LITMIR.BIZ

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mitochondria where it is a substrate for the enzyme PDH (PDH is actually a complex of three enzymes, sometimes called pyruvate dehydrogenase complex, PDC). PDC not only further oxidises pyruvate, but also removes one carbon, resulting in the formation of (2 carbon) acetyl-CoA which, as described earlier, can be fully oxidised in the TCA cycle. This reaction is essentially irreversible. The importance of this process is illustrated by looking at the energy yield of these pathways: glycolysis yields 2 ATPs by substrate-level phosphorylation, but much energy remains within the pyruvate molecule; full oxidation of pyruvate, via formation of acetyl-CoA and oxidation in the TCA cycle, yields a further 36 ATPs. This number is a theoretical maximum and allowing for some inefficiency the real figure is probably slightly lower than this, but it illustrates how much energy can be derived from oxidation, and hence how important mitochondria (TCA cycle, electron transport chain) are for producing ATP.

      Breakdown of glucose as far as acetyl-CoA can also be part of a synthetic process. Acetyl-CoA produced from glucose is the starting point for the pathways of lipid synthesis: lipogenesis, which usually refers to the synthesis of fatty acids from glucose, and cholesterol synthesis. These pathways, like most biosynthetic pathways, are cytosolic, and the acetyl-CoA must be transferred out of the mitochondria (to be expanded later – Box 5.4).

      1.3.2.1.5 Gluconeogenesis

Gluconeogenesis, despite its name (synthesis of new glucose), is a pathway typically active in catabolic states, when there is a need to make glucose from other fuels for organs that depend upon it. The pathway of glucose synthesis, gluconeogenesis, occurs primarily in liver cells (and to a lesser extent, in kidney) and is essentially a reversal of glycolysis (many of whose steps are freely reversible and shared by both pathways) although with some specific steps, circumventing the energy-yielding and largely irreversible steps of glycolysis (Figure 1.14). Reversal of the last step of glycolysis (phosphoenolpyruvate → pyruvate) requires formation of oxaloacetate, and spans the mitochondrion. The main regulatory enzyme of glycolysis, phosphofructokinase, must also be reversed, and for this gluconeogenesis uses fructose-1, 6-bisphosphatase. Finally, if free glucose is to be produced for export (liver), glucose 6-phosphate must be dephosphorylated to glucose by glucose-6-phosphatase – i.e. this is the final enzyme of both gluconeogenesis and glycogenolysis, both pathways allowing liver to export glucose and maintain blood glucose levels. The major substrate for gluconeogenesis is pyruvate; the major source of this under most conditions is lactate. Amino acids whose carbon skeletons can be converted to pyruvate (e.g. alanine, during starvation, discussed later) can also contribute, and in addition glycerol released from lipolysis of triacylglycerols in adipose tissue can enter the gluconeogenic pathway (and hence breakdown of storage lipids does yield a small amount of carbohydrate). Note that glucose is broken down to lactate (glycolysis) in red blood cells, for instance, and in anaerobic cells such as renal medulla: the lactate is transferred via the bloodstream to the liver where it is used to re-synthesise new glucose. This cycle is sometimes called the Cori Cycle (discussed further in Chapter 7). It does not result in irreversible loss of glucose from the body. Irreversible loss of glucose occurs after the action of PDH, as acetyl-CoA can no longer be reconverted to glucose (PDH is irreversible), and therefore acetyl-CoA is not a substrate for glucose synthesis.

      1.3.2.1.6 Glycogen metabolism

      Carbohydrate is stored in limited amounts as cytoplasmic glycogen granules in most tissues as an energy resource available within the tissue (and hence independent of blood supply) for rapid utilisation when required. Glycogen is a polymer of glucose whose structure was described earlier (Figure 1.8). Glycogen synthesis starts with glucose 6-phosphate (Figure 1.14) and involves sequential polymerisation of glucose units on a glycogenin protein backbone. Glucose units are added as UDP-glucose (derived from glucose 6-phosphate) to the enlarging glycogen molecule by the enzyme glycogen synthase. Glycogen synthase assembles the glucose units into a linear chain, but every 8–10 residues a branch point is introduced by a branching enzyme. This has the effect of producing a highly branched tree-like structure with many free (‘non-reducing’) ends (Figure 1.8). Glycogenolysis involves the reverse: sequential removal of glucose units. These multiple terminal glucose residues enable rapid glucose release during glycogen degradation, by the enzyme (glycogen) phosphorylase (and a debranching enzyme). Glucose 1-phosphate is released, and is converted into glucose 6-phosphate. In most tissues, which store glycogen for their own utilisation (e.g. muscle), the glucose 6-phosphate then enters the pathway of glycolysis for energy production. In the liver specifically (and to some extent in kidney, especially during starvation) the enzyme glucose 6-phosphatase is expressed (uniquely in these tissues) and converts glucose 6-phosphate to free glucose: thus, glucose derived from glycogenolysis or produced by gluconeogenesis may be released into the bloodstream to maintain blood glucose concentrations in the postabsorptive or the fasting state.

      1.3.2.1.7 Pentose phosphate pathway

      One further pathway of glucose metabolism will be mentioned briefly: the pentose phosphate pathway. Again, this pathway occurs in the cytosol. This involves the metabolism of glucose 6-phosphate through a complex series of reactions that generate pentose sugars, used in nucleic acid synthesis, and also reducing power in the form of NADPH (Figure 1.14).

      The pathway comprises two parts: an oxidative (irreversible) stage, initiated by the enzyme glucose-6-phosphate dehydrogenase, which generates NADPH and the pentose (5-carbon) sugar ribulose 5-phosphate, and then a non-oxidative (reversible) stage which interconverts the pentose sugar into a wide variety of 3 carbon (triose), 4 carbon (tetrose), 5 carbon (pentose), 6 carbon (hexose), and 7 carbon (heptose) sugars. These sugars are used for the synthesis of nucleotides and aromatic amino acids, whilst NADPH provides energy for many reductive biosyntheses – including lipogenesis and amination of 2-oxoacids to amino acids (glutamate dehydrogenase – see below); hence this is a pathway active in anabolic states. NADPH also maintains the antioxidant glutathione in its reduced (active) form (GSH). Because the relative requirements for the two products of the pentose phosphate pathway (pentose sugars and NADPH) varies, when NADPH demand exceeds pentose need, the sugar can be reinserted into glycolysis (hence ‘pentose phosphate shunt’).

      1.3.3 Lipid metabolism

      1.3.3.1 Pathways of lipid metabolism

Carbohydrate metabolism centres on the sugar molecule glucose, its interconversion with the carbohydrate storage form, glycogen, and its breakdown, ultimately by oxidation. Similarly, lipid metabolism concerns the fatty acids as the central carriers of energy, triacylglycerol as the storage form, and pathways for oxidation of fatty acids. (Here we will not discuss other forms of lipid such as cholesterol and phospholipids. Cholesterol was described in Section 1.2.1.1 and Figure 1.6 and will be covered again in later chapters.) There are four central pathways: (i) esterification of fatty acids with glycerol to form triacylglycerol, and (ii) the converse, hydrolysis of triacylglycerol to liberate fatty acids and glycerol: lipolysis, (iii) oxidation of fatty acids: β-oxidation, and (iv) synthesis of fatty acids from other precursors, known as de novo lipogenesis. These are shown in simplified form in Figure 1.16, and transport and storage of lipid in the body is represented in Figure 1.17.

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