Carbohydrate Metabolism

Core Concepts:

This article explores carbohydrate metabolism. It begins with the classification of carbohydrates and then examines the key metabolic pathways involved – including cellular respiration, the pentose phosphate pathway, glycogenesis, glycogenolysis, gluconeogenesis, and fermentation – and discusses how they are interconnected.

Carbohydrate Review

Carbohydrates are one of the three primary types of food molecules that the body uses for energy. They are seen in various food sources, including grains, fruits, vegetables, legumes, dairy products, and desserts. On a molecular level, carbohydrates are composed of carbon, hydrogen and oxygen, which typically follow the ratio 1:2:1 of carbon to hydrogen to oxygen. This general formula can be presented as C_(n)H_(2n)O_(n).

Carbohydrates are classified as either monosaccharides, disaccharides, oligosaccharides, or polysaccharides depending on how many sugar molecules are present. Monosaccharides are the simplest forms of carbohydrates, containing a single sugar molecule (from “mono”, meaning one). Examples of monosaccharides include:

Glucose: C₆H₁₂O₆

Galactose: C₆H₁₂O₆

Fructose: C₆H₁₂O₆

Note: As can be observed above, these three molecules contain the same chemical formula but vary in the position of their functional groups and arrangement of atoms. Glucose and galactose are stereoisomers, meaning that their chemical structure consists of the same sequence of atoms but with different orientations in space. Glucose/galactose and fructose are structural isomers in that they have the same chemical formula but different structural arrangement – fructose has a ketone functional group instead of an aldehyde group.

Monosaccharides are the building blocks for more complex carbohydrates. Two monosaccharides combined together in a glycosidic bond form a disaccharide (“di” meaning two). The most common disaccharides include:

Lactose = Glucose + Galactose ; C₁₂H₂₂O₁₁

Sucrose = Glucose + Fructose ; C₁₂H₂₂O₁₁

Maltose = Glucose + Glucose ; C₁₂H₂₂O₁₁

Oligosaccharides are carbohydrates composed of a short chain of monosaccharides (usually between 2 and 10 units ; “oligo” meaning few, little). An example is raffinose – a complex sugar made of galactose, glucose, and fructose.

Polysaccharides are long-chain carbohydrate molecules that typically consist of greater than 10 monosaccharides (“poly” meaning many). Their structures can be very complex, and some can consist of hundreds or thousands of monosaccharides. Examples include cellulose, starch, and glycogen.

EX: Glycogen (stored glucose)

Carbohydrate metabolism refers to the way in which the body breaks down, synthesizes, and stores carbohydrates. It involves several different biochemical processes including:

• Cellular Respiration: A series of events that lead to the breakdown of glucose and produces energy in the form of adenosine triphosphate (ATP), the cell’s primary energy carrier. It consists of several key steps:
  • Glycolysis
  • The Citric Acid Cycle
  • The Electron Transport Chain

• The Pentose Phosphate Pathway: A metabolic pathway used to generate NAPD for reductive biosynthensis and ribose 5-phosphate for nucleotide synthesis

• Fermentation: A process used to produce energy in the absence of oxygen

• Glycogenesis: (From “Glyco” meaning sugar, “genesis” meaning development or production of) A process in which the body stores sugars in the form of glycogen.

• Glycogenolysis: (From the term “glycogen/o” meaning glycogen, “lysis” meaning breakdown of) A process in which the body breaks down stored glycogen into glucose.

• Gluconeogenesis: (From the term “gluco” referring to glucose, “neo” meaning new, and “genesis” meaning development or production of) A process in which new glucose molecules are synthesized from non-carbohydrate sources.

• Galactose Metabolism: The Leloir pathway leads to galactose breakdown

• Fructolysis: The process by which fructose is metabolized

Altogether, these metabolic processes work together to help the body maintain homeostasis, particularly in regards to blood sugar regulation.

A Glance into the Processes of Carbohydrate Metabolism

Carbohydrate metabolism is a complex network of interconnected biological pathways. Each of the processes mentioned above involves multiple steps and detailed metabolic reactions. The purpose of this article is to review and become familiar with the major pathways that make up carbohydrate metabolism, as well as to develop an understanding of how these pathways are interconnected.

If you are interested in exploring the intricacies of each pathway, click on the images at the bottom of each section to access in-depth discussions of these topics in other ChemTalk articles!

