What is a metabolite
Metabolite
A metabolite is the intermediate end product of metabolism. The term "metabolite" is usually restricted to small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, catalytic activity of their own (usually as a cofactor to an enzyme), defense, and interactions with other organisms (e.g. pigments, odorants, and pheromones). A primary metabolite is directly involved in normal "growth", development, and reproduction. Ethylene is an example of a primary metabolite produced in large-scale by industrial microbiology. A secondary metabolite is not directly involved in those processes, but usually has an important ecological function. Examples include antibiotics and pigments such as resins and terpenes etc. Some antibiotics use primary metabolites as precursors, such as actinomycin which is created from the primary metabolite, tryptophan. Some sugars are metabolites, such as fructose or glucose, which are both present in the metabolic pathways.
Mometasone furoate
Extensive metabolic hepatic metabolism of mometasone furoate to multiple metabolites occurs. No principal metabolites are detectable in plasma. After "in vitro" incubation, one of the minor metabolites formed is furoate 6β-hydroxymometasone. In human hepatic microsomes, the formation of these metabolites is regulated by CYP3A4.
Ethion
In a parallel study in goats, radioactive labeled ethion with incorporated C was used. After identification of the C residues in organs of the goats like the liver, heart, kidneys, muscles and fat tissue, it appeared that 0.03 ppm or less of the C compounds present was non-metabolized ethion. The metabolites ethion monoxon and ethion dioxon were also not detected in any samples with a substantial threshold (0.005-0.01 ppm). 64 to 75% of the metabolites from the tissues were soluble in methanol. After addition of a protease, another 17 to 32% were solubilized. In the aqueous phase, at least four different radioactive metabolites were found. However, characterization of these compounds was repeatedly unsuccessful due to their high volatility. One compound was trapped from the kidney and was identified as formaldehyde. This is an indication that the C of ethion are used in the formation of natural products.
Secondary metabolism
Secondary metabolism (also called specialized metabolism) is a term for pathways and small molecule products of metabolism that are not absolutely required for the survival of the organism. Examples of the products include antibiotics and pigments. To distinguish non-secondary ("ordinary") metabolism, the term "basic metabolism" is sometimes used. Secondary metabolites are produced by many microbes, plants, fungi and animals.
Human Metabolome Database
The Human Metabolome Database (HMDB) is a comprehensive, high-quality, freely accessible, online database of small molecule metabolites found in the human body. Created by the Human Metabolome Project funded by Genome Canada. One of the first dedicated metabolomics databases, the HMDB facilitates human metabolomics research, including the identification and characterization of human metabolites using NMR spectroscopy, GC-MS spectrometry and LC/MS spectrometry. To aid in this discovery process, the HMDB contains three kinds of data: 1) chemical data, 2) clinical data, and 3) molecular biology/biochemistry data (Fig. 1-3). The chemical data includes 41,514 metabolite structures with detailed descriptions along with nearly 10,000 NMR, GC-MS and LC/MS spectra.
Metabolite damage
Metabolite damage can occur through enzyme promiscuity or spontaneous chemical reactions. Many metabolites are chemically reactive and unstable and can react with other cell components or undergo unwanted modifications. Enzymatically or chemically damaged metabolites are always useless and often toxic. To prevent toxicity that can occur from the accumulation of damaged metabolites, organisms have damage-control systems that:Damage-control systems can involve one or more specific enzymes.
Hydroxymethylfurfural
A major metabolite in humans is 5-hydroxymethyl-2-furoic acid (HMFA), which is excreted in urine.
In vivo magnetic resonance spectroscopy
In 1H Magnetic Resonance Spectroscopy each proton can be visualized at a specific chemical shift (peak position along x-axis) depending on its chemical environment. This chemical shift is dictated by neighboring protons within the molecule. Therefore, metabolites can be characterized by their unique set of 1H chemical shifts. The metabolites that MRS probes for have known (1H) chemical shifts that have previously been identified in NMR spectra. These metabolites include:
Terbufos
The amount of metabolites, caused by hydrolysis in vivo of an organophosphate compound such as terbufos, can be detected in the urine using gas chromatography and combined gas chromatography/mass spectrometry (GC-MC). Usually it is necessary to preserve the sample of the urine by addition of chloroform, to concentrate or extract the metabolites and to convert them to suitably-volatile derivatives. The detection can be useful to determine patterns of exposure. But the levels of metabolite alone cannot be considered a guide to hazard.
Sulfamethoxazole
Sulfamethoxazole is metabolized in the human liver to at least 5 metabolites. These metabolites are the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and an N-glucuronide conjugate. The CYP2C9 enzyme is responsible for the formation of the N4-hydroxy metabolite. In vitro studies suggest sulfamethoxazole is not a substrate of the P-glycoprotein transporter.
