Reverse Krebs cycle

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The Reductive/Reverse TCA Cycle (rTCA cycle). Shown are all of the reactants, intermediates and products for this cycle. Reductive TCA cycle.png
The Reductive/Reverse TCA Cycle (rTCA cycle). Shown are all of the reactants, intermediates and products for this cycle.

The reverse Krebs cycle (also known as the reverse tricarboxylic acid cycle, the reverse TCA cycle, or the reverse citric acid cycle, or the reductive tricarboxylic acid cycle, or the reductive TCA cycle) is a sequence of chemical reactions that are used by some bacteria and archaea [1] to produce carbon compounds from carbon dioxide and water by the use of energy-rich reducing agents as electron donors.

Contents

The reaction is the citric acid cycle run in reverse. Where the Krebs cycle takes carbohydrates and oxidizes them to CO2 and water, the reverse cycle takes CO2 and H2O to make carbon compounds. This process is used by some bacteria (such as Aquificota) to synthesize carbon compounds, sometimes using hydrogen, sulfide, or thiosulfate as electron donors. [2] [3] This process can be seen as an alternative to the fixation of inorganic carbon in the Calvin cycle which occurs in a wide variety of microbes and higher organisms.

Differences from Krebs cycle

In contrast to the oxidative citric acid cycle, the reverse or reductive cycle has a few key differences. There are three enzymes specific to the reductive citric acid cycle – citrate lyase, fumarate reductase, and α-ketoglutarate synthase.[ citation needed ]

The splitting of citric acid to oxaloacetate and acetate is in catalyzed by citrate lyase, rather than the reverse reaction of citrate synthase. [4] Succinate dehydrogenase is replaced by fumarate reductase and α-ketoglutarate synthase replaces α-ketoglutarate dehydrogenase.[ citation needed ]

The conversion of succinate to 2-oxoglutarate is also different. In the oxidative reaction this step is coupled to the reduction of NADH. However, the oxidation of 2-oxoglutarate to succinate is so energetically favorable, that NADH lacks the reductive power to drive the reverse reaction. In the rTCA cycle, this reaction has to use a reduced low potential ferredoxin. [5]

Relevance to early life

The reaction is a possible candidate for prebiotic early-Earth conditions and, therefore, is of interest in the research of the origin of life. It has been found that some non-consecutive steps of the cycle can be catalyzed by minerals through photochemistry, [6] while entire two and three-step sequences can be promoted by metal ions such as iron (as reducing agents) under acidic conditions. In addition, these organisms that undergo photochemistry can and do utilize the citric acid cycle. [2] However, the conditions are extremely harsh and require 1 M hydrochloric or 1 M sulfuric acid and strong heating at 80–140 °C. [7]

Along with these possibilities of the rTCA cycle contributing to early life and biomolecules, it is thought that the rTCA cycle could not have been completed without the use of enzymes. The kinetic and thermodynamic parameters of the reduction of highly oxidized species to push the rTCA cycle are seemingly unlikely without the necessary action of biological catalysts known as enzymes. The rate of some of the reactions in the rTCA cycle likely would have been too slow to contribute significantly to the formation of life on Earth without enzymes. Considering the thermodynamics of the rTCA cycle, the increase in Gibbs free energy going from product to reactant would make pyrophosphate an unlikely energy source for the conversion of pyruvate to oxaloacetate as the reaction is too endoergic. [8] However, it is suggested that a nonenzymatic precursor to the Krebs cycle, glyoxylate cycle, and reverse Krebs cycle might have originated, where oxidation and reduction reactions cooperated. The later use of carboxylation utilizing ATP could have given rise to parts of reverse Krebs cycle. [9]

It is suggested that the reverse Krebs cycle was incomplete, even in the last universal common ancestor. [10] [11] Many reactions of the reverse Krebs cycle, including thioesterification and hydrolysis, could have been catalyzed by iron-sulfide minerals at deep sea alkaline hydrothermal vent cavities. [12] More recently, aqueous microdroplets have been shown to promote reductive carboxylation reactions in the reverse Krebs cycle. [13]

Medical relevance

The reverse Krebs cycle is proposed to be a major role in the pathophysiology of melanoma. Melanoma tumors are known to alter normal metabolic pathways in order to utilize waste products. These metabolic adaptations help the tumor adapt to its metabolic needs. The most well known adaptation is the Warburg effect where tumors increase their uptake and utilization of glucose. Glutamine is one of the known substances to be utilized in the reverse Krebs cycle in order to produce acetyl-CoA. [14] This type of mitochondrial activity could provide a new way to identify and target cancer causing cells. [15]

Microbial use of the reverse Krebs cycle

Thiomicrospira denitrificans,Candidatus Arcobacter , and Chlorobaculum tepidum have been shown to utilize the rTCA cycle to turn CO2 into carbon compounds. The ability of these bacteria, among others, to use the rTCA cycle, supports the idea that they are derived from an ancestral proteobacterium, and that other organisms using this cycle are much more abundant than previously believed. [16]

See also

Related Research Articles

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The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle —is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, proteins, and alcohol. The chemical energy released is available in the form of ATP. The Krebs cycle is used by organisms that respire to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a "cycle", it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.

<span class="mw-page-title-main">Cellular respiration</span> Process to convert glucose to ATP in cells

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<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production.

<span class="mw-page-title-main">Green sulfur bacteria</span> Family of bacteria

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Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

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<span class="mw-page-title-main">Biological carbon fixation</span> Series of interconnected biochemical reactions

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<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

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<span class="mw-page-title-main">Glyoxylate cycle</span> Series of interconnected biochemical reactions

The glyoxylate cycle, a variation of the tricarboxylic acid cycle, is an anabolic pathway occurring in plants, bacteria, protists, and fungi. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of carbohydrates. In microorganisms, the glyoxylate cycle allows cells to use two carbons, such as acetate, to satisfy cellular carbon requirements when simple sugars such as glucose or fructose are not available. 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.