Cellular Respiration Part I: Glycolysis

When an individual consumes a meal containing carbohydrates, the carbohydrates are broken down into simple sugars during digestion. One of these sugars, glucose, serves as the body’s most readily available source of energy. Glucose is absorbed through the small intestine into the bloodstream and transported to the liver. In the liver, glucose can either be stored as glycogen for future energy needs or released back into the bloodstream, where it is taken up by cells and converted into energy. This latter process, known as cellular respiration, begins with glycolysis.

Glycolysis is the initial step in cellular respiration and is the only one that can occur under anaerobic conditions. It is a ten-step process that breaks down glucose into molecules of pyruvate, while producing energy in the form of ATP and NADH. Specifically, one molecule of glucose yields a net gain of two ATP molecules, two NADH molecules, and two pyruvate molecules. The molecules of ATP and NADH that are generated during this reaction are both considered high-energy carriers; ATP stories its energy in its phosphate bonds which is released through a hydrolysis reaction and NADH stores energy by acting as an electron carrier.Pyruvate, the final product of glycolysis, is used as the crucial link between glycolysis and the next step of cellular respiration. While glycolysis offers a rapid and efficient method of ATP production, it generates only a modest amount of ATP per glucose molecule and is not sustainable for long-term energy needs.

Every step of glycolysis occurs within the cytoplasm of the cell. Once the end products are produced, and if oxygen is present, they are moved to the mitochondria where the next step of cellular respiration occurs – the citric acid cycle.

Cellular Respiration Part II: The Citric Acid Cycle

The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle (named after its discoverer, Hans Krebs), is the second stage of cellular respiration. While glycolysis produces two important molecules—NADH and pyruvate—only the fate of pyruvate is directly addressed in the citric acid cycle. The role of NADH will be discussed later, as it becomes important in the final stage of cellular respiration. For now, let’s focus on what happens to pyruvate.

After its formation, pyruvate is transported into the mitochondrial matrix, where it is oxidized to acetyl-CoA by the pyruvate dehydrogenase complex. The resulting acetyl-CoA then enters the citric acid cycle.

The Citric Acid Cycle is so aptly named because the end product in this series of reactions is the exact one needed to initiate its process. It is an eight step process, beginning when Acetyl-CoA reacts with oxaloacetate and ends when oxaloacetate is formed as the final product. At this point, it is ready to react with another acetylene-CoA and the cycle can repeat again.

The citric acid cycle is an eight step process.

The citric acid cycle produces additional molecules of NADH and also introduces two other high-energy carriers: flavin adenine dinucleotide (FAD) and guanosine triphosphate (GTP). Like NADH, FADH₂ serves as an energy carrier by donating its electrons to the electron transport chain in the next step in cellular respiration. GTP, similarly to ATP, acts as an energy source by releasing energy when its phosphate bonds are hydrolyzed. GTP can be converted to ATP when one phosphate group from GTP is transferred to ADP using nucleoside-diphosphate kinase. Each turn of the cycle generates 3 NADH, 1 FADH₂, and 1 GTP—resulting in a total of 6 NADH, 2 FADH₂, and 2 GTP per glucose molecule (remember each glucose yields two pyruvate molecules, and thus two cycles ensue). 

These energy-yielding molecules—along with the NADH produced during glycolysis—enter the third and final stage of cellular respiration: the electron transport chain.

Cellular Respiration Part III: The Electron Transport Chain

The electron transport chain (ETC) is the final stage of cellular respiration and is  responsible for harvesting electrons to produce energy for the body. Like the citric acid cycle, the ETC operates only in aerobic conditions and occurs within the mitochondria. It is comprised of a series of protein complexes embedded in the inner mitochondrial membrane—a phospholipid bilayer folded into structures called cristae. The ETC uses the energy released from transporting electrons to create a proton-motive force (an electrochemical gradient formed by the movement of protons across the membrane). NADH and FADH₂, produced during earlier stages of respiration, donate electrons to the beginning of the chain. Ultimately, the ETC involves a series of redox (oxidation-reduction) reactions that culminate in the production of ATP. The ETC functions to create an electrochemical gradient by moving protons across the mitochondrial intermembrane space.

The electron transport chain is made up of four membrane-bound complexes:

• Complex I (NADH-CoQ oxidoreductase): Within this complex, NADH transfers 2 electrons to coenzyme Q. During this process, four protons are moved into the intermembrane space from the mitochondrial matrix and contribute to the electrochemical gradient.