Noretynodrel
The major metabolites of noretynodrel in the circulation are 3α-hydroxynoretynodrel (formed by ) and to a lesser extent 3β-hydroxynoretynodrel (formed by ), and more minor metabolites of noretynodrel are norethisterone (formed by δ-isomerase) and possibly ethinylestradiol (formed by aromatase or possibly other cytochrome P450 enzymes, most likely monooxygenases). Due to its very short elimination half-life and its low affinities for steroid hormone receptors in receptor binding assays, noretynodrel is considered to be a prodrug which is rapidly transformed into its active metabolites in the intestines and liver following oral administration. Some researchers have stated that it is specifically a prodrug of norethisterone. According to other researchers however, there is, due to a lack of research, insufficient data to unequivocally show this to be the case at present.
Bremelanotide
Bremelanotide is a cyclic heptapeptide lactam analogue of α-melanocyte-stimulating hormone (α-MSH). It has the amino acid sequence Ac-Nle-"cyclo"[Asp-His--Phe-Arg-Trp-Lys]-OH, and is also known as "cyclo"-[Nle,Asp,-Phe,Lys]α-MSH-(4-10). Bremelanotide is an active metabolite of melanotan II that lacks the C-terminal amide group.
Secondary metabolite
Secondary metabolites are organic compounds produced by bacteria, fungi, or plants which are not directly involved in the normal growth, development, or reproduction of the organism. Unlike primary metabolites, absence of secondary metabolites does not result in immediate death, but rather in long-term impairment of the organism's survivability, fecundity, or aesthetics, or perhaps in no significant change at all. Specific secondary metabolites are often restricted to a narrow set of species within a phylogenetic group. Secondary metabolites often play an important role in plant defense against herbivory and other interspecies defenses. Humans use secondary metabolites as medicines, flavorings, pigments, and recreational drugs.
Isotopic labeling
The figure demonstrates the ability to use different labels to determine the flux through a certain reaction. Assume the original metabolite, a three carbon compound, has the ability to either split into a two carbon metabolite and one carbon metabolite in one reaction then recombine or remain a three carbon metabolite. If the reaction is provided with two isotopes of the metabolite in equal proportion, one completely labeled (blue circles), commonly known as uniformly labeled, and one completely unlabeled (white circles). The pathway down the left side of the diagram does not display any change in the metabolites, while the right side shows the split and recombination. As shown, if the metabolite only takes the pathway down the left side, it remains in a 50–50 ratio of uniformly labeled to unlabeled metabolite. If the metabolite only takes the right side new labeling patterns can occur, all in equal proportion. Other proportions can occur depending on how much of the original metabolite follows the left side of the pathway versus the right side of the pathway. Here the proportions are shown for a situation in which half of the metabolites take the left side and half the right, but other proportions can occur. These patterns of labeled atoms and unlabeled atoms in one compound represent isotopomers. By measuring the isotopomer distribution of the differently labeled metabolites, the flux through each reaction can be determined.
5-MAPB
Little formal knowledge exists on 5-MAPB. It does not share the neurotoxicity of MDA caused by the alpha-methyldopamine metabolite. A study in rats indicated that the major metabolites of 5-MAPB are 5-APB and 3-carboxymethyl-4-hydroxymethamphetamine.
Enzyme inhibitor
Enzyme inhibitors are also important in metabolic control. Many metabolic pathways in the cell are inhibited by metabolites that control enzyme activity through allosteric regulation or substrate inhibition. A good example is the allosteric regulation of the glycolytic pathway. This catabolic pathway consumes glucose and produces ATP, NADH and pyruvate. A key step for the regulation of glycolysis is an early reaction in the pathway catalysed by phosphofructokinase-1 (PFK1). When ATP levels rise, ATP binds an allosteric site in PFK1 to decrease the rate of the enzyme reaction; glycolysis is inhibited and ATP production falls. This negative feedback control helps maintain a steady concentration of ATP in the cell. However, metabolic pathways are not just regulated through inhibition since enzyme activation is equally important. With respect to PFK1, fructose 2,6-bisphosphate and ADP are examples of metabolites that are allosteric activators.
4-Hydroxyphenylacetone
4-Hydroxyphenylacetone is the para-hydroxy analog of phenylacetone, an inactive metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced directly from the inactive metabolite phenylacetone.
Metabolite damage
Similarly to DNA and proteins, metabolites are prone to damage, which can occur chemically or through enzyme promiscuity. Much less is known about metabolite damage than about DNA and protein damage, in part due to the huge variety and number of damage-prone metabolites.
