Energy Production: The Synthesis of ATP

In order to survive, organisms need to be able to acquire energy from the food sources that they consume and from stored sources within bodily tissues. Metabolism is the breakdown of these organic molecules in order to produce energy.

Dietary energy sources include carbohydrates, fats, and proteins, which four calories, nine calories, and four calories, respectively. At the molecular level, adenosine triphosphate (ATP) is the final compound that is broken down to release the energy required for the body’s executive functions. (4)

As a simplified process, when the highly energized molecule of ATP is hydrolyzed, its energy is released for immediate use, and the ATP molecule is cleaved into low energy molecules, adenosine diphosphate (ADP) and phosphate (Pi). Importantly, ATP molecules can be re-synthesized by ATP synthase proteins through phosphorylation reactions. The cellular concentration ratios of ATP to ADP and Pi can play a role in driving the ATP phosphorylation and hydrolysis reactions. (5)

The body has two overarching metabolic pathways that are used in order to produce ATP: anaerobic and aerobic metabolism. (7)

man running next to a body of water, outside
Dietary energy sources include carbohydrates, fats and proteins, which four calories, nine calories and four calories, respectively.

Anaerobic and Aerobic Metabolism

Anaerobic metabolism creates ATP (as well as CO2 and lactic acid) without the use of oxygen molecules, whereas aerobic metabolism produces ATP in the presence of oxygen. (9) Both the anaerobic and aerobic pathways require the breakdown of carbohydrates, fats and/or proteins, though they yield different amounts of ATP. While anaerobic metabolism is quicker and produces substrates that can also be used during aerobic metabolism, its ATP production is not as efficient as that of aerobic cellular respiration. (4)

As they progress through the metabolic pathways, carbohydrates are broken down into glucose, fats are broken down into fatty acids, and proteins are broken down into amino acids. In preferential order, glucose, fatty acids, and amino acids are then converted for use in subsequent energy-yielding mechanisms, though these processes occur simultaneously and are dependent on one another. The common product in the oxidation of glucose, fatty acids, and amino acids is the intermediate product, acetyl CoA. (4)

Carbohydrates

Carbohydrates are the primary and most readily available source of energy used in the creation of ATP.

Carbohydrates can take several different forms. Monosaccharides are composed of one molecule (e.g. glucose, fructose, galactose). Disaccharides are composed of two monosaccharides (e.g. sucrose, lactose, maltose). Oligosaccharides have three to nine monosaccharides (e.g. fructo-oligosaccharides, malto-oligosaccharides). Polysaccharides have greater than ten monosaccharides (e.g. starches: amylose, amylopectin, maltodextrins; non-starches/fibres: cellulose, pectins, hemicelluloses, gums, inulin).  (8)

In order to be used in the synthesis of ATP, and to enter the first steps of the metabolic pathways, poly-, oligo- and disaccharides need to be digested into monosaccharides by breaking the glycosidic bonds between glucose molecules. For some carbohydrates, this begins as soon as the carbohydrate enters the mouth, though most digestion occurs in the stomach and small intestine. Ultimately, the monosaccharides can then be absorbed into the liver. Fructose and galactose molecules can be converted to glucose for storage (in the form of glycogen for future breakdown via glycogenolysis) or used in the anaerobic pathway of glycolysis. (6) Upon absorption, free glucose is phosphorylated to glucose 6-phosphate so that it may then be converted to glycogen in the liver and muscle, or further altered to fructose 6-phosphate as a part of the glycolytic pathway in the cytosol of cells. (1)

Fats

Fats can be made available through their ingestion in the diet, from stores in adipose tissue, or through hepatic synthesis.

Most dietary fats come in the form of triglycerides and to a secondary degree, cholesterol. Triglycerides are made from the combination of glycerol and three fatty acid chains. Each fatty acid chain can be classified as a short-, medium-, long-, or very long-chain fatty acid (all of which can be further classified as saturated, monounsaturated or polyunsaturated fatty acids).

