Question

1) In (Kaleta et al) analysis in (In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans), they identified acetone as an important intermediate in the conversion pathway from fatty acids to glucose. What is the source of acetone in the body and how is it generated under conditions of starvation? Please be specific and use diagrams if necessary. Hint: You do not need to show the complex pathways discussed in the paper.

2) List a limitation to the study in (In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans) and offer suggestions as to how this limitation can be addressed.

Answer 1

1. A significant fraction of acetyl CoA after utilisation in citric acid cycle small fraction of left over of  acetyl-coA undergo Ketogenesis. This occurs in liver mitochondria where acetyl CoA is converted to acetoacetate or D beta hydroxybutyrate. These products together with acetone are referred to as Ketone bodies. Under normal circumstances the body uses only glucose as its energy source but during starvation Ketone bodies become the brain major fuel source. Ketone body are water soluble equivalent of fatty acids. Acetoacetate formation occurs in three reactions and the overall reaction is catalysed by HMG- CoA synthase and HMG- CoA lyase.

Acetoacyl-CoA + H2O -------------> acetoacetate +CoA

Acetoacetate may be reduced to D-beta hydroxybutyrate by beta hydroxybutyrate dehydrogenase

Acetoacetate ---------------> D-beta- Hydroxy butyrate

Acetoacetate being a beta ketoacid also undergo relatively facile non enzymatic decarboxylation to acetone and carbon dioxide Therefore the breathe of the individual with ketosis , a pathological condition in which aceto Acetate is produced faster then it can be metabolized and has characteristic sweet smell of acetone, a symptom of diabetes.

2. The limitation in conversion of fatty acid to glucose from the acetyl coA produced after the oxidation of fatty acids is that it cannot be converted to oxalo acetate. Therefore Glycerol, a triacylglycerol breakdown product is converted to glucose by the synthesis of a glycolytic intermediate dihydroxyacetone phosphate(DHAP). Mobilization of triacylglycerol stored in adipose tissue involve their hydrolysis to glycerol and free fatty acid by triacylglycerol lifespace hormone