Many metabolites are chemically reactive and unstable, and thus prone to chemical damage. In general, any reaction that occurs "in vitro" under physiological conditions can also occur "in vivo". Some metabolites are so reactive that their half-life in a cell is measured in minutes. For example, the glycolytic intermediate 1,3-bisphosphoglyceric acid has a half-life of 27 minutes "in vivo". Typical types of chemical damage reactions that can occur to metabolites are racemization, rearrangement, elimination, photodissociation, addition, and condensation.
Glossary of phytopathology
secondary metabolite
Mulukbu
Chinci
MDMA
Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research. 80% of MDMA is metabolised in the liver, and about 20% is excreted unchanged in the urine.
Tranilast
Tranilast is an analog of a metabolite of tryptophan, and its chemical name is 3′,4′-dimethoxycinnamoyl) anthranilic acid (N-5′).
Metabolome
The metabolome reflects the interaction between an organism’s genome and its environment. As a result, an organism’s metabolome can serve as an excellent probe of its phenotype (i.e. the product of its genotype and its environment). Metabolites can be measured (identified, quantified or classified) using a number of different technologies including NMR spectroscopy and mass spectrometry. Most mass spectrometry (MS) methods must be coupled to various forms of liquid chromatography (LC), gas chromatography (GC) or capillary electrophoresis (CE) to facilitate compound separation. Each method is typically able to identify or characterize 50-5000 different metabolites or metabolite “features” at a time, depending on the instrument or protocol being used. See Figure 2 for an illustration of the relationship between different analytical methods and their sensitivity. Currently it is not possible to analyze the entire range of metabolites by a single analytical method.
2,3-Dihydroxycinnamic acid
It is a metabolite found in human urine.
Metabolic network modelling
Enzyme promiscuity and spontaneous chemical reactions can damage metabolites. This metabolite damage, and its repair or pre-emption, create energy costs that need to be incorporated into models. It is likely that many genes of unknown function encode proteins that repair or pre-empt metabolite damage, but most genome-scale metabolic reconstructions only include a fraction of all genes.
Amphetamine
CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including , , , benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are , , and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:
Albendazole
Albendazole sulfoxide is converted to the inactive albendazole sulfone by cytochrome P450 oxidases, thought to include CYP3A4 and/or CYP2C. Other inactive metabolites include: 2-aminosulfone, ω-hydroxysulfone, and β-hydroxysulfone. The major final metabolites that are excreted by humans are:
There are also some minor hydroxylated sulfated or glucuronidated derivatives. No unchanged albendazole is excreted, as it is metabolized too quickly.
Glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is the metabolite that occurs as an intermediate in several central pathways of all organisms. With the chemical formula H(O)CCH(OH)CHOPO, this anion is a monophosphate ester of glyceraldehyde.
Cocaine
Cocaine has a short half life of 0.7-1.5 hours and is extensively metabolized by cholinesterase enzymes (primarily in the liver and plasma), with only about 1% excreted unchanged in the urine. The metabolism is dominated by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite, and other significant metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine. Further minor metabolites of cocaine include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. If consumed with alcohol, cocaine combines with alcohol in the liver to form cocaethylene. Studies have suggested cocaethylene is both more euphoric, and has a higher cardiovascular toxicity than cocaine by itself.
Metabolic syndrome
There is debate regarding whether obesity or insulin resistance is the cause of the metabolic syndrome or if they are consequences of a more far-reaching metabolic derangement. A number of markers of systemic inflammation, including C-reactive protein, are often increased, as are fibrinogen, interleukin 6, tumor necrosis factor-alpha (TNF-α), and others. Some have pointed to a variety of causes, including increased uric acid levels caused by dietary fructose.
Glutathione-ascorbate cycle
The glutathione-ascorbate cycle is a metabolic pathway that detoxifies hydrogen peroxide (HO), which is a reactive oxygen species that is produced as a waste product in metabolism. The cycle involves the antioxidant metabolites: ascorbate, glutathione and NADPH and the enzymes linking these metabolites.
Pralatrexate
Antifolates, such as pralatrexate, are part of a group of compounds known as antimetabolites with structural similarity to naturally occurring molecules involved in DNA synthesis. Cancer cells mistake antimetabolites for normal metabolites allowing the compound to stop or slow critical enzymes involved in DNA synthesis which then triggers cell death. Because of their primary effect on DNA synthesis, the antimetabolites are most effective against actively dividing cells and are largely cell-cycle phase specific.
Metabolon
In biochemistry, a metabolon is a temporary structural-functional complex formed between sequential enzymes of a metabolic pathway, held together both by non-covalent interactions and by structural elements of the cell, such as integral membrane proteins and proteins of the cytoskeleton.
