Glyoxylate cycle

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Overview of the Glyoxylate Cycle

The glyoxylate cycle, a variation of the

succinate for the synthesis of carbohydrates.[1] In microorganisms, the glyoxylate cycle allows cells to use two carbons (C2 compounds), such as acetate, to satisfy cellular carbon requirements when simple sugars such as glucose or fructose are not available.[2] The cycle is generally assumed to be absent in animals, with the exception of nematodes at the early stages of embryogenesis. In recent years, however, the detection of malate synthase (MS) and isocitrate lyase (ICL), key enzymes involved in the glyoxylate cycle, in some animal tissue has raised questions regarding the evolutionary relationship of enzymes in bacteria and animals and suggests that animals encode alternative enzymes of the cycle that differ in function from known MS and ICL in non-metazoan species.[1][3]

Plants as well as some algae and bacteria can use acetate as the carbon source for the production of carbon compounds. Plants and bacteria employ a modification of the TCA cycle called the glyoxylate cycle to produce four carbon dicarboxylic acid from two carbon acetate units. The glyoxylate cycle bypasses the two oxidative decarboxylation reactions of the TCA cycle and directly converts isocitrate through isocitrate lyase and malate synthase into malate and succinate.

The glyoxylate cycle was discovered in 1957 at the University of Oxford by Sir Hans Kornberg and his mentor Hans Krebs, resulting in a Nature paper Synthesis of Cell Constituents from C2-Units by a Modified Tricarboxylic Acid Cycle.[4]

Similarities with TCA cycle

The glyoxylate cycle uses five of the eight enzymes associated with the

malate, catalyzed by malate synthase.[1]
Malate is also formed in parallel from succinate by the action of succinate dehydrogenase and fumarase.

Role in gluconeogenesis

oxidized to carbon dioxide. This pathway thus allows cells to obtain energy
from fat. To use acetate from fat for biosynthesis of carbohydrates, the glyoxylate cycle, whose initial reactions are identical to the TCA cycle, is used.

Cell-wall containing organisms, such as

seed germination
in plants), the glyoxylate cycle permits the synthesis of glucose from lipids via acetate generated in fatty acid β-oxidation.

The glyoxylate cycle bypasses the steps in the citric acid cycle where carbon is lost in the form of CO2. The two initial steps of the glyoxylate cycle are identical to those in the citric acid cycle: acetate → citrate → isocitrate. In the next step, catalyzed by the first glyoxylate cycle enzyme,

phosphoenolpyruvate, which is the product of phosphoenolpyruvate carboxykinase, the first enzyme in gluconeogenesis. The net result of the glyoxylate cycle is therefore the production of glucose from fatty acids. Succinate generated in the first step can enter into the citric acid cycle to eventually form oxaloacetate.[2]

Function in organisms

Plants

In plants the

glyoxylate cycle occurs in special peroxisomes which are called glyoxysomes. This cycle allows seeds to use lipids as a source of energy to form the shoot during germination
. The seed cannot produce biomass using photosynthesis because of lack of an organ to perform this function. The lipid stores of germinating seeds are used for the formation of the carbohydrates that fuel the growth and development of the organism.

The glyoxylate cycle can also provide plants with another aspect of metabolic diversity. This cycle allows plants to take in acetate both as a carbon source and as a source of energy. Acetate is converted to acetyl CoA (similar to the TCA cycle). This acetyl CoA can proceed through the glyoxylate cycle, and some succinate is released during the cycle. The four carbon succinate molecule can be transformed into a variety of carbohydrates through combinations of other metabolic processes; the plant can synthesize molecules using acetate as a source for carbon. The acetyl CoA can also react with glyoxylate to produce some NADPH from NADP+, which is used to drive energy synthesis in the form of ATP later in the electron transport chain.[5]

Pathogenic fungi

The glyoxylate cycle may serve an entirely different purpose in some species of pathogenic

virulent in studies with mice compared to the wild type. The exact link between these two observations is still being explored, but it can be concluded that the glyoxylate cycle is a significant factor in the pathogenesis of these microbes.[6][7]

Vertebrates

Vertebrates were once thought to be unable to perform this cycle because there was no evidence of its two key enzymes, isocitrate lyase and malate synthase. However, some research suggests that this pathway may exist in some, if not all, vertebrates. [8] [9] Specifically, some studies show evidence of components of the glyoxylate cycle existing in significant amounts in the liver tissue of chickens. Data such as these support the idea that the cycle could theoretically occur in even the most complex vertebrates.[10] Other experiments have also provided evidence that the cycle is present among certain insect and marine invertebrate species, as well as strong evidence of the cycle's presence in nematode species. However, other experiments refute this claim.[11] Some publications conflict on the presence of the cycle in mammals: for example, one paper has stated that the glyoxylate cycle is active in hibernating bears,[12] but this report was disputed in a later paper.[13] Evidence exists for malate synthase activity in humans due to a dual functional malate/B-methylmalate synthase of mitochondrial origin called CLYBL expressed in brown fat and kidney.[14] Vitamin D may regulate this pathway in vertebrates.[10][15]

Inhibition of the glyoxylate cycle

Due to the central role of the

glyoxylate cycle in the metabolism of pathogenic species including fungi and bacteria, enzymes of the glyoxylate cycle are current inhibition targets for the treatment of diseases. Most reported inhibitors of the glyoxylate cycle target the first enzyme of the cycle (ICL). Inhibitors were reported for Candida albicans for potential use as antifungal agents.[16] The mycobacterial glyoxylate cycle is also being targeted for potential treatments of tuberculosis.[17][18]

Engineering concepts

The prospect of engineering various

pseudogenic in mammals, meaning that the gene is not necessarily absent, rather, it is merely "turned off".[1]

In order to engineer the pathway into cells, the genes responsible for coding for the enzymes had to be isolated and sequenced, which was done using the bacteria E.coli, from which the AceA gene, responsible for encoding for

epithelial cells.[20]

Efforts to engineer the pathway into more complex animals, such as sheep, have not been effective. This illustrates that much more research needs to be done on the topic, and suggests it is possible that a high expression of the cycle in animals would not be tolerated by the chemistry of the cell. Incorporating the cycle into mammals will benefit from advances in nuclear transfer technology, which will enable engineers to examine and access the pathway for functional integration within the genome before its transfer to animals.[19]

There are possible benefits, however, to the cycle's absence in mammalian cells. The cycle is present in

glyoxylate cycle, which would kill the disease-causing microorganisms that depend on the cycle for their survival, yet would not harm humans where the cycle, and thus the enzymes that the antibiotic would target, are absent.[2]

See also

References

  1. ^
    PMID 17059607
    .
  2. ^
    PMID 12455685
    .
  3. S2CID 30856607
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  4. S2CID 40858130
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  5. ^ Berg JM, Tymoczko JL, Stryer L (2002). Biochemistry. New York: W. H. Freeman.
  6. S2CID 4330954
    .
  7. PMID 19684068
    .
  8. S2CID 30856607
    .
  9. S2CID 13181926
    .
  10. ^
    S2CID 39607621
    .
  11. ISBN 978-0-471-41090-4
    .
  12. PMID 2310778
    .
  13. PMID 10584301
    .
  14. PMID 24334609
    .
  15. PMID 2553083
    .
  16. PMID 24781056
    .
  17. PMID 28458043
    .
  18. PMID 25649791
    .
  19. ^
    PMID 10675896
    .
  20. S2CID 41676957
    .

External links
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