Human Metabolism. Keith N. Frayn

into a peptide chain. They comprise a central (‘α’) carbon, with characteristic chemical groups attached to its four valencies: an amino (NH₂) group, a carboxyl (COOH) group, a hydrogen atom, and finally a variable (‘R’) group which defines the actual amino acid species (for example, if R = a methyl group, CH₃, then the resulting amino acid is alanine), illustrated in Figure 1.11. At acid pH, the amino group is ionised (NH₃⁺) whilst at alkaline pH the carboxyl group is ionised (COO⁻); at physiological pH (7.4) the amino acid is present as a Zwitter ion (both amino and carboxyl groups ionised). Proteins are assembled by adjacent amino acids forming a peptide bond between the carboxyl group of one and the amino group of another. This always leaves a terminal amino group and a terminal carboxyl group on any protein, hence all proteins act as buffers, able to gain or lose a proton. The carbon ‘backbone’ of individual amino acids is relatively energy rich and can be oxidised to yield energy once the amino group has been removed.

Figure 1.11 Structure of an amino acid. At physiological pH (7.4) the carboxyl group is ionised to COO⁻ and the amino group to NH₃⁺. The nature of the ‘R’ group, or side-chain, defines the particular amino acid: the 20 different amino acids which constitute proteins each have a different R group.

      1.3 General overview of metabolism

      1.3.1 Human metabolic pathways

      The body requires energy for chemical and mechanical work in order to maintain homeostasis; functions include maintenance of ionic gradients, transport, biosynthesis, heat generation and muscle contraction. Metabolism describes the series of biochemical reactions which provide the body with the energy it requires to maintain these biological functions. This energy must ultimately be derived from food, and is sourced from three groups of energy-rich substrates: carbohydrates, lipids, and amino acids (proteins). Multiple groups are utilised because they all have chemical and thermodynamic advantages and disadvantages, and together they provide energy under widely varying conditions and demands. All three nutrient groups exist in large, energy-rich macromolecular storage forms, discussed further in Chapter 7; they are all related to daily fluxes of energy substrates in the body.

For energy mobilisation these are sequentially broken down into less energy-rich metabolites, the energy liberated being captured by intermediary reduction-oxidation molecules which carry the energy to a common pathway of oxidation linked to the phosphorylation of ADP to ATP. Hence, the energy is used to synthesise ATP, the common energy carrier to which most energy- requiring biological processes are linked. At a whole-body level this process is termed ‘catabolism’ (from the Greek: κατα (kato) – ‘down’ and βαλλω (ballo) – ‘throw’). Conversely, in energy-rich states when energy intake exceeds expenditure, these metabolic pathways can be reversed, whereby ingested nutrients from all three groups are assembled into large storage macromolecules (‘anabolism’; again, from the Greek: ανα [ana] – ‘up’). The process of assembling excess energy-rich substrate precursors into complex energy storage molecules is termed anabolism, whilst processes converting substrates into energy-poor end-products to mobilise biologically usable energy, are termed catabolism (Figure 1.12 and Box 1.4). Imbalance of these pathways leads to cachexia (wasting) or obesity, with implications for both energy provision and health. Tissues have specialised metabolic functions – e.g. adipose tissue stores energy, muscle oxidises substrate, lactating mammary gland exports substrate. The liver is a metabolic ‘transformer’ that regulates substrate supply between tissues, and pancreas is the principal afferent detector, and signaller, of nutritional status.

Figure 1.12 Catabolism and anabolism.

Box 1.4 Anabolism and catabolism

      The terms anabolism and catabolism are useful but can be confusing and have frequently been misused. They should be used to refer to whole-body energy strategy:

      Hence, in the postprandial state, after a meal, we are entering an anabolic state, whereas in the post-absorptive state, following absorption and disposition of the meal, we are entering a catabolic state. This is signalled by insulin.

      Classic physiological catabolic states include fasting/starvation (decreased energy intake) and exercise (increased energy expenditure). Diabetes mellitus is an example of a pathological catabolic state (failure of insulin signalling).

      If the terms are applied to individual metabolic pathways, or even individual steps, confusion can arise. For example glycolysis may be thought of as ‘catabolic’ in exercising muscle, breaking down glucose to provide energy for contraction (net energy mobilisation), but ‘anabolic’ in liver in the well-fed postprandial state, when absorbed glucose is converted to pyruvate, but the resulting acetyl-CoA undergoes lipogenesis to fat for energy storage. When analysing metabolism it is important to consider the whole body (anabolic? catabolic?) as well as individual tissues, as these all have specialised metabolic profiles and functions (see Chapter 5).

      The body is subject to many catabolic signals (e.g. ‘stress hormones,’ catecholamines, glucocorticoids, glucagon etc., but one major anabolic signal – insulin. Insulin inhibits catabolism, and therefore when it declines, unopposed catabolism results. This is one rea- son why insulin is such a crucial signal, and diabetes such an important disease.

      The rate of energy production is measured under basal conditions (no voluntary muscle contraction; thermoneutrality) – ‘basal metabolic rate’ (BMR), and is affected by many factors, including muscle contraction, food ingestion, size, gender, age, temperature, sepsis, and several hormones, including thyroid hormones and catecholamines. The metabolic rate can be estimated by measuring the oxygen consumption (VO₂; indirect calorimetry). For carbohydrate metabolism the rate of CO₂ production (VCO₂) equals VO₂ (C₆H₁₂O₆ + 6O₂ → 6CO₂ + 6H₂O) and the ratio VCO₂/VO₂, termed the respiratory quotient (RQ), is 6/6 = 1. For lipid oxidation, however, this is not true (e.g. tripalmitin: 2C₅₁H₉₈O₆ + 145O₂ → 102CO₂ + 98H₂O; RQ = 102/145 = 0.70) and measurement of RQ can provide useful information on substrate selection and utilisation. This will be discussed further in Chapter 11 (Box 11.2).