Natural product
Within the field of organic chemistry, the definition of natural products is usually restricted to mean purified organic compounds isolated from natural sources that are produced by the pathways of primary or secondary metabolism. Within the field of medicinal chemistry, the definition is often further restricted to secondary metabolites. Secondary metabolites are not essential for survival, but nevertheless provide organisms that produce them an evolutionary advantage. Many secondary metabolites are cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against prey, predators, and competing organisms.
Metabolism
Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen, reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate), ferrous iron (FeII) or ammonia as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite. These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.
Pesticide degradation
The issue is specifically addressed in major regulatory frameworks. In Europe, for instance, “nonrelevant” metabolites are distinguished from metabolites that are “relevant for groundwater resources” or even “ecotoxicologically relevant”. The latter are those whose risk to soil or aquatic biota is comparable or higher than the parent and must meet the same standards as their parent. Groundwater-relevant metabolites are those likely to reach groundwater in concentrations above 0.1 μg/liter and to display the same toxicity as the parent compound. In the past toxicology issues typically emerged only decades after market introduction. Examples are the detection of chloridazon products (first marketed in 1964) in surface and groundwater, or tolylfluanid (first marketed in 1971). That these substances were overlooked for so long may partially be attributable to prior limits on analytical capabilities. However, labeling some metabolites as nonrelevant may have resulted in directing attention away from them. The decision to tolerate up to 10 μg/liter of “nonrelevant” metabolites in groundwater and drinking water is politically highly contentious in Europe. Some consider the higher limit acceptable as no imminent health risk can be proven, whereas others regard it as a fundamental deviation from the precautionary principle.
Metabolite damage
In humans, L-2-Hydroxyglutaric aciduria was the first disease linked to a missing metabolite repair enzyme. Mutations in the "L2HGDH" gene cause accumulation of L-2-hydroxyglutarate, which is a structural analog to glutamate and alpha-ketoglutarate and presumably inhibits other enzymes or transporters.
Ethinylestradiol sulfate
Ethinylestradiol sulfate (EE sulfate), also known as 17α-ethynylestradiol 3-sulfate, is an estrogen ester – specifically, the C3 sulfuric acid (sulfate) ester of the synthetic estrogen ethinylestradiol (EE) – and is the major metabolite of EE. Circulating levels of EE sulfate range from 6 to 22 times those of EE when EE is taken orally. EE sulfate can be transformed back into EE via steroid sulfatase, and it has been suggested that EE sulfate may serve as a circulating reservoir for EE, similarly to the case of estrone sulfate with estradiol. However, the EE sulfate pool with EE is far smaller than the pool of estrone sulfate that occurs with estradiol (with estrone sulfate levels approximately 200-fold higher than estradiol levels on average with oral estradiol). In addition, in contrast to the case of estrone sulfate and estrone, the conversion rate of EE sulfate back into EE is relatively low, and has been said probably isn't of clinical significance. However, other studies have suggested that EE sulfate may nonetheless contribute up to 20% of total EE levels.
Primary metabolite
Conversely, a secondary metabolite is not directly involved in those processes, but usually has an important ecological function (i.e. a relational function). A secondary metabolite is typically present in a taxonomically restricted set of organisms or cells (Plants, Fungi, Bacteria...). Some common examples of secondary metabolites include: ergot alkaloids, antibiotics, naphthalenes, nucleosides, phenazines, quinolines, terpenoids, peptides and growth factors.
Metabolomics
Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule intermediates and products of metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles. The metabolome represents the complete set of metabolites in a biological cell, tissue, organ or organism, which are the end products of cellular processes. mRNA gene expression data and proteomic analyses reveal the set of gene products being produced in the cell, data that represents one aspect of cellular function. Conversely, metabolic profiling can give an instantaneous snapshot of the physiology of that cell, and thus, metabolomics provides a direct "functional readout of the physiological state" of an organism. One of the challenges of systems biology and functional genomics is to integrate genomics, transcriptomic, proteomic, and metabolomic information to provide a better understanding of cellular biology.
Opioid-induced hyperalgesia
A number of opioids undergo metabolism by cytochrome P450 enzymes in order to generate active metabolites. Only by generating these active metabolites can analgesic effects occur. The enzyme CYP2D6 is used to metabolize several opioids including codeine, methadone, hydrocodone, and tramadol. The level of expression of CYP2D6 can vary dramatically between different individuals. Individuals with low expression of CYP2D6 are designated as poor metabolizers while individuals with high expression of CYP2D6 are designated as ultra-rapid metabolizers. This information is important for healthcare professionals to know as it determines the dose of opioids a patient will need in order to achieve the desired analgesic effect. If given the same starting dose of codeine, a poor metabolizer will feel very little pain relief while an ultra-rapid metabolizer may feel a large reduction in pain. Conversely patients who are ultra-rapid metabolizers should be given minimal amounts of opioids such as tramadol in order to avoid respiratory depression. Information regarding a patient's CYP2D6 expression can be found by running a genomic test such as 23andMe. This information is also helpful to healthcare professionals so they may modify the dosing of other drugs that may have drug-drug interactions with opioids such as rifampin.
