bodies. They are produced in mitochondria, and usually occur in response to low blood glucose levels. In the mitochondria, the acetyl-CoA will not undergo TCA when the amount of acetyl-CoA widely exceeds that of oxaloacetate, as the first step cannot proceed. Along with the fatty acids, deaminated ketogenic amino acids can be converted into intermediates in TCA and produce ketone bodies.

Ketogenesis produces one ketone body per two acetyl-CoA. Two acetyl-CoA will condense to form acetoacetyl-CoA via thiolase. Acetoacetyl-CoA will momentarily combine with another acetyl-CoA via HMG-CoA synthase to form hydroxy-β-methylglutaryl-CoA. Hydroxy-β-methylglutaryl-CoA will form acetoacetate via HMG-CoA lyase. Acetoacetate can then reversibly convert to D-β-hydroxybutyrate via D--β-hydroxybutyrate dehydrogenase. Another option here is acetoacetate can spontaneously degrade to acetone and carbon dioxide. From here, all three ketone bodies (acetoacetate, D--β-hydroxybutyrate, and acetone) have been formed, but acetoacetate and D--β-hydroxybutyrate are in much greater concentrations.

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