Metabolism
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Two very hyperketotic children
Key points from this exercise:
In peripheral tissues, beta-hydroxybutyrate is oxidised to acetoacetate linked to the reduction of NAD to NADH; this provides ~2.5 ATP more per mol of beta-hydroxybutyrate metabolised compared with acetoacetate. Reduction of acetoacetate to beta-hydroxybutyrate is thus a way of exporting reducing equivalents, and indirectly ATP, from the liver to extra-hepatic tissues.
Acetoacetyl CoA is formed from acetoacetate by transfer of the CoA from succinyl CoA. The reaction of acetoacetate succinyl CoA transferase by-passes the reaction of succinyl CoA synthase in the citric acid cycle, shown in the box on the right, in which succinyl CoA is hydrolysed to succinate + CoASH, linked to the condensation of either ADP and inorganic phosphate to yield ATP or GDP and inorganic phosphate (to yield GTP). The GDP-linked isoenzyme of succinyl CoA synthase is found only in tissues that catalyse gluconeogenesis (liver, kidney and to a small extent, small intestinal mucosa). In other tissues the enzyme uses ADP and forms ATP.
There is a small energy advantage to the formation of acetoacetyl CoA by transfer of the CoA form succinyl CoA. Esterification of a fatty acid to CoASH has an effective cost of 2 x ATP, since the reaction yields AMP and pyrophosphate. By contrast, if succinyl CoA is used as the source of CoA then the cost is only the 1 x ATP (or GTP) that is lost when the reaction of succinyl CoA synthase is bypassed by acetoacetate succinyl CoA transferase.
There is a significant metabolic advantage of this reaction in terms of controlling the rate of entry of acetoacetate into metabolism. Acetoacetyl CoA will be metabolised through the citric acid cycle .Succinyl CoA will only be available to transfer CoA onto acetoacetate at the same rate as it is being formed in the citric acid cycle - and hence the uptake of acetoacetate will be controlled by the need for it as a substrate for oxidation in the cycle.
Acetoacetyl CoA is cleaved to yield 2 mol of acetyl CoA by beta-ketothiolase. The mitochondrial isoenzyme of beta-ketothiolase in extra-hepatic tissues differs from that in the liver (which is involved in ketone body synthesis, not utilisation).