https://www.nature.

com/scitable/topicpage/nutrient-utilization-
in-humans-metabolism-pathways-14234029

Nutrient Utilization in Humans: Metabolism Pathways

By: Andrea T. Da Poian, Ph.D. (Instituto de Bioquimica Medica, Universidade Federal do Rio de
Janeiro), Tatiana El-Bacha, Ph.D. (Instituto de Bioquimica Medica, Universidade Federal do Rio de
Janeiro) & Mauricio R. M. P. Luz, Ph.D. (Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz) © 2010 Nature
Education
Citation: Da Poian, A. T., El-Bacha, T. & Luz, M. R.M.P. (2010) Nutrient Utilization in Hum ans: Metabolism
Pathw ays. Nature Education 3(9):11
Energy is trapped in the chemical bonds of nutrient molecules. How is it then made
usable for cellular functions and biosynthetic processes?
Aa Aa Aa
Where does the energy that makes life possible come from? Humans obtain energy from three classes of fuel
molecules: carbohydrates, lipids, and proteins. The potential chemical energy of these molecules is transformed into
other forms, such as thermal, kinetic, and other chemical forms.

Nutrients of Human Metabolism

Carbohydrates, lipids, and proteins are the major constituents of foods and serve as fuel molecules for the human
body. The digestion (breaking dow n into smaller pieces) of these nutrients in the alimentary tract and the subsequent
absorption (entry into the bloodstream) of the digestive end products make it possible for tissues and cells to
transform the potential chemical energy of food into useful work.

The major absorbed end products of food digestion are monosaccharides, mainly glucose (from carbohydrates);
monoacylglycerol and long-chain fatty acids (from lipids); and small peptides and amino acids (from protein). Once in
the bloodstream, different cells can metabolize these nutrients. We have long know n that these three classes of
molecules are fuel sources for human metabolism, yet it is a common misconception (especially among
undergraduates) that human cells use only glucose as a source of energy. This misinformation may arise from the
w ay most textbooks explain energy metabolism, emphasizing glycolysis (the metabolic pathw ay for glucose
degradation) and omitting fatty acid or amino acid oxidation. Here w e discuss how the three nutrients (carbohydrates,
proteins, and lipids) are metabolized in human cells in a w ay that may help avoid this oversimplified view of the
metabolism.

Historical Overview of Energy Metabolism

Figure 1

During the eighteenth century, the initial studies, developed by Joseph Black, Joseph Priestley, Carl Wilhelm
Scheele, and Antoine Lavoisier, played a special role in identifying tw o gases, oxygen and carbon dioxide, that are
central to energy metabolism. Lavoisier, the French nobleman w ho owns the title of "father of modern chemistr y,"
characterized the composition of the air w e breathe and conducted the first experiments on energy conservation
and transformation in the organism.
One of Lavoisier's main questions at this time w as: How does oxygen's role in combustion relate to the process
of respiration in living organisms? Using a calorimeter to make quantitative measurements w ith guinea pigs and later
on w ith himself and his assistant, he demonstrated that respiration is a slow f orm of combustion (Figure 1). Based on
the concept that oxygen burned the carbon in food, Lavoisier showed that the exhaled air contained carbon dioxide,
w hich was formed from the reaction betw een oxygen (present in the air) and organic molecules inside the organism.
Lavoisier also observed that heat is continually produced by the body during respiration. It w as then, in the middle of
the nineteenth century, that Justus Liebig conducted animal studies and recognized that proteins, carbohydrates, and
fats w ere oxidized in the body. Finally, pioneering contributions to metabolism and nutrition came from the studies of
a Liebig's protégé, Carl von Voit, and his talented student, Max Rubner. Voit demonstrated that oxygen consumption
is the result of cellular metabolism, w hile Rubner measured the major energy value of certain foods in order to
calculate the caloric values that are still used today. For example, carbohydrates and proteins produce approximately
4 kcal/g of energy, whereas lipids can generate up to 9 kcal/g. Rubner's observations proved that, for a resting
animal, heat production w as equivalent to heat elimination, confirming that the law of conservation of energy, implied
in Lavoisier's early experiments, was applicable to living organisms as w ell. Therefore, what makes life possible is the
transformation of the potential chemical energy of fuel molecules through a series of reactions within a cell, enabled
by oxygen, into other forms of chemical energy, motion energy, kinetic energy, and thermal ener gy.

