Human Metabolism, Energy, Nutrients    (2024)

Carbohydrates,lipids, and proteins are the major constituents of foods and serve as fuelmolecules for the human body. The digestion (breaking down into smaller pieces)of these nutrients in the alimentary tract and the subsequent absorption (entryinto the bloodstream) of the digestive end products make it possible fortissues and cells to transform the potential chemical energy of food intouseful work.

Themajor absorbed end products of food digestion are monosaccharides, mainlyglucose (from carbohydrates); monoacylglycerol and long-chain fatty acids (fromlipids); and small peptides and amino acids (from protein). Once in thebloodstream, different cells can metabolize these nutrients. We have long knownthat these three classes of molecules are fuelsources for human metabolism, yet it is a common misconception (especiallyamong undergraduates) that human cells use only glucose as a source of energy. Thismisinformation may arise from the way most textbooks explain energy metabolism,emphasizing glycolysis (the metabolic pathway for glucose degradation) andomitting fatty acid or amino acid oxidation. Here we discuss how the threenutrients (carbohydrates, proteins, and lipids) are metabolized in human cellsin a way that may help avoid this oversimplified view of the metabolism.

Duringthe eighteenth century, the initial studies, developed by Joseph Black, JosephPriestley, Carl Wilhelm Scheele, and Antoine Lavoisier, played a special rolein identifying two gases, oxygen and carbon dioxide, that are central to energymetabolism. Lavoisier, the French nobleman who owns the title of "father ofmodern chemistry," characterized the composition of the air we breathe andconducted the first experiments on energy conservation and transformation inthe organism.

Oneof Lavoisier's main questions at this time was: How does oxygen's role incombustion relate to the process of respiration in living organisms? Using acalorimeter to make quantitative measurements with guinea pigs and later onwith himself and his assistant, he demonstrated that respiration is a slow formof combustion (Figure 1). Based on the concept that oxygen burned the carbon infood, Lavoisier showed that the exhaled air contained carbon dioxide, which wasformed from the reaction between oxygen (present in the air) and organicmolecules inside the organism. Lavoisier also observed that heat is continuallyproduced by the body during respiration. It was then, in the middle of the nineteenthcentury, that Justus Liebig conducted animal studies and recognized thatproteins, carbohydrates, and fats were oxidized in the body. Finally,pioneering contributions to metabolism and nutrition came from the studies of aLiebig's protégé, Carl von Voit, and his talented student, Max Rubner. Voitdemonstrated that oxygen consumption is the result of cellular metabolism, while Rubner measured the major energy value of certain foods in orderto calculate the caloric values that are still used today. For example, carbohydrates and proteins produce approximately4 kcal/g of energy, whereas lipids can generate up to 9 kcal/g. Rubner'sobservations proved that, for a resting animal, heat production was equivalentto heat elimination, confirming that the law of conservation of energy, impliedin Lavoisier's early experiments, was applicable to living organisms as well. Therefore,what makes life possible is the transformation of the potential chemical energyof fuel molecules through a series of reactions within a cell, enabled byoxygen, into other forms of chemical energy, motion energy, kinetic energy, andthermal energy.

Energy metabolism is thegeneral process by which living cells acquire and use the energy needed to stayalive, to grow, and to reproduce. How is the energy released while breaking thechemical bonds of nutrient molecules captured for other uses by the cells? Theanswer lies in the coupling between the oxidation of nutrients and thesynthesis of high-energy compounds, particularly ATP, which works as the mainchemical energy carrier in all cells.

There are two mechanisms of ATP synthesis: 1. oxidativephosphorylation, the process by which ATP is synthesized from ADP and inorganicphosphate (Pi) that takes place in mitochondrion; and 2. substrate-levelphosphorylation, in which ATP is synthesized through the transfer of high-energy phosphorylgroups from high-energy compounds to ADP. The latter occurs in both themitochondrion, during the tricarboxylic acid (TCA) cycle, and in the cytoplasm,during glycolysis. In the next section, we focus on oxidativephosphorylation, the main mechanism of ATP synthesis in most of human cells. Laterwe comment on the metabolic pathways in which the three classes of nutrientmolecules are degraded

Themetabolic reactions are energy-transducing processes in which theoxidation-reduction reactions are vital for ATP synthesis. In these reactions,the electrons removed by the oxidation of fuel molecules are transferred to two major electron carrier coenzymes,nicotinamide adenine dinucleotide (NAD⁺) and flavin adeninedinucleotide (FAD), that are converted to their reduced forms, NADH and FADH₂.Oxidative phosphorylation depends on the electron transport from NADH or FADH₂to O₂, forming H₂O. The electrons are"transported" through anumber of protein complexes located in the inner mitochondrial membrane,which contains attached chemical groups (flavins, iron-sulfur groups, heme, andcooper ions) capable of accepting or donating one or more electrons (Figure 2).These protein complexes, known as the electron transfer system (ETS), allow distributionof the free energy between the reduced coenzymes and the O₂ and moreefficient energy conservation.

