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
A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...
that are used by some bacteria to produce carbon compounds from
carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...
and water by the use of
energy
In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of hea ...
-rich
reducing agent
In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ).
Examples of substances that are commonly reducing agents include the Earth me ...
s as electron donors.
The reaction is the
citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
run in reverse. Where the
Krebs cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
takes
carbohydrates and oxidizes them to CO
2 and water, the reverse cycle takes CO
2 and H
2O to make carbon compounds.
This process is used by some
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
(such as
Aquificota
The ''Aquificota'' phylum is a diverse collection of bacteria that live in harsh environmental settings. The name ''Aquificota'' was given to this phylum based on an early genus identified within this group, '' Aquifex'' (“water maker”), whic ...
) to synthesize carbon compounds, sometimes using
hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
,
sulfide, or
thiosulfate
Thiosulfate ( IUPAC-recommended spelling; sometimes thiosulphate in British English) is an oxyanion of sulfur with the chemical formula . Thiosulfate also refers to the compounds containing this anion, which are the salts of thiosulfuric acid, ...
as
electron donor
In chemistry, an electron donor is a chemical entity that donates electrons to another compound. It is a reducing agent that, by virtue of its donating electrons, is itself oxidized in the process.
Typical reducing agents undergo permanent chemi ...
s.
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.
The splitting of
citric acid
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in ...
to
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
and
acetate is in catalyzed by
citrate lyase, rather than the reverse reaction of
citrate synthase
The enzyme citrate synthase E.C. 2.3.3.1 (previously 4.1.3.7)] exists in nearly all living cells and stands as a pace-making enzyme in the first step of the citric acid cycle (or Krebs cycle). Citrate synthase is localized within eukaryotic cel ...
.
Succinate dehydrogenase is replaced by fumarate reductase and α-ketoglutarate synthase replaces α-ketoglutarate dehydrogenase.
The conversion of
succinate
Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...
to
2-oxoglutarate is also different. In the oxidative reaction this step is coupled to the reduction of
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
. 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.
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
In biology, abiogenesis (from a- 'not' + Greek bios 'life' + genesis 'origin') or the origin of life is the natural process by which life has arisen from non-living matter, such as simple organic compounds. The prevailing scientific hypothes ...
. It has been found that some non-consecutive steps of the cycle can be
catalyzed
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
by minerals through
photochemistry
Photochemistry is the branch of chemistry concerned with the chemical effects of light. Generally, this term is used to describe a chemical reaction caused by absorption of ultraviolet (wavelength from 100 to 400 nm), visible light (400– ...
, while entire two and three-step sequences can be promoted by
metal
A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typicall ...
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s such as
iron
Iron () is a chemical element with Symbol (chemistry), symbol Fe (from la, Wikt:ferrum, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 element, group 8 of the periodic table. It is, Abundanc ...
(as
reducing agent
In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ).
Examples of substances that are commonly reducing agents include the Earth me ...
s) under
acidic conditions. In addition, these organisms that undergo photochemistry can and do utilize the citric acid cycle.
However, the conditions are extremely harsh and require 1 M hydrochloric or 1 M sulfuric acid and strong heating at 80–140 °C.
Along with the these possibilities of the rTCA cycle contributing to early life and
biomolecules
A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or development. Biomolecules include lar ...
, 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
Thermodynamics is a branch of physics that deals with heat, work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quantities is governed by the four laws of th ...
of the rTCA cycle, the increase in
Gibb’s Free Energy going from product to reactant would make this cycle an unlikely feat without the help of enzymes.
Medical relevance
The reverse Krebs cycle is proposed to be a major role in the pathophysiology of
melanoma. Melanoma tumors are know 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 know adaptation is the
Warburg effect where tumors increase their uptake and utilization of glucose.
Glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
is one of the known substances to be utilized in the reverse Krebs cycle in order to produce acetyl CoA. This type of mitochondrial activity could provide us with a new way to identify and target cancer causing cells.
Microbial use of the reverse Krebs cycle
''
Thiomicrospira denitrificans'' and "''Candidatus''
Arcobacter" have been shown to utilize the rTCA (reverse Krebs cycle) cycle to turn CO
2 into a food source. The ability of these bacteria, among others, to use the rTCA cycle supports the idea that they are derived from an ancestral proteobacteria, and that other organisms using this cycle are much more abundant than previously believed.
See also
*
Carbon fixation
*
Calvin cycle
References
{{reflist
Citric acid cycle
Metabolic pathways
Origin of life