Energy Conservation: Mechanisms of ATP Synthesis

Energy metabolism is the general process by which living cells acquire and use the energy needed to stay alive, to
grow , and to reproduce. How is the energy released w hile breaking the chemical bonds of nutrient molecules
captured for other uses by the cells? The answ er lies in the coupling betw een the oxidation of nutrients and the
synthesis of high-energy compounds, particularly ATP, w hich works as the main chemical energy carrier in all cells.
There are tw o mechanisms of ATP synthesis: 1. oxidative phosphorylation, the process by which ATP is synthesized
from ADP and inorganic phosphate (Pi) that takes place in mitochondrion; and 2. substrate-level phosphorylation, in
w hich ATP is synthesized through the transfer of high-energy phosphoryl groups from high-energy compounds to
ADP. The latter occurs in both the mitochondrion, during the tricarboxylic acid (TCA) cycle, and in the cytoplasm,
during glycolysis. In the next section, w e focus on oxidative phosphorylation, the main mechanism of ATP synthesis
in most of human cells. Later w e comment on the metabolic pathw ays in w hich the three classes of nutrient
molecules are degraded

Oxidative Phosphorylation: The Main Mechanism of ATP Synthesis in Most

Human Cells

Figure 2: The electron transport system (ETS) in the inner mitochondrial m embrane.
(A) Electron micrograph of a human cell section show ing three mitochondria. (B) Scheme of the protein complexes
that form the ETS, show ing the mitochondrial membranes in blue and red; NADH dehydrogenase in light green;
succinate dehydrogenase in dark green; the complex formed by acyl-CoA dehydrogenase, electron transfer
flavoprotein (ETFP), and ETFP-ubiquinone oxidoreductase in yellow and orange; ubiquinone in green labeled w ith a
Q; cytochrome c reductase in light blue; cytochrome c in dark blue labeled w ith cytC; cytochrome c oxidase in pink;
and the ATP synthase complex in lilac. The flux of electrons is represented by red arrows and e-, and the flux of
protons is represented by red arrows and H+.

© 2010 Nature Education All rights reserved.

Figure Detail
The metabolic reactions are energy-transducing processes in w hich the oxidation-reduction reactions are vital for
ATP synthesis. In these reactions, the electrons removed by the oxidation of fuel molecules are transferred to tw o
major electron carrier coenzymes, nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD),
that are converted to their reduced forms, NADH and FADH2. Oxidative phosphorylation depends on the electron
transport from NADH or FADH2 to O2, forming H2O. The electrons are "transported" through a number of protein
complexes located in the inner mitochondrial membrane, w hich contains attached chemical groups (flavins, iron-
sulfur groups, heme, and cooper ions) capable of accepting or donating one or more electrons (Figure 2). These
protein complexes, know n as the electron transfer system (ETS), allow distribution of the free energy between the
reduced coenzymes and the O2 and more efficient energy conservation.
The electrons are transferred from NADH to O2 through three protein complexes: NADH dehydrogenase, cytochrome
reductase, and cytochrome oxidase. Electron transport between the complexes occurs through other mobile electron
carriers, ubiquinone and cytochrome c. FAD is linked to the enzyme succinate dehydrogenase of the TCA cycle and
another enzyme, acyl-CoA dehydrogenase of the fatty acid oxidation pathway. During the reactions catalyzed by
these enzymes, FAD is reduced to FADH2, w hose electrons are then transferred to O2 through cytochrome reductase
and cytochrome oxidase, as described for NADH dehydrogenase electrons (Figure 2).
The electron transfer through the components of ETS is associated with proton (H+) pumping from the
mitochondrial matrix to intermembrane space of the mitochondria. These observations led Peter Mitchell, in 1961, to
propose his revolutionary chemiosmotic hypothesis. In this hypothesis, Mitchell proposed that H+ pumping generates
w hat he called the proton motive force, a combination of the pH gradient across the inner mitochondrial membrane
and the transmembrane electrical potential, w hich drives the ATP synthesis from ADP and Pi. ATP is synthesized by
the ATP synthase complex, through w hich H+ protons return to the mitchondrial matrix (Figure 2, far right). Paul
Boyer first described the ATP synthase catalytic mechanism and show ed both that the energy input from the
H+ gradient w as used for ATP release from the catalytic site, and that the three active sites of the enzyme w orked
cooperatively in such a w ay that ATP from one site could not be released unless ADP and Pi w ere available to bind to
another site.

