![Reductive TCA cycle](https://upload.wikimedia.org/wikipedia/commons/b/b3/Reductive_TCA_cycle.png)
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 transpar ...
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 heat a ...
-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 meta ...
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 proteins ...
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
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
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 biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
(such as
Aquificota) 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, an ...
,
sulfide
Sulfide (British English also sulphide) is an inorganic anion of sulfur with the chemical formula S2− or a compound containing one or more S2− ions. Solutions of sulfide salts are corrosive. ''Sulfide'' also refers to chemical compounds lar ...
, 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 donors.
This process can be seen as an alternative to the fixation of inorganic carbon in the
reductive pentose phosphate cycle
The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...
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 t ...
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
An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...
is in catalyzed by
citrate lyase, rather than the reverse reaction of
citrate synthase.
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
Ferredoxins (from Latin ''ferrum'': iron + redox, often abbreviated "fd") are iron–sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co. and applied t ...
.
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 (400–7 ...
, 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 conven ...
s such as
iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
(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 meta ...
s) under
acid
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
ic 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, it is thought that the rTCA cycle could not have been completed without the use of enzymes. The
kinetic
Kinetic (Ancient Greek: κίνησις “kinesis”, movement or to move) may refer to:
* Kinetic theory of gases, Kinetic theory, describing a gas as particles in random motion
* Kinetic energy, the energy of an object that it possesses due to i ...
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
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
. 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 the ...
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, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
. 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
''Arcobacter'' is a genus
Genus ( plural genera ) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biol ...
" 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
Biological carbon fixation or сarbon assimilation is the process by which inorganic carbon (particularly in the form of carbon dioxide) is converted to organic compounds by living organisms. The compounds are then used to store energy and as ...
*
Calvin cycle
The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...
References
{{reflist
Citric acid cycle
Metabolic pathways
Origin of life