• Complex II (Also known as Succinate dehydrogenase): During this step, complex II receives electrons from succinate (an intermediate in the citric acid cycle) to form CoQH2. CoQH2 is used as a substrate in Complex III. No protons are translocated across the mitochondrial membrane in this step.

• Complex III (also called cytochrome c reductase): Complex III involves the transfer of electrons from ubiquinol (CoQH2) to cytochrome c using two step process called the Q cycle. This complex moves four protons to the intermembrane space.

• Complex IV (Also known as cytochrome c oxidase): This complex involves the transfer of electrons from cytochrome c to oxygen, the final electron acceptor in aerobic cellular respiration. The free energy from the electron transfer causes four protons to move into the intermembrane space and contribute to the proton gradient.

Once a proton gradient has been established by these four complexes, the gradient is utilized to generate ATP in a process called oxidative phosphorylation. 

In oxidative phosphorylation, the electrochemical gradient of protons is now used to provide the potential energy to drive ATP synthase. ATP synthase is a large enzyme complex composed of two main parts – F0 domain which is embedded in the membrane and acts as a proton channel and F1 domain which is located in the mitochondrial matrix and contains the catalytic machinery for ATP synthesis. Protons flow through the F0 domain down their concentration gradient and drive the rotation of a protein complex within the F1 domain. This rotation converts ADP and an inorganic phosphate into ATP. The movement of ions across a selectively permeable membrane and down their electrochemical gradient is referred to as chemiosmosis.

The electron transport chain and oxidative phosphorylation are the most efficient way for cells to produce ATP. After entering the electron transport chain, each NADH yields 2.5 ATP, while each FADH2 yields 1.5 ATP. The net yield of ATP for one glucose molecule that undergoes oxidative phosphorylation is approximately 34 ATP. Coupled with the ATP produced from glycolysis and the citric acid cycle, cellular respiration can produce a total of 36-38 molecules of ATP. 

The Pentose Phosphate Pathway: An Alternate Route to Glycolysis

Although greatly utilized, glycolysis – along with the rest of cellular respiration – is not the only fate for glucose molecules. Other than contributing to the production of ATP, glucose can also enter into the pentose phosphate pathway. The pentose phosphate pathway is an alternate branch off of glycolysis and produces NADPH and precursors for nucleotide synthesis, in particular ribose 5-phosphate.

The phenotype phosphate pathway consists of an oxidative and a non-oxidative phase. The oxidate phase produces NADPH, a crucial reducing agent used in a variety of cellular processes such as biosynthesis and protection against oxidative stress. The non-oxidative phase uses ribulose-5-phosphate as a precursor to create ribose-5-phosphate – an important precursor to create the sugars that make up DNA and RNA. Ribulose-5-phosphate can also be converted, if needed, to other pentose phosphates like xylulose-5-phosphate. These pentose phosphates are rearranged by transketolase and transaldolase to generate intermediates for glycolysis.

Fermentation

Let’s revisit the beginning of the article, where we discussed glycolysis. We noted that the end product of glycolysis is pyruvate, which is converted into acetyl-CoA and enters the citric acid cycle when oxygen is present. But what happens to pyruvate when oxygen is absent?

Under anaerobic conditions, fermentation occurs. This can take the form of either lactate fermentation or alcohol fermentation.

In many cells, such as muscle cells, lactate fermentation takes place. In this process, pyruvate is converted to lactate by the enzyme lactate dehydrogenase. This reaction regenerates NAD+ from NADH, which is essential for maintaining glycolysis. By reducing the concentration of pyruvate and oxidizing NADH back to NAD+, lactate dehydrogenase prevents the accumulation of metabolites that would otherwise inhibit glycolysis. Situations that create oxygen-poor environments—such as intense skeletal muscle activity, heart attacks, or strokes—can trigger lactate fermentation.

Fermentation can also occur in yeast cells through a process known as alcohol fermentation. In this pathway, pyruvate (a three-carbon molecule) is converted into ethanol (a two-carbon molecule) and carbon dioxide (a one-carbon molecule). Like lactate fermentation, this process regenerates NAD+, allowing glycolysis to continue in the absence of oxygen.

Glycogenesis, Glycogenolysis, Gluconeogenesis – Oh my!

