Human Metabolism. Keith N. Frayn
Chemical energy transduction is the process of transferring energy between different forms, and involves two main biochemical energy carrier types: (i) ATP (and also, less ubiquitously, GTP and creatine phosphate) which carries energy in the form of ‘high energy’ phosphate groups and (ii) NADH, NADPH, and FADH2, which carry energy in the form of an electron (actually, as discussed above, a hydrogen atom with an extra electron – a hydride ion: H−). The energy status of the cell may be quantified with either of these systems – hence, (i) the ‘energy charge’ (phosphorylation potential) of the cell is an index of the degree of ATP phosphorylation (the amount of AMP that is phosphorylated to ADP and ATP: = [ATP] + [½ADP] ÷ [ATP] + [ADP] + [AMP]), and (ii) the ‘redox potential’ of the cell denotes the degree of reduction of NAD+ (i.e. the NADH:NAD+ ratio) and NADP+ (NADPH:NADP+). Besides carrying energy ‘down’ (catabolism) or ‘up’ (anabolism) metabolic pathways (Figure 1.12), the energy charge/phosphorylation potential and redox potential are major regulators of metabolic pathways to ensure appropriate energy provision.
1.3.1.2 Energy substrates
By utilising three, chemically diverse, fuel groups, overall metabolic flexibility and hence efficiency are achieved. Energy derived from these compounds is all based on a reduced carbon atom i.e. the C–H bond. Hence, the more C–H bonds, the more reduced the molecule and the more energy it contains, whereas oxidised or partially oxidised carbon (C–O) lacks biochemically usable energy (see Section 1.2.1.3). However, generally speaking, the more reduced the substrate, the less water soluble it is likely to be. This may be an advantage or a disadvantage, depending on the role of the substrate.
Carbohydrates are partially oxidised and hence do not contain as much energy (17 kJ g−1) as the highly reduced (–CH rich) lipids. However, carbohydrates are soluble, hence quickly mobilised and utilised, and are relatively non-toxic. Furthermore, some energy can be derived from them anaerobically during hypoxia or ischaemia. However, their water solubility means that in storage form (glycogen) they retain significant water of hydration (about three times their own weight), lowering their energy density and efficiency as energy stores (see Figure 1.10): only very limited amounts are stored (hepatic glycogen ∼ 100g only), but since they can be converted to many other substances, including lipids and intermediates of the tricarboxylic acid (TCA) cycle (also known as the Krebs cycle – see Section 1.3.1.4), they are therefore metabolically ‘flexible’ – carbohydrates are able to supply intermediary metabolites to maintain pathway integrity (anaplerosis, again from the Greek ανα (ana), up, πληρω (plero), to fill) in contrast to lipids, oxidation of which leads to depletion of intermediary metabolites (cataplerosis): hence some carbohydrate is always required for metabolism to proceed efficiently, as captured in the old aphorism ‘fat burns in the fire of carbohydrate.’ This is discussed later (Box 5.3).
Fats are the most energy-dense metabolic fuels (∼37 kJ g−1): lipids are highly reduced (energetic), water-insoluble, and very energy-dense, hence their function as the principal energy store for free-living animals, and are major energy providers to most (oxidative) tissues. However, their water-insolubility makes lipids problematic and slow to mobilise, and unlike carbohydrates they cannot yield energy anaerobically – they must be oxidised, therefore cannot be used by red blood cells (erythrocytes) and renal medulla. Because they are more reduced, relatively more oxygen is required to extract energy from lipids (2.8 ATP/O2) compared to carbohydrates (3.7 ATP/O2) and this may be critical in high work-load oxygen-challenged tissues such as myocardium (and exercising skeletal muscle). The storage form of lipids for energy provision is triacylglycerol, which comprises three fatty acids esterified to a glycerol backbone. Being highly hydrophobic and reduced, triacylglycerols are very energy dense and a highly efficient energy store. However, triacylglycerols are relatively slow to mobilise, must be oxidised to yield energy and cannot provide energy anaerobically, and the NEFAs from which they are assembled are amphipathic (detergent- like) and hence potentially toxic in high concentrations, disrupting structural lipids especially in the central nervous system: they cannot cross the blood-brain barrier so also cannot be used by the central nervous system (more detail in Section 5.6). Furthermore, fatty acids cannot be converted into carbohydrates or proteins, limiting their metabolic flexibility.
Proteins (polymers of amino acids) have similar energy content to carbohydrates (∼17 kJ g−1), but each protein has a specific biological function and they are not used as dedicated energy stores. Amino acids (proteins) have similar energy yields to carbohydrates i.e. they are partially oxidised to about the same extent as carbohydrates, and overall have comparable solubility; since most can be converted into glucose (‘glucogenic’), they have similar metabolic flexibility to carbohydrates. In catabolic states of carbohydrate depletion (e.g. starvation), however, proteins are broken down to their constituent amino acids for conversion into glucose to supply glucose-dependent tissues such as brain and erythrocytes for energy, and also to provide general tissue anaplerosis – hence proteins constitute a ‘virtual’ carbohydrate store in catabolic states of carbohydrate exhaustion.
1.3.1.3 Metabolic strategy
Whole body metabolic strategy comprises breaking down large macronutrient storage molecules (triacylglycerols, glycogen, protein – by lipolysis, glycogenolysis, and proteolysis respectively) into smaller energy-rich substrate molecules (NEFAs, glucose, amino acids) with distinct characteristics and roles. In the next stage of metabolism these small substrates are converted into a common fuel, acetyl-CoA (by β-oxidation, glycolysis and amino acid metabolism respectively). In the final stage of metabolism the acetyl-CoA is fully oxidised by the TCA cycle into carbon dioxide within the mitochondria. The step-wise release of energy from these pathways is carried as a hydride (H−) ion by NAD+ and FAD as their reduced forms, NADH and FADH2: these redox carriers are then reoxidised by the electron transport chain, the energy derived being used to phosphorylate ADP to ATP (oxidative phosphorylation). By contrast, in anabolism these pathways are reversed, chemical energy being used to synthesise complex energy-rich storage macromolecules from simple precursor substrates (Figure 1.12).
Three key features of metabolism impact metabolic strategy and energy provision:
Most energy stored in the body is in the form of lipid (triacylglycerols);
This lipid cannot be converted to carbohydrate; and
All tissues require some glucose for normal metabolic functioning, and some tissues (glycolytic, lacking mitochondria such as erythrocytes) have an absolute requirement for glucose or cannot utilise NEFAs (brain).
Since very little carbohydrate is stored (∼100 g hepatic glycogen; <1 day if it was the sole fuel), in catabolic states glucose is rapidly depleted and alternative mechanisms are required to provide or replace glucose: under these conditions breakdown of protein to amino acids, and then conversion of these to glucose by gluconeogenesis, becomes an essential pathway. Indeed, the ability of the body to divert protein from its primary (e.g. contractile) function to a secondary function of glucose provision has been the adaptation that has allowed such limited stores of the energy density- inefficient glycogen to be permitted. Another mechanism is ketogenesis, whereby the liver converts triacylglycerol-derived NEFAs into small, soluble (non-amphipathic) ketone bodies, which can be utilised by many tissues, including brain, hence acting as a ‘glucose-sparing’ substrate.
During conditions of energy repletion, energy in excess of current requirements is stored in a tissue-specific manner (lipid as triacylglycerols principally in adipose tissue; carbohydrate as glycogen in most tissues but specifically in liver for glucose release to maintain blood glucose concentration; amino acids ‘virtually’ in labile, expendable proteins, e.g. skeletal muscle contractile protein). In subsequent periods of limited energy ingestion (postabsorptive,