Glyoxylate Cycle

The glyoxylate cycle is an anabolic pathway that is considered a variation of the tricarboxylic acid (TCA) cycle. The TCA cycle occurs in plants, bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, and fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, and acetyl-CoA is converted into succinate. The glyoxylate cycle was thought not to occur in animals due to the absence of the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes isocitrate lyase and malate synthase; however, this hypothesis is being explored. The glyoxylate cycle occurs in glyoxysomes, which are specialized peroxisomes. There are no decarboxylation reactions in the glyoxylate cycle. The glyoxylate cycle allows cells to utilize 2 carbon units of acetate, and convert them into 4 carbon units, succinate, for energy production and biosynthesis. Additionally, each turn of the cycle produces a molecule of FADH2 and NADH.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Function

Vertebrates

  • 2 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that are required for the glyoxylate cycle are not found in vertebrates:
    • Isocitrate lyase
    • Malate synthase
  • Glyoxylate cycle may occur in some complex vertebrates by the participation of similar enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
  • However, the subject is experimental and under investigation.

Plants

  • Seeds cannot carry out photosynthesis as they lack chloroplasts.
  • However, seeds have specific peroxisomes known as glyoxysomes, where the glyoxylate cycle can occur.
  • Glyoxylate cycle occurs in seeds during germination so that:
    • Lipids stored in seeds can be used as an energy source for the formation of carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates for the growth and development of the shoot.
    • Acetate is converted to acetyl-CoA, which in turn is:
      • Utilized as a source of carbon and energy
      • Used to produce NADPH, which drives ATP synthesis in the electron transport chain Electron transport chain The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC)

Fungi

  • Glyoxylate cycle in fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview occurs primarily in infectious species.
  • Isocitrate lyase and malate synthase levels increase upon contact with a human host.
  • Glyoxylate cycle plays a major role in the pathogenesis of microbes:
    • Enzymes participating in the glyoxylate cycle increase during a pathogenic phase.
    • Fungi lacking the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are less virulent.
  • The mechanism of pathogenesis of this cycle in fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview is under investigation.
  • Examples:
    • Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis albicans
    • Saccharomyces cerevisiae
    • Cryptococcus Cryptococcus Cryptococcosis is an opportunistic, fungal infection caused by the Cryptococcus species. The principal pathogens in humans are C. neoformans (primary) and C. gattii. Cryptococcus neoformans is typically found in pigeon droppings and acquired by inhaling dust from contaminated soil. The majority of affected patients are immunocompromised. Cryptococcus/Cryptococcosis neoformans

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Reactions, Yield, and Energy Balance

Plants, fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, and bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview require carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates for energy and cell wall synthesis (e.g., cellulose, chitin, and glycans). The glyoxylate cycle enables organisms to produce carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates using acetyl-CoA from the β-oxidation of fatty acids.

Reactions

  1. The pathway begins with 2 molecules of acetyl-CoA.
  2. Citrate synthase converts 1 of the acetyl-CoA molecules to citrate.
  3. Citrate is converted to isocitrate by the enzyme aconitase.
  4. Isocitrate is converted to glyoxylate and succinate.
  5. Succinate is converted to fumarate by succinate dehydrogenase.
  6. The next step involves the formation of 2 molecules of malate:
    • 1 molecule of malate is formed by the combination of acetyl-CoA and glyoxylate.
    • The 2nd molecule is formed by the conversion of fumarate to malate in the presence of fumarase.
  7. Malate dehydrogenase converts 2 malate molecules into 2 oxaloacetate molecules.
  8. 1 molecule of oxaloacetate is converted to citrate, and 1 molecule of oxaloacetate is used for gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis.
The glyoxylate cycle

Figure representing the glyoxylate cycle

Image by Lecturio.

Key enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the glyoxylate cycle

The 2 key enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in the glyoxylate cycle produce 2 malate molecules, which in turn produce 2 oxaloacetate molecules. The spare oxaloacetate molecule is used in gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis for glucose production. The 2 key enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are:

  • Isocitrate lyase: converts isocitrate (containing 6 carbons) to succinate (containing 4 carbons) and glyoxylate
  • Malate synthase: combines acetyl CoA and glyoxylate to yield malate

Summary of the glyoxylate cycle

  • Input: 4 carbons in the form of 2 acetyl-CoA molecules
  • Output: Each turn of the cycle produces 1 NADH, 1 flavin adenine dinucleotide (FADH2), and 2 oxaloacetate molecules.
  • Does not release CO2
  • 2 oxidative reactions occur.
  • There is net synthesis of glucose (due to the formation of an extra oxaloacetate molecule).

