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.

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 to produce carbon compounds from carbon dioxide and water by the use of energy-rich reducing agents
as electron donors.

The reaction is the

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.[1][2] This process can be seen as an alternative to the fixation of inorganic carbon in the reductive pentose phosphate 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

α-ketoglutarate dehydrogenase.[citation needed
]

The conversion 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.[4]

Relevance to early life

The reaction is a possible candidate for

catalyzed by minerals through photochemistry,[5] 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.[1] However, the conditions are extremely harsh and require 1 M hydrochloric or 1 M sulfuric acid and strong heating at 80–140 °C.[6]

Along with these possibilities of the rTCA cycle contributing to early life and

endoergic.[7] 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.[8]

It is suggested that the reverse Krebs cycle was incomplete, even in the last universal common ancestor.[9][10] 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.[11] More recently, aqueous microdroplets have been shown to promote reductive carboxylation reactions in the reverse Krebs cycle.[12]

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.[13] This type of mitochondrial activity could provide a new way to identify and target cancer causing cells.[14]

Microbial use of the reverse Krebs cycle

proteobacterium, and that other organisms using this cycle are much more abundant than previously believed.[15]

See also

References

  1. ^
    PMID 5219700
    .
  2. S2CID 2753977
    .
  3. PMID 22200662
    .
  4. PMID 22200662
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  5. PMID 17165745
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  6. PMID 28970480
    .
  7. S2CID 2208326
    .
  8. PMID 31043728
    .
  9. PMID 35868450
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  10. S2CID 220671580
    .
  11. PMID 37126695
    .
  12. S2CID 261609019
    .
  13. PMID 22360810
    .
  14. PMID 22106302
    .
  15. PMID 15838028
    .
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