<span class="mw-page-title-main">Phosphoenolpyruvate carboxylase</span> Class of enzymes

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References

  1. ↑ Garritano AN, Song W, Thomas T (October 4, 2022). "Carbon fixation pathways across the bacterial and archaeal tree of life". PNAS Nexus. 1 (5) pgac226. doi: 10.1093/pnasnexus/pgac226 . PMC   9802188 . PMID   36712370.
  2. 1 2 Evans MC, Buchanan BB, Arnon DI (April 1966). "A new ferredoxin-dependent carbon reduction cycle in a photosynthetic bacterium". Proceedings of the National Academy of Sciences of the United States of America. 55 (4): 928–934. Bibcode:1966PNAS...55..928E. doi: 10.1073/pnas.55.4.928 . PMC   224252 . PMID   5219700.
  3. ↑ Buchanan BB, Arnon DI (1990). "A reverse KREBS cycle in photosynthesis: consensus at last". Photosynthesis Research. 24: 47–53. doi:10.1007/BF00032643. PMID   11540925. S2CID   2753977.
  4. ↑ Bar-Even A, Noor E, Milo R (March 2012). "A survey of carbon fixation pathways through a quantitative lens". Journal of Experimental Botany. 63 (6): 2325–2342. doi: 10.1093/jxb/err417 . PMID   22200662.
  5. ↑ Bar-Even A, Noor E, Milo R (March 2012). "A survey of carbon fixation pathways through a quantitative lens". Journal of Experimental Botany. 63 (6): 2325–2342. doi: 10.1093/jxb/err417 . PMID   22200662.
  6. ↑ Zhang XV, Martin ST (December 2006). "Driving parts of Krebs cycle in reverse through mineral photochemistry". Journal of the American Chemical Society. 128 (50): 16032–16033. doi:10.1021/ja066103k. PMID   17165745.
  7. ↑ Muchowska KB, Varma SJ, Chevallot-Beroux E, Lethuillier-Karl L, Li G, Moran J (November 2017). "Metals promote sequences of the reverse Krebs cycle". Nature Ecology & Evolution. 1 (11): 1716–1721. doi:10.1038/s41559-017-0311-7. PMC   5659384 . PMID   28970480.
  8. ↑ Ross DS (February 2007). "The viability of a nonenzymatic reductive citric acid cycle--kinetics and thermochemistry". Origins of Life and Evolution of the Biosphere. 37 (1): 61–65. Bibcode:2007OLEB...37...61R. doi:10.1007/s11084-006-9017-6. PMID   17136437. S2CID   2208326.
  9. ↑ Muchowska, Kamila B.; Varma, Sreejith J.; Moran, Joseph (1 May 2019). "Synthesis and breakdown of universal metabolic precursors promoted by iron". Nature. 569 (7754): 104–107. Bibcode:2019Natur.569..104M. doi:10.1038/s41586-019-1151-1. ISSN   1476-4687. PMC   6517266 . PMID   31043728.
  10. ↑ Harrison SA, Palmeira RN, Halpern A, Lane N (November 2022). "A biophysical basis for the emergence of the genetic code in protocells". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1863 (8): 148597. doi: 10.1016/j.bbabio.2022.148597 . PMID   35868450.
  11. ↑ Muchowska KB, Varma SJ, Moran J (August 2020). "Nonenzymatic Metabolic Reactions and Life's Origins" (PDF). Chemical Reviews. 120 (15): 7708–7744. doi:10.1021/acs.chemrev.0c00191. PMID   32687326. S2CID   220671580.
  12. ↑ Akbari A, Palsson BO (May 2023). "Metabolic homeostasis and growth in abiotic cells". Proceedings of the National Academy of Sciences of the United States of America. 120 (19): e2300687120. Bibcode:2023PNAS..12000687A. doi:10.1073/pnas.2300687120. PMC   10175716 . PMID   37126695.
  13. ↑ Ju, Yun; Zhang, Hong; Jiang, Yanxiao; Wang, Wenxin; Kan, Guangfeng; Yu, Kai; Wang, Xiaofei; Liu, Jilin; Jiang, Jie (2023-09-07). "Aqueous microdroplets promote C–C bond formation and sequences in the reverse tricarboxylic acid cycle". Nature Ecology & Evolution: 1–11. doi:10.1038/s41559-023-02193-8. ISSN   2397-334X. PMID   37679455. S2CID   261609019.
  14. ↑ Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW (May 2012). "Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells". Pigment Cell & Melanoma Research. 25 (3): 375–383. doi:10.1111/j.1755-148X.2012.00989.x. PMC   3329592 . PMID   22360810.
  15. ↑ Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, et al. (December 2011). "Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability". Proceedings of the National Academy of Sciences of the United States of America. 108 (49): 19611–19616. Bibcode:2011PNAS..10819611W. doi: 10.1073/pnas.1117773108 . PMC   3241793 . PMID   22106302.
  16. ↑ Hügler M, Wirsen CO, Fuchs G, Taylor CD, Sievert SM (May 2005). "Evidence for autotrophic CO2 fixation via the reductive tricarboxylic acid cycle by members of the epsilon subdivision of proteobacteria". Journal of Bacteriology. 187 (9): 3020–3027. doi:10.1128/JB.187.9.3020-3027.2005. PMC   1082812 . PMID   15838028.
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