ADME
Compounds begin to break down as soon as they enter the body. The majority of small-molecule drug metabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolites. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug (see prodrug).
Desipramine
Desipramine is the major metabolite of imipramine and lofepramine.
Gepefrine
It is a known metabolite of amphetamine in rats.
Pholcodine
Pholcodine is slowly biotransformed in the body via oxidation and conjugation to a series of metabolites that are eliminated primarily in the urine. With an average half-life of approximately 2.3 days, steady-state in someone taking the drug chronically would not be reached for nearly 2 weeks. Nearly one-half of a single dose is eventually excreted as free or conjugated parent drug. The most important urinary metabolite is conjugated morphine, which may be detectable for days or weeks after the last dose. This could trigger a positive result for opiates in a urine drug testing program.
Metabolic syndrome
The International Diabetes Federation consensus worldwide definition of the metabolic syndrome (2006) is:
Central obesity (defined as waist circumference with ethnicity-specific values) AND any two of the following:
If FPG is >5.6 mmol/L or 100 mg/dL, an oral glucose tolerance test is strongly recommended, but is not necessary to define presence of the syndrome.
Bromantane
The main metabolite of bromantane is 6β-hydroxybromantane.
Metabolite pool
Metabolite pool is a collective term for all of the substances involved in the metabolic process in a biological system.
Metabolic pools are within cells (or organelles such as chloroplasts) and refer to the reservoir of molecules upon which enzymes can operate. The size of the reservoir is referred to as its "metabolic pool." The metabolic pool concept is important to cellular biology.
Bisphenol F
Studies into the metabolism and excretion processes for the molecule have shown that the compound undergoes two primary phase II biotransformations to form the corresponding glucuronide and sulfate. Different cell types have a bias towards which metabolite gets produced, with the human hepatoma cell line primarily metabolizing to the corresponding sulfate, and hepatocytes metabolizing to both the glucuronide and the sulfate compounds. Additionally, phase I metabolism produces various hydroxylated metabolites of BPF, with the main metabolites being meta-hydroxylated BPF, ortho-hydroxylated BPF and dihydroxybenzophenone (DHB). These metabolic pathways are P450 dependent.
Agaritine
These metabolites have been shown to cause stomach cancer in mice and cause lasting DNA damage after a single dose in mice.
5-Hydroxyeicosatetraenoic acid
5-Hydroxyeicosatetraenoic acid (5-HETE, 5("S")-HETE, or 5"S"-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5("S")-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5("S"),15("S")-dihydroxyeicosatetraenoic acid (5("S"),15("S")-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15("S")-HETE).
Secondary metabolite
Secondary metabolites also have a strong impact on the food humans eat. Some researchers believe that certain secondary metabolite volatiles are responsible for human food preferences that may be evolutionarily based in nutritional food. This area of interest has not been thoroughly researched, but has interesting implications for human preference. Many secondary metabolites aid the plant in gaining essential nutrients, such as nitrogen. For example, legumes use flavonoids to signal a symbiotic relationship with nitrogen fixing bacteria (rhizobium) to increase their nitrogen uptake. Therefore, many plants that utilize secondary metabolites are high in nutrients and advantageous for human consumption.
1,4,6-Androstatriene-3,17-dione
ATD may cause a positive test for the anabolic steroid boldenone, of which it is a metabolite and is also prohibited in amateur and professional sports which forbids aromatase inhibitors.
Natural product
Following Albrecht Kossel's original proposal in 1891, natural products are often divided into two major classes, the primary and secondary metabolites. Primary metabolites have an intrinsic function that is essential to the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that mainly affects other organisms. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment. Because of their ability to modulate biochemical and signal transduction pathways, some secondary metabolites have useful medicinal properties.
Exometabolomics
While the same analytical approaches used for profiling metabolites apply to exometabolomics, including liquid-chromatography mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) and gas chromatography–mass spectrometry (GC–MS), analysis of exometabolites provides specific challenges and is most commonly focused on investigation of the transformations of exogenous metabolite pools by biological systems. Typically, these experiments are performed by comparing metabolites at two or more time points, for example, spent vs. uninoculated/control culture media; this approach can differentiate different physiological states of wild-type yeast and between yeast mutants. Since, in many cases, the exometabolite (extracellular) pool is less dynamic than endometabolite (intracellular) pools (which are often perturbed during sample processing) and chemically defined media can be used, it reduces some of the experimental challenges of metabolomics.
