0.6. Given that acetyl coenzyme A cannot be a substrate for gluconeogenesis, why is its production in fatty acid oxidation essential for gluconeogenesis?
Acetyl coenzyme A inhibits the pyruvate dehydrogenase complex and activates pyruvate carboxylase, pushing pyruvate to gluconeogenesis and away from oxidation.
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I. OVERVIEW
A constant source of blood glucose is an absolute requirement for human life. Glucose is the greatly preferred energy source for the brain and the required energy source for cells with few or no mitochondria such as mature red blood cells. Glucose is also essential as an energy source for exercising muscle, where it is the substrate for anaerobic glycolysis. Blood glucose can be obtained from three primary sources: the diet, glycogen degradation, and gluconeogenesis. Dietary intake of glucose and glucose precursors, such as starch (a polysaccharide), disaccharides, and monosaccharides, is sporadic and, depending on the diet, is not always a reliable source of blood glucose. In contrast, gluconeogenesis (see p. 117) can provide sustained synthesis of glucose, but it is somewhat slow in responding to a falling blood glucose level. Therefore, the body has developed mechanisms for storing a supply of glucose in a rapidly mobilized form, namely, glycogen. In the absence of a dietary source of glucose, this sugar is rapidly released into the blood from liver glycogen. Similarly, muscle glycogen is extensively degraded in exercising muscle to provide that tissue with an important energy source. When glycogen stores are depleted, specific tissues synthesize glucose de novo, using glycerol, lactate, pyruvate, and amino acids as carbon sources for gluconeogenesis (see Chapter 10). Figure 11.1 shows the reactions of glycogen synthesis and degradation as part of the essential pathways of energy metabolism.
II. STRUCTURE AND FUNCTION
The main stores of glycogen are found in skeletal muscle and liver, although most other cells store small amounts of glycogen for their own use. The function of muscle glycogen is to serve as a fuel reserve for the synthesis of ATP during muscle contraction. That of liver glycogen is to maintain the blood glucose concentration, particularly during the early stages of a fast (Fig. 11.2; also see p. 329). [Note: Liver glycogen can maintain blood glucose for <24 hours.]
A. Amounts in liver and muscle
Approximately 400 g of glycogen make up 1%–2% of the fresh weight of resting muscle, and ~100 g of glycogen make up to 10% of the fresh weight of a well-fed adult liver. What limits the production of glycogen at these levels is not clear. However, in some glycogen storage diseases (GSD) (see Fig. 11.8), the amount of glycogen in the liver and/or muscle can be significantly higher. [Note: In the body, muscle mass is greater than liver mass. Consequently, most of the body’s glycogen is found in skeletal muscle.]
B. Structure
Glycogen is a branched-chain polysaccharide made exclusively from α-Dglucose. The primary glycosidic bond is an α(1→4) linkage. After an average of 8–14 glucosyl residues, there is a branch containing an α(1→6) linkage (Fig. 11.3). A single glycogen molecule can contain up to 55,000 glucosyl residues. These polymers of glucose exist as large, spherical, cytoplasmic granules (particles) that also contain most of the enzymes necessary for glycogen synthesis and degradation.