The ketone bodies metabolic pathway is used to convert acetyl-CoA formed in the liver into "ketone bodies": acetone, and more importantly acetoacetate and 3-hydroxybutyrate, which are transported in the blood to extrahepatic tissues where they are converted to acetyl-CoA and oxidized via the citrate cycle pathway for energy. The brain, which usually uses glucose for energy, can utilize ketone bodies under starvation conditions, when glucose is not available. When acetyl-CoA is not being metaboli
zed in the citrate cycle pathway during starvation, its conversion to ketone bodies and export from the liver permits continued operation of the fatty acid beta degradation pathway. To form ketone bodies, two molecules of acetyl-CoA are condensed by acetyl-CoA C-acetyltransferase (Acat1) into acetoacetyl-CoA. Several pathway enzymes have mitochondrial and cytosolic isoforms; the former, predominantly operant enzymes are shown in the forefront in the diagram. Another molecule of acetyl-CoA is then condensed with acetoacetyl-CoA by 3-hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) to form 3-hydroxy-3-methylglutaryl-CoA. This is cleaved by 3-hydroxy-3-methylglutaryl-CoA lyase to generate acetyl-CoA and acetoacetate. The acetoacetate is reduced reversibly by 3-hydroxybutyrate dehydrogenase (Bdh1) to yield 3-hydroxybutyrate, or is decarboxylated spontaneously or via acetoacetate decarboxylase (Adc) to generate acetone. To date, the Adc gene has only been cloned from prokaryotes, although enzyme activity has been studied in mammals (see PMID: 12726989). Outside the liver, 3-hydroxybutyrate is oxidized back to acetoacetate (Bdh1), which is then converted to acetoacetyl-CoA by 3-oxoacid CoA transferase (Oxct1), with succinyl-CoA donating its coenzyme. This reaction can also be performed by acetoacetate CoA synthetase (Aacs) using coenzyme A. Acat1 cleaves the acetoacetyl-CoA into two molecules of acetyl-CoA, which can generate energy by entering the citric acid cycle pathway. In diabetes, reduced insulin enhances ketone body production by activating lipase and Hmgcs2 and inhibiting acetyl CoA carboxylase-mediated conversion of acetyl-CoA to malonyl-CoA, the first step of the fatty acid biosynthetic pathway. This lifts the malonyl-CoA-mediated inhibition of fatty acid transport across the mitochondrial membrane by carnitine palmitoyltransferase 1 where they are oxidized via the fatty acid beta degradation pathway into ketone bodies. To see the ontology report for annotations, GViewer and download click here [Click here to see related GO term - GO:0042180, associated KEGG map - map00072 and entry at Reactome - REACT_1861.3]...(less)