The metabolism of triglycerides starts in the intestine where they are broken into free fatty acids so that they may cross the intestinal membranes before being reformed into triglycerides. Along with cholesterol molecules, triglycerides are transported throughout the circulatory system to either arrive at the liver for lipolysis, or to fat cells for storage after they have been packaged into chylomicrons. The hydrophobic nature of fats prevents navigation through the aqueous environment of the blood and lymphatic system without the assistance of chylomicrons. (3)

Initially, triglycerides are hydrolyzed in the cellular cytoplasm into their three fatty acid and glycerol components. Fatty acids are then further metabolized in the mitochondria after they have been transported across the mitochondrial membrane using the compound, carnitine, via β-oxidation to produce two acetyl CoA molecules. (4) After the conversion of glycerol to pyruvic acid, both the pyruvic acid and acetyl CoA can enter the citric acid/Krebs cycle to produce ATP and other intermediates used in the electron transport chain to also produce ATP. (4)

In times of carbohydrate scarcity, the body can enter a state of ketosis where it begins to shift the proportion of energy derived primarily from carbohydrate metabolism towards greater reliance on the breakdown of fatty acids stored in adipocytes. These fatty acids can then be β-oxidized for use in the Krebs cycle for ATP synthesis. If this cycle becomes saturated with acetyl CoA molecules, the excess acetyl CoA can also be converted to ketone bodies in the liver, and be respectively oxidized to synthesize ATP. (3)

Proteins

Proteins can be made available for use in energy production through their ingestion in the diet, or through deamination reactions to form amino acids and other substrates of the metabolic pathways. This generally only occurs when glucose and fatty acid stores are low. There are approximately 20 amino acids that are used in the creation of the proteins in the body to execute major functions, nine of which are considered essential amino acids; they cannot be synthesized in the body. (4)

The digestion of dietary proteins starts in the stomach where they begin to be denatured by the acidic environment, as well as by the proteolytic enzyme, pepsin. Other proteolytic enzymes further digest proteins into free amino acids in the lumen and cellular membrane of the small intestine. The resultant amino acids, dipeptides, and tripeptides can be absorbed into the blood for transport to tissues throughout the body. (4)

In states of starvation or when amino acids are not needed in the building blocks of the various proteins in the body, amino acids can be degraded primarily in the liver. The process of deamination involves the removal of a nitrogen group from the amino acids. The resultant α-ketoacids can then be further metabolized to precursors of glucose or other oxidized intermediates involved in the Krebs cycle. (4) This includes pyruvate, acetyl CoA, acetoacetyl CoA, α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate.4 Of these, acetyl CoA and acetoacetyl CoA are ketogenic products as they can result in the creation of ketone bodies and fatty acids. In comparison, pyruvate, α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate are considered as glutagenic products as they can be ultimately altered to glucose. (4) These products can thus be used in the metabolic pathways of glycolysis, the Krebs cycle and the electron transport chain.

Glycolysis

Glycolysis is the energy system/metabolic pathway responsible for the metabolism of glucose molecules to form ATP and other metabolic products. As glucose enters the pathway, it ultimately produces ATP, pyruvate and other molecules that can be used in the citric acid/Krebs cycle and electron transport chain. The overarching glycolytic reaction can be summarized as follows (4):

Glucose + 2Pi + 2 ADP + 2 NAD+ → 2 pyruvate + 2 ATP + 2 NADH + 2H+ + 2H2O

Under anaerobic conditions, pyruvate can be reduced to lactate, which allows for the regeneration of NAD+ molecules, which are required for continued glycolytic production of ATP. Under aerobic conditions, NAD+ molecules can be regained by transferring electrons to oxygen molecules from NADH in the electron transport chain. (4)

Under aerobic conditions, the pyruvate molecules can undergo oxidative decarboxylation by the enzyme pyruvate dehydrogenase, after it has been transported into the mitochondria. This produces CO2, acetyl CoA (for use in the Krebs cycle) and NADH (for use in the electron transport chain). (4)