Metabolism
The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions.
Ramelteon
The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT and MT receptors, respectively, and is 17–25-fold less potent than ramelteon in "in vitro" functional assays. Although the potency of M-II at MT and MT receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20–100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.
Secondary metabolite
Secondary metabolites aid a host in important functions such as protection, competition, and species interactions, but are not necessary for survival. One important defining quality of secondary metabolites is their specificity. Usually, secondary metabolites are specific to an individual species, though there is considerable evidence that horizontal transfer across species or genera of entire pathways plays an important role in bacterial (and, likely, fungal) evolution. Research also shows that secondary metabolic can affect different species in varying ways. In the same forest, four separate species of arboreal marsupial folivores reacted differently to a secondary metabolite in eucalypts. This shows that differing types of secondary metabolites can be the split between two herbivore ecological niches. Additionally, certain species evolve to resist secondary metabolites and even use them for their own benefit. For example, monarch butterflies have evolved to be able to eat milkweed (Asclepias) despite the toxic secondary metabolite it contains. This ability additionally allows the butterfly and caterpillar to be toxic to other predators due to the high concentration of secondary metabolites consumed.
Alcaftadine
Alcaftadine is typically administrated as an eye drop which keeps its effects regional as compared to systemic effects. The main metabolite of alcaftadine is a carboxylic acid metabolite that has minimal systemic effects. The maximum concentration of its main active metabolite is 0.06ng/ml at Tmax of 15 minutes. The minimal absorption of alcaftadine, leads to minimal systemic accumulation. The half life of the major metabolite of alcaftadine is two hours after ocular administration. Except for the metabolite, the rest of alcaftadine is excreted unchanged. Since alcaftadine is administrated at a small concentration and at a local site (the eye), it seems to have minimal systemic effects.
Antimetabolite
An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.
Primary metabolite
Plant growth regulators may be classified as both primary and secondary metabolites due to their role in plant growth and development. Some of them are intermediates between primary and secondary metabolism.
JWH-018
Metabolism of JWH-018 was assessed using Wistar rats which had been administered an ethanolic extract containing JWH-018. Urine was collected for 24 hours, followed by extraction of JWH-018 metabolites using both liquid-liquid extraction and solid-phase extraction. GC-MS was utilized to separate and identify the extracted compounds. JWH-018 and its N-dealkylated metabolite were only detected in small amounts, with hydroxylated N-dealkylated metabolites comprising the primary signal. The observed mass shift indicates that it is likely that hydroxylation occurs in both the naphthalene and indole portions of the molecule. Human metabolites were similar although most metabolism took place on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with glucuronide.
Polyketide
Polyketides are a large group of secondary metabolites which either contain alternating carbonyl and methylene groups (-CO-CH2-), or are derived from precursors which contain such alternating groups.
2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) is a major metabolite of methadone.
Delta ratio
Mathematically this is reflected in a high anion gap, but because the bicarbonate was high to start, it will appear to fall only a small amount. When this happens the numerator is large, the denominator is small, and the result is a delta ratio which is high [ > 2 ]. This means a combined high anion gap metabolic acidosis and a pre-existing either respiratory acidosis or metabolic alkalosis (causing the high bicarbonate) - i.e. a mixed acid - base metabolic acidosis.
Nicotine
Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6) and FMO3, which selectively metabolizes ("S")-nicotine. A major metabolite is cotinine. Other primary metabolites include nicotine "N"'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. Under some conditions, other substances may be formed such as myosmine.
Evolutionary history of plants
Secondary metabolites are essentially low molecular weight compounds, sometimes having complex structures, that are not essential for the normal processes of growth, development, or reproduction. They function in processes as diverse as immunity, anti-herbivory, pollinator attraction, communication between plants, maintaining symbiotic associations with soil flora, or enhancing the rate of fertilization, and hence are significant from the evo-devo perspective. Secondary metabolites are structurally and functionally diverse, and it is estimated that hundreds of thousands of enzymes might be involved in the process of producing them, with about 15–25% of the genome coding for these enzymes, and every species having its unique arsenal of secondary metabolites. Many of these metabolites, such as salicylic acid are of medical significance to humans.
