Human Metabolism. Keith N. Frayn
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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.
Figure 1.16 Pathways of lipid metabolism in the cell. Synthesis of fatty acids from acetyl-CoA (lipogenesis) is driven by NADPH (from the pentose phosphate pathway), whilst the opposite pathway, breakdown of fatty acids to form acetyl-CoA (β-oxidation) also produces NADH (and FADH2). Esterification of fatty acids to glycerol produces triacylglycerols; the glycerol is released when the triacylglycerol undergoes lipolysis. Hence triacylglycerols are ‘storage’ forms of acetyl-CoA. Acetyl-CoA can be transported in the form of ketone bodies.
Figure 1.17 Lipid metabolism pathways. Importance of lipolysis and esterification pathways in lipid metabolism. Dietary fat, in the form of triacylglycerol, is hydrolysed in the intestinal lumen by pancreatic lipase and the products taken up into enterocytes (more detail in Section 4.2.3.2.3). Within the enterocytes, the fatty acids are re-esterified to glycerol [in fact some are taken up as monoacylglycerols and this is the basis for esterification – see Section 4.3.3]. The triacylglycerol is exported into plasma in the form of large lipoprotein droplets, the chylomicrons. Lipolysis of this circulating triacylglycerol by a lipase bound to endothelial cells (lipoprotein lipase) allows fatty acids to be taken up into cells for further esterification (adipose tissue) or for oxidation (muscle and other tissues). Triacylglycerol stored in adipocytes may be hydrolysed by intracellular lipases (further details in Chapter 5, Figure 5.10) to release fatty acids, which can travel through plasma for delivery to other tissues for oxidation. Most tissues also contain smaller amounts of triacylglycerol, formed by esterification of incoming fatty acids. Lip, lipolysis step; Est, esterification step. Structures are shown very diagrammatically. Fatty acids are represented by short wavy lines (more detail in box) but see Figures 1.4 and 1.9 for more detail.
Fatty acids are the lipids utilised for energy production in oxidative tissues; however, since they are amphipathic and detergent-like (Figure 1.4) they are potentially toxic, and are stored as triacylglycerol, mainly in specialised cells known as adipocytes. Unlike carbohydrates such as glucose, lipids are (by definition) not water-soluble. As discussed in Figure 1.4, triacylglycerol is very hydrophobic, making it a very dense and efficient energy store. Whilst this is an advantage for energy storage, it necessitates specialised forms of intracellular storage and mechanisms for transport through the plasma.
Triacylglycerol within cells is stored in the form of lipid droplets, discrete droplets each bounded – and stabilised – by a monolayer of phospholipids, together with some specific proteins (described in more detail later, Box 5.7). This phospholipid coat is similar to the structure of a cell membrane shown in Figure 1.5, but with just the outer layer of phospholipids. In specialised cells for fat storage, adipocytes, there may be just one large lipid droplet, occupying much of the volume of the cell (and discussed in more detail in Chapter