Glycogenesis, glycogenolysis, and gluconeogenesis are all metabolic processes that help regulate blood glucose levels. At first glance they may seem easy to mix up, but breaking each term down into its grammatical components can help clarify their meanings.

Glycogenesis comes from the prefix “glyco-,” referring to sugar or glycogen, and the suffix “–genesis,” meaning creation or production. Given these components, it is easy to interpret that glycogenesis is the formation of glycogen. Glycogen, the stored form of glucose, is a branched polymer composed of glucose units. Glycogenesis helps lower blood glucose levels by storing excess glucose as glycogen. This process is needed when blood glucose levels are too high, such as after eating a meal, and is stimulated by insulin – a hormone produced by the pancreas.

Glycogenolysis works in opposition to glycogenesis. Whereas glycogenesis works to lower blood sugar levels, glycogenolysis works to raise blood sugar levels. The word glycogenolysis can be broken down into the prefix “glycogen/o,“ referring to glycogen, and the suffix “-lysis,” meaning break down of. Glycogenolysis, therefore, is the breakdown of stored glycogen into glucose so it can be released back into the bloodstream. This would happen when blood sugar is too low, such as during a state of fasting, and is stimulated by glucagon – a hormone produced by the pancreas.

Last but not least, gluconeogenesis is a metabolic process that works essentially as the reverse of glycolysis. Gluconeogenesis can be broken down into the root word “gluco-“ meaning glucose, the prefix “neo,” meaning new, and the suffix “-genesis,” meaning the development or production of. It is the formation of glucose from non-carbohydrate containing sources and is utilized to help to raise blood sugar levels. Sources for gluconeogenesis include glycerol 3-phosphate (from stored fates, or triacylglycerols, in adipose tissue), lactate (from anaerobic glycolysis), and glucogenic amino acids (from muscle proteins).

The Breakdown of Additional Sugar Molecules: Galactose and Fructose Metabolism

Although glucose is the primary carbohydrate broken down by the body for energy, various other carbohydrates are also digested and absorbed to serve as fuel for cells.

Galactose is one of the components composing lactose, a disaccharide present in milk. Lactose is hydrolyzed to galactose and glucose by the enzyme lactase. Galactose metabolism primarily occurs using what is referred to as the Leloir pathway.

Fructose is a natural sugar commonly found in honey, fruit, and the disaccharide sucrose (common table sugar). It is broken down into a process called fructolysis, during which fructose is converted into fructose-1-phosphate and then cleaved into dihydroxyacetone phosphate and glyceraldehyde by the enzyme fructose-1-phosphate aldolase. Dihydroxyacetone phosphate can then be converted into glucose.

Key Metabolites and Reversible Reactions: The Links Connecting Carbohydrates’ Metabolic Pathways

Carbohydrate metabolism can be viewed as a web, with each silken strand representing a distinct metabolic pathway. These pathways are each unique and intricate, yet are also interconnected to form a larger, unified system. There are a couple of ways to begin unraveling this metabolic web and examining how the pathways intersect. This can be achieved by tracing the flow of key metabolites to observe how they move between pathways or by studying the reversible reactions that occur among the stepwise processes.

Metabolites that are common to several different pathways and therefore connect the system together include:

• Glucose has several different fates once it enters the bloodstream. It can be directed into glycogenesis or glycolysis
  • Glycogenesis – If the glucose molecule is to be stored, it is transported to the liver, where it is converted into glycogen. Later, glycogen can be broken back down into glucose via glycogenolysis when the body needs it.
  • Glycolysis – When the body requires energy, glucose is broken down to produce ATP. Although glycolysis generates only a small amount of ATP, it serves as the initial step in both cellular respiration and fermentation.

• Glucose-6-phosphate (G6P) is a central metabolite in carbohydrate metabolism that is formed by the phosphorylation of glucose during the first step of glycolysis. Once G6P is produced, it can follow several metabolic pathways:
  • Glycolysis – G6P can continue through glycolysis, ultimately being converted into pyruvate.
  • Glycogenesis – G6P can be converted into glucose-1-phosphate, which then enters glycogenesis to get stored as glycogen.
  • Pentose Phosphate pathway – G6P can enter the pentose phosphate pathway to produce NADPH and ribose 5 -phosphate.