Energy production

  • Each cycle produces 1 molecule of FADH2 and 1 molecule of NADH.
  • Subsequently, NADH produces 2.5 ATP and FADH2 produces 1.5 ATP to yield a total of 4 ATP.

Key Differences From the Tricarboxylic Acid (TCA) Cycle

The TCA cycle is the primary means of generating energy in the body.

  • Both TCA and glyoxylate cycles use acetyl-CoA as starting products. The outputs of these cycles differ:
    • In the TCA cycle, 1 NAD+ molecule is reduced to yield CO2.
    • Succinate is produced in the glyoxylate cycle and is used for carbohydrate synthesis.
  • The cycles occur in different organisms:
    • Glyoxylate cycle predominantly occurs in plants and fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview. There is emerging evidence that vertebrates have the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes necessary for the glyoxylate cycle to occur.
    • TCA cycle occurs in animals.
  • TCA and glyoxylate cycles have 5 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in common. There are some important differences between the steps, which result in different outcomes:
    • Isocitrate lyase in the glyoxylate cycle converts isocitrate into glyoxylate and succinate.
    • Molecules undergo decarboxylation in the TCA cycle. The glyoxylate cycle does not involve any decarboxylation reactions; thus, products from the cycle can be used for carbohydrate synthesis.
  • More energy is produced in the TCA cycle than in the glyoxylate cycle.
Table: Key differences between the glyoxylate cycle and tricarboxylic acid cycle
Glyoxylate cycle Tricarboxylic acid cycle
Site Glyoxysomes of plants, fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, and possibly vertebrates Mitochondria of animals
Number of carbons Input of 4 carbons Input of 2 carbons
CO2 molecules released None 2
Number of oxidative reactions 2 4
Energy produced per cycle
  • 1 NADH
  • 1 FADH2
  • 3 NADH
  • 1 FADH2
  • 1 GTP
Net glucose synthesis Net synthesis of glucose due to the formation of 1 extra oxaloacetate molecule No net synthesis of glucose
FADH2: flavin adenine dinucleotide
GTP: guanosine triphosphate

Clinical Relevance

Glyoxylate cycle genes have been identified in 2 organisms capable of surviving in macrophages: the bacterium M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis and the fungus C. albicans. Enzymes required for the glyoxylate cycle to progress are not present in humans, and are, therefore, ideal targets for novel antibiotics.

  • C. albicans: an opportunistic pathogen that causes candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis in humans. The glyoxylate cycle enables C. albicans to survive in nutrient-deprived environments; hence, the enzyme isocitrate lyase has been targeted to achieve antifungal effects. Three compounds (caffeic acid, rosmarinic acid, and apigenin) were found to have antifungal activity against C. albicans when tested under glucose-depleted conditions.
  • M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis: an acid-fast, facultative intracellular bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus that causes the respiratory infection known as TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis. The glyoxylate cycle in mycobacteria is being studied to develop potential treatments for TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis.

References

  1. Berg, J.M., Tymoczko, J.L., Stryer, L. (2002). The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate. https://www.ncbi.nlm.nih.gov/books/NBK22383/
  2. Ahern, K., Rajagopal, I., Tan, T. (Eds.) (2019). Citric Acid Cycle & Related Pathways. In Ahern, K., et al. (Ed.) Biochemistry Free For All. Libre Texts. https://bio.libretexts.org/Bookshelves/Biochemistry/Book%3A_Biochemistry_Free_For_All_(Ahern_Rajagopal_and_Tan)/06%3A_Metabolism/6.02%3A_Citric_Acid_Cycle__Related_Pathways
  3. Bruce, D. (2001). Glyoxylate Cycle as Drug Target? Genome Biol 2, spotlight-20010710-01. https://link.springer.com/article/10.1186/gb-spotlight-20010710-01
  4. Cheah, H.L., Vuanghao, L., Sandai, D. (2014). Inhibitors of the Glyoxylate Cycle Enzyme ICL1 in Candida albicans for Potential Use as Antifungal Agents. https://www.researchgate.net/publication/261997138

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