Troglitazone
Since the withdrawal in 2000, mechanisms of troglitazone hepatotoxicity have been extensively studied using a variety of in vivo, in vitro and computational methods. These studies have suggested that hepatotoxicity of troglitazone results from a combination of nonmetabolic and metabolic factors. The nonmetabolic toxicity is a complex function of drug-protein interactions in the liver and biliary system. Initially the metabolic toxicity was largely associated with reactive metabolite formation from the thiazolidinedione and chromane rings of troglitazone. Moreover, the formation of quinone and o-quinone methide reactive metabolites were proposed to be formed by metabolic oxidation of the OH group of the chromane ring. Detailed quantum chemical analysis of the metabolic pathways for troglitazone has shown that quinone reactive metabolite is generated by oxidation of the OH group, but o-quinone methide reactive metabolite is formed by the oxidation of the methyl (CH) groups ortho to the OH group of the chromane ring. This understanding has been recently used in the design of novel troglitazone derivatives with antiproliferative activity in breast cancer cell lines.
Clofibric acid
Clofibric acid is a metabolite of the cholesterol-lowering pharmaceutical drug clofibrate, as well as that of the lipid regulators clofibrate, etofibrate, and theofibrate.
Metabolic syndrome
The metabolic syndrome quintuples the risk of type 2 diabetes mellitus. Type 2 diabetes is considered a complication of metabolic syndrome. In people with impaired glucose tolerance or impaired fasting glucose, presence of metabolic syndrome doubles the risk of developing type 2 diabetes. It is likely that prediabetes and metabolic syndrome denote the same disorder, defining it by the different sets of biological markers.
Yeast Metabolome Database
The Yeast Metabolome Database (YMDB) is a comprehensive, high-quality, freely accessible, online database of small molecule metabolites found in or produced by Saccharomyces cerevisiae (Baker’s yeast). The YMDB was designed to facilitate yeast metabolomics research, specifically in the areas of general fermentation as well as wine, beer and fermented food analysis. YMDB supports the identification and characterization of yeast metabolites using NMR spectroscopy, GC-MS spectrometry and Liquid chromatography–mass spectrometry (LC-MS spectrometry). The YMDB contains two kinds of data: 1) chemical data and 2) molecular biology/biochemistry data. The chemical data includes 2027 metabolite structures with detailed metabolite descriptions along with nearly 4000 NMR, GC-MS and LC/MS spectra.
Finasteride
Finasteride is extensively metabolized in the liver, first by hydroxylation via CYP3A4 and then by aldehyde dehydrogenase. It has two major metabolites, which are the "tert"-butyl side chain monohydroxylated and monocarboxylic acid metabolites. These metabolites show approximately 20% of the inhibitory activity of finasteride on 5α-reductase. Hence, the metabolites of finasteride are not particularly active. The drug has a terminal half-life of 5 to 6 hours in adult men (18–60 years of age) and a terminal half-life of 8 hours or more in elderly men (more than 70 years of age). It is eliminated as its metabolites 57% in the feces and 40% in the urine.
Aquaculture of sea sponges
Understanding the environmental factors that affect metabolite biosynthesis or the ecological role of the metabolite, can be used as a competitive advantage to maximise metabolite production and total yield. For example, if the ecological role of the secondary target metabolite was to deter predators, mimicking predation via wounding the sponge before harvesting may be an efficient technique to maximise metabolite production.
Hydroxymetronidazole
Hydroxymetronidazole is a metabolite of metronidazole.
Pregnanediol glucuronide
Pregnanediol glucuronide, or 5β-pregnane-3α,20α-diol 3α-glucuronide, is the major metabolite of progesterone and the C3α glucuronide conjugate of pregnanediol (5β-pregnane-3α,20α-diol). Approximately 15 to 30% of a parenteral dose of progesterone is metabolized into pregnanediol glucuronide. While this specific isomer is referred to as "pregnanediol glucuronide" and is the most major form, there are actually many possible isomers of the metabolite.
Plant secondary metabolism
Research into secondary plant metabolism primarily took off in the later half of the 19th century, however, there was still much confusion over what the exact function and usefulness of these compounds were. All that was known was that secondary plant metabolites were "by-products" of the primary metabolism and were not crucial to the plant's survival. Early research only succeeded as far as categorizing the secondary plant metabolites but did not give real insight into the actual function of the secondary plant metabolites. The study of plant metabolites is thought to have started in the early 1800s when Friedrich Willhelm Serturner isolated morphine from opium poppy, and after that new discoveries were made rapidly. In the early half of the 1900s, the main research around secondary plant metabolism was dedicated to the formation of secondary metabolites in plants, and this research was compounded by the use of tracer techniques which made deducing metabolic pathways much easier. However, there was still not much research being conducted into the functions of secondary plant metabolites until around the 1980s. Before then, secondary plant metabolites were thought of as simply waste products. In the 1970s, however, new research showed that secondary plant metabolites play an indispensable role in the survival of the plant in its environment. One of the most ground breaking ideas of this time argued that plant secondary metabolites evolved in relation to environmental conditions, and this indicated the high gene plasticity of secondary metabolites, but this theory was ignored for about half a century before gaining acceptance. Recently, the research around secondary plant metabolites is focused around the gene level and the genetic diversity of plant metabolites. Biologists are now trying to trace back genes to their origin and re-construct evolutionary pathways.
