Ketogenesis
Encyclopedia
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...
are produced as a result of fatty acid breakdown
Fatty acid metabolism
Fatty acids are an important source of energy and adenosine triphosphate for many cellular organisms. Excess fatty acids, glucose, and other nutrients can be stored efficiently as fat. Triglycerides yield more than twice as much energy for the same mass as do carbohydrates or proteins. All cell...
.
Production
Ketone bodies are produced mainly in the mitochondria of liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
cells. Its synthesis occurs in response to low glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
levels in the blood, and after exhaustion of cellular carbohydrate stores, such as glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
. The production of ketone bodies is then initiated to make available energy that is stored as fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s. Fatty acids are enzymatically broken down in β-oxidation
Beta oxidation
Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle....
to form acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
. Under normal conditions, acetyl-CoA is further oxidized and its energy transferred as electrons to NADH, FADH2, and GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
in the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
(TCA cycle). However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle or if activity in the TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA
HMG-CoA
HMG-CoA is an intermediate in the Mevalonate pathway. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase.HMG-CoA reductase converts it into mevalonic acid....
).
Besides its role in the synthesis of ketone bodies, HMG-CoA is also an intermediate in the synthesis of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
.
Types of ketone bodies
The three ketone bodies are:- Acetoacetate, which, if not oxidized to form usable energy, is the source of the two other ketone bodies below
- AcetoneAcetoneAcetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
, which is not used as an energy source, but is instead exhaled or excreted as waste - β-hydroxybutyrateBeta-hydroxybutyratebeta-Hydroxybutyric acid is a ketone body. It is a chiral compound having two enantiomers, D-3-hydroxybutyric acid and L-3-hydroxybutyric acid. Like the other ketone bodies , levels of beta-hydroxybutyrate are raised in ketosis...
, which is not, in the technical sense, a ketoneKetoneIn organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
according to IUPAC nomenclature.
Each of these compounds is synthesized from acetyl-CoA molecules.
Regulation
Ketogenesis may or may not occur, depending on levels of available carbohydrates in the cell or body. This is closely related to the paths of acetyl-CoA:- When the body has ample carbohydrates available as energy source, glucoseGlucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
is completely oxidized to CO2Carbon dioxideCarbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
; acetyl-CoA is formed as an intermediate in this process, first entering the citric acid cycleCitric acid cycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
followed by complete conversion of its chemical energy to ATPAdenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
in oxidative phosporylation. - When the body has excess carbohydrates available, some glucose is fully metabolized, and some of it is stored by using acetyl-CoA to create fatty acids. (CoA is also recycled here.)
- When the body has no free carbohydrates available, fat must be broken down into acetyl-CoA in order to get energy. Acetyl-CoA is not being recycled through the citric acid cycle because the citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesisGluconeogenesisGluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.
Pathology
Ketone bodies are created at moderate levels in everyone's bodies, such as during sleep and other times when no carbohydrates are available. However, when ketogenesis is happening at higher-than-normal levels, the body is said to be in a state of ketosisKetosis
Ketosis is a state of elevated levels of ketone bodies in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when the liver glycogen stores are depleted...
. It is unknown whether ketosis has negative long-term effects.
Both acetoacetate and beta-hydroxybutyrate are acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
ic, and, if levels of these ketone bodies are too high, the pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of the blood drops, resulting in ketoacidosis
Ketoacidosis
Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate....
. Ketoacidosis is known to occur in untreated Type I diabetes (see diabetic ketoacidosis
Diabetic ketoacidosis
Diabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...
) and in alcoholics after prolonged binge-drinking without intake of sufficient carbohydrates (see alcoholic ketoacidosis). Less commonly, some patients with poorly controlled Type 2 diabetes may have detectable levels of plasma ketones without significant acidosis.
External links
- Fat metabolism at University of South AustraliaUniversity of South AustraliaThe University of South Australia is a public university in the Australian state of South Australia. It was formed in 1991 with the merger of the South Australian Institute of Technology and Colleges of Advanced Education. It is the largest university in South Australia, with more than 36,000...
- James Baggott. (1998) Synthesis and Utilization of Ketone Bodies at University of UtahUniversity of UtahThe University of Utah, also known as the U or the U of U, is a public, coeducational research university in Salt Lake City, Utah, United States. The university was established in 1850 as the University of Deseret by the General Assembly of the provisional State of Deseret, making it Utah's oldest...
Retrieved 23 May 2005. - Richard A. Paselk. (2001) Fat Metabolism 2: Ketone Bodies at Humboldt State UniversityHumboldt State UniversityHumboldt State University is the northernmost campus of the California State University system, located in Arcata within Humboldt County, California, USA. The main campus, nestled at the edge of a coast redwood forest, is situated on Preston hill overlooking Arcata and with commanding views of...
Retrieved 23 May 2005.