Krebs Cycle

Acetyl CoA is the main substrate derived from glucose, fatty acids, and amino acids that enters the Krebs cycle to produce ATP. In the presence of sufficient oxaloacetic acid and acetyl CoA, the Krebs cycle can proceed in the production of ATP, as well as in the generation of electron-donating compounds (NADH and FADH2) in the mitochondria. These electron donors ultimately produce high amounts of ATP in the electron transport chain. (4)

The Electron Transport Chain

The electron transport chain is the main metabolic pathway that is used to generate ATP in the presence of aerobic respiration. At its core, the electron transport chain involves the transfer of electrons to O2 molecules. This releases energy to create a proton gradient across the inner mitochondrial membrane. As protons flow across the membrane back into the mitochondrial matrix, mechanical energy is generated through the turbine-shaped ATP synthase to phosphorylate ADP with Pi to create ATP. (4)

The mitochondrial membrane contains a series of proteins that carry out the transfer of electrons from donors to acceptors by creating the proton gradient. These proteins are called NADH-Q oxidoreductase (complex I), Q-cytochrome c oxido-reductase (complex III), and cytochrome c oxidase (complex IV). Succinate-Q reductase (complex II) is another protein involved in the transfer of electrons from FADH2 from the Krebs cycle, but does not generate a proton gradient. (4)

The NADH electrons derived from glycolysis, pyruvate dehydrogenase and the Krebs cycle can first enter the electron transport chain with complex I. They are then transferred to complex III by ubiquinone. Ubiquinone can also transfer the electrons from FADH2 from complex II to complex III. Cytochrome c functions by transferring the electrons from complex III to complex IV. This fourth and final complex reduces O2 using the transferred electrons. The reaction involves the addition of H+ protons found within the mitochondrial matrix, ultimately forming H2O. As electrons are transferred from NADH and FADH2 throughout the chain, H+ protons are pumped out of the mitochondrial matrix through complex I, III and IV (leaving NAD+ and FAD to be recycled), building the electrochemical gradient on the exterior of the inner membrane. H+ protons then flow back into the mitochondrial matrix, catalyzing the phosphorylation of ADP to ATP. (4)

One Molecule of Glucose: What Does it Yield?

As glucose is the most readily available molecule used in the creation of ATP and is used in both anaerobic and aerobic respiration, it is interesting to note how much ATP one glucose molecule will yield.

As the glucose molecule proceeds through glycolysis, and its intermediates are then used in the Krebs cycle and electron transport chain, one molecule of glucose will generate 36 ATP under conditions of aerobic respiration. In comparison, an 18-carbon fatty acid (containing the same number of carbon units as three glucose molecules) will generate 30 ATP in β-oxidation and an additional 90 ATP (120 ATP total) when the nine acetyl-CoA are formed and enter the Krebs cycle and electron transport chain. (7) Amino acids have a much more complicated ATP yield since each of the twenty amino acid have different compositions and associated energy costs in their possible fates (i.e. gluconeogenesis, fatty acid synthesis, formation of pyruvate, acetyl-CoA, etc.). (2)

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  2. Bender, D. A. (2012). The metabolism of “surplus” amino acids. British Journal of Nutrition, 108, S113-S121.
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  5. Dalessandro, M., & Melandri, B. A. (2010). ATP hydrolysis in ATP synthases can be differently coupled to proton transport and modulated by ADP and phosphate: A structure based model of the mechanism. Biochimica Et Biophysica Acta (BBA) – Bioenergetics, 1797, 26.
  6. Insel, P., Ross, D., McMahon, K., & Bernstein, M. (2019). Carbohydrates: Simple Sugars and Complex Chains (D. McKay & E. Mohn, Eds.). In Discovering Nutrition (6th ed., pp. 102-133). Boston, MA: Jones & Bartlett Learning, LLC. Retrieved from http://samples.jblearning.com/9781284139464/9781284139563_CH04_Insel.pdf?_ga=2.100253342.1239697587.1550067407-1753141255.1550067407
  7. Goetzman, E. S. (2011). Animal Models of Human Disease. In Progress in Molecular Biology and Translational Science. Elsevier. Retrieved February 13, 2019, from https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/beta-oxidation.
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