• Pyruvate, the final product of glycolysis, is a key metabolite in several pathways of carbohydrate metabolism. Once formed, pyruvate can follow different fates depending on cellular conditions.
  • Fermentation – In the absence of oxygen, pyruvate can undergo fermentation. In animal muscle cells and certain bacteria, it is converted into lactate (lactic acid fermentation). In yeast cells, it is converted into ethanol and carbon dioxide (alcohol fermentation).
  • Cellular Respiration – In the presence of oxygen, pyruvate enters the mitochondria, where it is converted into acetyl-CoA and enters the citric acid cycle for further ATP production.
  • Gluconeogenesis – Pyruvate can be converted into oxaloacetate, an intermediate in gluconeogenesis, the pathway that synthesizes glucose from non-carbohydrate sources.

• Lactate, which is produced as a byproduct during glycolysis, can either become converted to pyruvate or glucose
  • Cellular Respiration – Lactate can be converted to pyruvate by the enzyme lactate dehydrogenase and enter the TCA cycle to generate ATP if oxygen is present.
  • Gluconeogenesis – Pyruvate is transported to the liver and kidneys where it is converted to glucose. When lactate is produced in the muscles and converted to glucose in the liver, this process is referred to as the Cori Cycle.

• Ribose-5-phosphate is a key product formed in the pentose phosphate pathway and can enter glycolysis.
  • Glycolysis – Ribose-5-phosphate can enter glycolysis through conversion into fructose-6-phosphate and glyceraldehyde-3-phosphate, which are intermediates of glycolysis.

• Fructose-6-phosphate is an intermediate in glycolysis but can also enter the pentose phosphate pathway
  • Pentose Phosphate Pathway- fructose-6-phosphate can be converted to glucose-6-phosphate and enter the pentose phosphate pathway to generate NADPH and ribose-5-phosphate.

• Glyceraldehyde-3-phosphate is formed during glycolysis, gluconeogenesis, and the pentose phosphate pathway.
  • Glycolysis – Glyceraldehyde-3-phosphate is a substrate formed during glycolysis.
  • Gluconeogenesis – This substrate can be converted back into glucose in the kidneys and liver.
  • Pentose Phosphate Pathway – This substrate can be converted to fructose-6-phosphate, an intermediate of the non-oxidative phase of the pentose phosphate pathway

It is essential that the pathways of carbohydrate metabolism maintain a degree of flexibility that allows it to meet the demands of the body in any particular moment and reach a level of homeostasis. This is obtained through reversible reactions, which allow metabolites to flow between the different pathways based on the immediate need of the cell. These pathways are regulated by cellular signals and the activity of enzymes which can catalyze a reaction in both directions or override the progression of a reaction. Examples of reversible reactions include:

• Interconversion of glucose-6-phosphate and glucose-1-phosphate to allow for either the continuation of glucose or gluconeogenesis.
• Steps 2, 4, 5, 7, 8, and 9 of glycolysis are reversible and allow the conversion of either glucose to pyruvate or pyruvate to glucose.
• Glycogen can be broken down in to glucose-1-phosphate to be used for energy and glucose can be converted into glucose-1-phosphate for glycogen storage.
• Conversion of fructose-6-phosphate to fructose-1,6-bisphosphate by phophofructokinase-1 in glycolysis is irreversible, but the reverse reaction can be bypassed by the enzyme fructose-1,6-bisphosphatase so that gluconeogenesis can occur.
• As mentioned earlier, pyruvate can be converted to lactate by lactate dehydrogenase and lactate an be converted back to pyruvate via the Cori Cycle.
• The non-oxidate phase of the pentose phosphate pathway is reversible by the actions of transaldolase and transketolase. allowing for the flexible production of metabolites that can be used for nucleotide synthesis or ATP production.

Conclusion

Carbohydrates are the most commonly utilized energy source in the body and serve as the primary source of energy for both the brain and muscles. It is estimated that 45-65% of the calories in an adult’s diet should come from carbohydrates. However, carbohydrate metabolism represents only one component of the broader metabolic system. Lipid metabolism – the breakdown of fats – and protein metabolism – the break down of proteins – are essential pathways for energy production and other physiological functions.

Carbohydrate metabolism can also vary between organisms. For example, plants synthesize carbohydrates from carbon dioxide and water through photosynthesis. They use glucose not only for energy production, but also as a building block for as structural components of the cell wall. Plants also store glucose as starch, which differs in source and structure from glycogen. Certain bacteria can also break down complex carbohydrates like cellulose – something humans are unable to do. Despite these differences, carbohydrate metabolism is essential to sustaining life.