Substrates for Gluconeogenesis

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Chapter: Biochemistry : Gluconeogenesis

Gluconeogenic precursors are molecules that can be used to produce a net synthesis of glucose. The most important gluconeogenic prescurors are glycerol, lactate, and the α-keto acids obtained from the metabolism of glucogenic amino acids.


SUBSTRATES FOR GLUCONEOGENESIS

Gluconeogenic precursors are molecules that can be used to produce a net synthesis of glucose. The most important gluconeogenic prescurors are glycerol, lactate, and the α-keto acids obtained from the metabolism of glucogenic amino acids. [Note: Alanine, which directly gives rise to pyruvate, is an important example of a glucogenic amino acid.]

 

A. Glycerol

Glycerol is released during the hydrolysis of triacylglycerols in adipose tissue and is delivered by the blood to the liver. Glycerol is phosphorylated by glycerol kinase to glycerol phosphate, which is oxidized by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate, an intermediate of glycolysis. [Note: Adipocytes cannot phosphorylate glycerol because they essentially lack glycerol kinase.]

 

B. Lactate

Lactate is released into the blood by exercising skeletal muscle and by cells that lack mitochondria such as RBCs. In the Cori cycle, bloodborne glucose is converted by exercising muscle to lactate, which diffuses into the blood. This lactate is taken up by the liver and reconverted to glucose, which is released back into the circulation (Figure 10.2).

 

C. Amino acids

Amino acids derived from hydrolysis of tissue proteins are the major sources of glucose during a fast. The metabolism of the glucogenic amino acids generates α-keto acids. α-Keto acids, such as α-ketoglutarate can enter the tricarboxylic acid (TCA) cycle and form oxaloacetate (OAA), a direct precursor of phosphoenolpyruvate (PEP). [Note: Acetyl coenzyme A (CoA) and compounds that give rise only to acetyl CoA (for example, acetoacetate and amino acids such as lysine and leucine) cannot give rise to a net synthesis of glucose. This is due to the irreversible nature of the pyruvate dehydrogenase (PDH) reaction, which converts pyruvate to acetyl CoA. These compounds give rise instead to ketone bodies and are, therefore, termed ketogenic.]


Figure 10.2 The intertissue Cori cycle. [Note: Diffusion of lactate across membranes is facilitated by a transport protein.]

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