The electrons are transferredfrom NADH to O₂ through three protein complexes: NADH dehydrogenase,cytochrome reductase, and cytochrome oxidase. Electron transport between thecomplexes occurs through other mobile electron carriers, ubiquinone andcytochrome c. FAD is linked to the enzyme succinate dehydrogenase ofthe TCA cycle and another enzyme, acyl-CoA dehydrogenase of the fatty acidoxidation pathway. During the reactions catalyzed by these enzymes, FAD isreduced to FADH₂, whose electrons are then transferred to O₂through cytochrome reductase and cytochrome oxidase, as described for NADHdehydrogenase electrons (Figure 2).

The electron transfer throughthe components of ETS is associated with proton (H⁺) pumping fromthe mitochondrial matrix to intermembrane space of the mitochondria. Theseobservations led Peter Mitchell, in 1961, to propose his revolutionarychemiosmotic hypothesis. In this hypothesis, Mitchell proposed that H⁺pumping generates what he called the proton motive force, a combination of thepH gradient across the inner mitochondrial membrane and the transmembraneelectrical potential, which drives the ATP synthesis from ADP and Pi. ATP is synthesized by the ATP synthase complex, through which H+ protons return to the mitchondrial matrix (Figure 2, far right). Paul Boyer firstdescribed the ATP synthase catalytic mechanism and showed both that the energyinput from the H⁺ gradient was used for ATP release from the catalyticsite, and that the three active sites of the enzyme worked cooperatively in such a way that ATP fromone site could not be released unless ADP and Pi were available to bind toanother site.

Interconversionof energy between reduced coenzymes and O₂ directs ATPsynthesis, but how (and where) areNADH and FADH₂ reduced? In aerobic respiration or aerobiosis, allproducts of nutrients' degradation converge to a central pathway in themetabolism, the TCA cycle. In this pathway, the acetyl group of acetyl-CoAresulting from the catabolism of glucose, fatty acids, and some amino acids is completelyoxidized to CO₂ with concomitant reduction of electron transportingcoenzymes (NADH and FADH₂). Consisting of eight reactions, the cyclestarts with condensing acetyl-CoA and oxaloacetate to generate citrate (Figure 3). The next seven reactions regenerate oxaloacetate and include four oxidationreactions in which energy is conserved with the reduction of NAD⁺and FAD coenzymes to NADH and FADH₂, whose electrons will then betransferred to O₂ through the ETS. In addition, a GTP or an ATPmolecule is directly formed as an example of substrate-level phosphorylation.In this case, the hydrolysis of the thioester bond of succinyl-CoA withconcomitant enzyme phosphorylation is coupled to the transfer of anenzyme-bound phosphate group to GDP or ADP. Importantly, although O₂does not participate directly in this pathway, the TCA cycle only operates inaerobic conditions because the oxidized NAD⁺ and FAD are regeneratedonly in the ETS. Also noteworthy is that TCA cycle intermediates may also beused as the precursors of different biosynthetic processes.

TheTCA cycle is also known as the Krebs cycle, named after its discoverer, SirHans Kreb. Krebs based his conception of this cycle on four main observations madein the 1930s. The first was the discovery in 1935 of the sequence of reactionsfrom succinate to fumarate to malate to oxaloacetate by Albert Szent-Gyorgyi,who showed that these dicarboxylic acids present in animal tissues stimulate O₂consumption. The second was the finding of the sequence from citrate toα-ketoglutarate to succinate, in 1937, by Carl Martius and Franz Knoop. Nextwas the observation by Krebs himself, working on muscle slice cultures, thatthe addition of tricarboxylic acids even in very low concentrations promotedthe oxidation of a much higher amount of pyruvate, suggesting a catalyticeffect of these compounds. And the fourth was Krebs's observation thatmalonate, an inhibitor of succinate dehydrogenase, completely stopped theoxidation of pyruvate by the addition of tricarboxylic acids and that theaddition of oxaloacetate in the medium in this condition generated citrate,which accumulated, thus elegantly showing the cyclic nature of the pathway.