Oxidation of Carbohydrates, Proteins, and Fats Converge on the Tricarboxylic

Acid Cycle

Figure 3: Reactions of tricarboxylic acid cycle

The reactions catalyzed by the dehydrogenases that result in NAD+ and FAD reduction are highlighted. The reaction
catalyzed by succinyl-CoA synthetase (in w hich GTP synthesis occurs) is an example of substrate-level
phosphorylation.
© 2010 Nature Education All rights reserved.
Figure Detail
Interconversion of energy between reduced coenzymes and O2 directs ATP synthesis, but how (and where) are
NADH and FADH2 reduced? In aerobic respiration or aerobiosis, all products of nutrients' degradation converge to a
central pathw ay in the metabolism, the TCA cycle. In this pathw ay, the acetyl group of acetyl-CoA resulting from the
catabolism of glucose, fatty acids, and some amino acids is completely oxidized to CO2 w ith concomitant reduction of
electron transporting coenzymes (NADH and FADH2). Consisting of eight reactions, the cycle starts with condensing
acetyl-CoA and oxaloacetate to generate citrate (Figure 3). The next seven reactions regenerate oxaloacetate and
include four oxidation reactions in w hich energy is conserved with the reduction of NAD+ and FAD coenzymes to
NADH and FADH2, w hose electrons will then be transferred to O2 through the ETS. In addition, a GTP or an
ATP molecule is directly formed as an example of substrate-level phosphorylation. In this case, the hydrolysis of the
thioester bond of succinyl-CoA with concomitant enzyme phosphorylation is coupled to the transfer of an enzyme-
bound phosphate group to GDP or ADP. Importantly, although O2does not participate directly in this pathw ay, the
TCA cycle only operates in aerobic conditions because the oxidized NAD+ and FAD are regenerated only in the ETS.
Also notew orthy is that TCA cycle intermediates may also be used as the precursors of different biosynthetic
processes.
The TCA cycle is also know n as the Krebs cycle, named after its discoverer, Sir Hans Kreb. Krebs based his
conception of this cycle on four main observations made in the 1930s. The first was the discovery in 1935 of the
sequence of reactions from succinate to fumarate to malate to oxaloacetate by Albert Szent-Gyorgyi, who showed
that these dicarboxylic acids present in animal tissues stimulate O2 consumption. The second w as the finding of the
sequence from citrate to α-ketoglutarate to succinate, in 1937, by Carl Martius and Franz Knoop. Next w as the
observation by Krebs himself, w orking on muscle slice cultures, that the addition of tricarboxylic acids even in very
low concentrations promoted the oxidation of a much higher amount of pyruvate, suggesting a catalytic effect of these
compounds. And the fourth w as Krebs's observation that malonate, an inhibitor of succinate dehydrogenase,
completely stopped the oxidation of pyruvate by the addition of tricarboxylic acids and that the addition of
oxaloacetate in the medium in this condition generated citrate, w hich accumulated, thus elegantly showing the cyclic
nature of the pathw ay.

Pathways for Nutrient Degradation that Converge onto the TCA Cycle
Glycolysis

Figure 4

Figure Detail

Glycolysis is the pathw ay in w hich one glucose molecule is degraded into tw o pyruvate molecules. Interestingly,
during the initial phase, energy is consumed because tw o ATP molecules are used up to activate glucose and
fructose-6-phosphate. Part of the energy derived from the breakdow n of the phosphoanhydride bond of ATP is
conserved in the formation of phosphate-ester bonds in glucose-6-phosphate and fructose-1,6-biphosphate (Figure
4).
In the second part of glycolysis, the majority of the free energy obtained from the oxidation of the aldehyde group of
glyceraldehyde 3-phosphate (G3P) is conserved in the acyl-phosphate group of 1,3- bisphosphoglycerate (1,3-BPG),
w hich contains high free energy. Then, part of the potential energy of 1,3BPG, released during its conversion to 3-
phosphoglycerate, is coupled to the phosphorylation of ADP to ATP. The second reaction w here ATP synthesis
occurs is the conversion of phosphoenolpyruvate (PEP) to pyruvate. PEP is a high-energy compound due to its
phosphate-ester bond, and therefore the conversion reaction of PEP to pyruvate is coupled w ith ADP
phosphorylation. This mechanism of ATP synthesis is called substrate-level phosphorylation.
For complete oxidation, pyruvate molecules generated in glycolysis are transported to the mitochondrial matrix to be
converted into acetyl-CoA in a reaction catalyzed by the multienzyme complex pyruvate dehydrogenase (Figure 5).
When Krebs proposed the TCA cycle in 1937, he thought that citrate w as synthesized from oxaloacetate and
pyruvate (or a derivative of it). Only after Lipmann's discovery of coenzyme A in 1945 and the subsequent work of R.
Stern, S. Ochoa, and F. Lynen did it become clear that the molecule acetyl-CoA donated its acetyl group to
oxaloacetate. Until this time, the TCA cycle w as seen as a pathway to carbohydrate oxidation only. Most high school
textbooks reflect this period of biochemistry knowledge and do not emphasize how the lipid and amino
acid degradation pathw ays converge on the TCA cycle.

The Fatty Acid Oxidation Pathway Intersects the TCA Cycle

Figure 5

Figure Detail
In 1904, Knoop, in a classic experiment, decisively show ed that fatty acid oxidation w as a process by w hich tw o -
carbon units w ere progressively removed from the carboxyl end fatty acid molecule. The process consists of four
reactions and generates acetyl-CoA and the acyl-CoA molecule shortened by tw o carbons, with the concomitant
reduction of FAD by enzyme acyl-CoA dehydrogenase and of NAD+ by β-hydroxyacyl-CoA dehydrogenase. This
pathw ay is known as β-oxidation because the β-carbon atom is oxidized prior to w hen the bond betw een carbons β
and α is cleaved (Figure 6). The four steps of β-oxidation are continuously repeated until the acyl-CoA is entirely
oxidized to acetyl-CoA, which then enters the TCA cycle. In the 1950s, a series of experiments verified that the
carbon atoms of fatty acids w ere the same ones that appeared in the acids of TCA cycle.

Amino Acid Transamination/Deamination Contributes to the TCA Cycle

Figure 6

Tw o points must be considered regarding the use of amino acids as fuels in energy metabolism. The first is the
presence of nitrogen in amino acid composition, w hich must be removed before amino acids become metabolically
useful. The other is that there are at least tw enty different amino acids, each of w hich requires a different degradation
pathw ay. For our purpose here, it is important to mention tw o kinds of reactions involving amino acid: transamination
and deamination. In the first kind of reaction, the enzymes aminotransferases convert amino acids to their respective
α-ketoacids by transferring the amino group of one amino acid to an α-ketoacid. This reaction allow s the amino acids
to be interconverted. The second kind of reaction, deamination, removes the amino group of the amino acid in the
form of ammonia. In the liver, the oxidative deamination of glutamate results in α-keto-glutarate (a TCA cycle
intermediate) and ammonia, w hich is converted into urea and excreted. Deamination reactions in other organs form
ammonia that is generally incorporated into glutamate to generate glutamine, w hich is the main transporter of amino
groups in blood. Hence, all amino acids through transamination/deamination reactions can be converted into
intermediates of TCA cycle, directly or via conversion to pyruvate or acetyl-CoA (Figure 5).

Summary
The transformation of the chemical energy of fuel molecules into useful energy is strictly regulated, and several
factors control the use of glucose, fatty acids, and amino acids by the different cells. For instance, not all cells have
the enzyme machinery and the proper cellular compartments to use all three fuel molecules. Red blood cells are
devoid of mitochondria and are therefore unable to oxidize neither fatty acids nor amino acids, relying only on glucose
for ATP synthesis. In addition, even in cells that can use all nutrients, the type of food substrate that is oxidized
changes according to the physiological situation of the cell, such as the fed and fasting states. Different signals
dictate how cells can adapt to each situation, such as hormones, w hich may exert powerful effects by switching key
enzyme activities in a matter of seconds, or how they may modulate gene expression profile, changing the w hole cell
metabolic profile. We must therefore understand all metabolic pathw ays as integrated events controlling energy
regulation and conversion

References and Recommended Reading

Blaxter, K. Energy Metabolism in Animals and Man. Cambridge: Cambridge University Press, 1989.

Holmes, F. L. Lavoisier and the Chemistry of Life. Madison: University of Wisconsin Press, 1985.
Krebs, H. Nobel Prize Lecture (1953). Nobelprize.org, 2010.
Kresge, N., Simoni, R. D., & Hill, R. L. ATP synthesis and the binding change mechanism: The w ork of Paul D.
Boyer. Journal of Biological Chemistry281, e18 (2006).
Lusk, G. The Elements of the Science of Nutrition, 4th ed. Philadelphia: W. B. Saunders, 1931.
Luz, M. R. M. P. Glucose as the sole metabolic fuel: A study on the possible influence of teachers' knowledge on the
establishment of a misconception among Brazilian high school stucents. Advances in Physiological Education 32,
225–230 (2008) doi:10.1152/advan.00050.2007.
Luz, M. R. M. P. et al. Glucose as the sole metabolic fuel: The possible influence of formal teaching on the
establishment of a misconception about the energy-yielding metabolism among Brazilian students. Biochemistry and
Molecular Biology Education 36, 407–416 (2008) doi:10.1002/bmb.20235.
Oliveira, G. A. et al. Students' misconception about energy yielding metabolism: Glucose as the sole metabolic
fuel. Advances in Physiological Education 27, 97–101 (2003 doi:10.1152/advan.00009.2003.