Heroin
The major metabolites of diamorphine, 6-MAM, morphine, morphine-3-glucuronide and morphine-6-glucuronide, may be quantitated in blood, plasma or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Most commercial opiate screening tests cross-react appreciably with these metabolites, as well as with other biotransformation products likely to be present following usage of street-grade diamorphine such as 6-acetylcodeine and codeine. However, chromatographic techniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the diamorphine usage history of the individual, since a chronic user can develop tolerance to doses that would incapacitate an opiate-naive individual, and the chronic user often has high baseline values of these metabolites in his system. Furthermore, some testing procedures employ a hydrolysis step before quantitation that converts many of the metabolic products to morphine, yielding a result that may be 2 times larger than with a method that examines each product individually.
Drug metabolism
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is called pharmacokinetics.
15-Hydroxyeicosatetraenoic acid
Most studies have analyzed the action of 15("S")-HETE but not that of its less stable precursor 15("S")-HpETE. Since this precursor is rapidly converted to 15("S")-HETE in cells, it is likely that the two metabolites share similar activities. In many studies, however, is not clear that these activities reflect their intrinsic action or reflect their conversion to the metabolites sited above.
Dynamic reserve
Dynamic reserve, in the context of the Dynamic energy budget theory, refers to the set of metabolites (mostly polymers and lipids) that an organism can use for metabolic purposes.. These chemical compounds can have active metabolic functions, however. They are not just "set apart for later use." Reserve differs from structure in the first place by its dynamics. Reserve has an implied turnover, because it is synthesized from food (or other substrates in the environment) and used by metabolic processes occurring in cells. The turnover of structure depends on the maintenance of an organism. Maintenance is not required for reserve. A freshly laid egg consists almost exclusively of reserve, and hardly respires. The chemical compounds in the reserve have the same turnover, while that in the structure can have a different turnover, and so it depends on the compound.
Metapristone
Metapristone (developmental code name RU-42633; also known as desmethylmifepristone) is the major metabolite of mifepristone (RU-486, RU-38486) and a selective progesterone receptor modulator (SPRM) which itself was never marketed. It is formed from mifepristone in the liver by the enzyme CYP3A4 via monodemethylation, and circulates at concentrations higher than those of mifepristone. The metabolite retains partial but considerable affinity for the progesterone receptor (PR) and the glucocorticoid receptor (GR) ( = 21% and 61% of that of mifepristone for the human forms of these receptors, respectively). On the basis of actions that are apparently independent of its hormonal activity, metapristone is being researched as a potential cancer metastatic chemopreventive agent.
MetaboAnalyst
MetaboAnalyst is part of a suite of metabolomics databases that also includes Human Metabolome Database (HMDB), DrugBank, Toxin and Toxin-Target Database, and The Small Molecule Pathway Database. The HMDB has over 7900 human metabolites and roughly 7200 associated DNA and protein sequences, that are linked to these metabolite entries. While DrugBank includes information on 6707 drugs and 4228 non-redundant drug targets, enzymes, transporters, and carriers, T3DB houses over 2900 common toxins and environmental pollutants. The suite is rounded out by SMPDB with its pathway diagrams for more than 350 human metabolic and disease pathways.
Bupropion
Bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6. It has several active metabolites: "R,R"-hydroxybupropion, "S,S"-hydroxybupropion, "threo"-hydrobupropion and "erythro"-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Both bupropion and its primary metabolite hydroxybupropion act in the liver as potent inhibitors of the enzyme CYP2D6, which metabolizes not only bupropion itself but also a variety of other drugs and biologically active substances. This mechanism creates the potential for a variety of drug interactions.
3,5-Dihydroxycinnamic acid
It is a metabolite found in human urine.
ALOX12
The metabolic syndrome is a clustering of at least three of five of the following medical conditions: abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose (or overt diabetes), high serum triglycerides, and low high-density lipoprotein (HDL) levels. ALOX12 and its metabolite, 12("S")-HETE, are elevated in the islets of Langerhans of patients with type 1 diabetes or type 2 diabetes as well as in the fat cells of white adipose tissue of morbidly obese type 2 diabetic patients. The PP cells (i.e. gamma cells) of the pancreas islets appear to be the major if not only site where ALOX12 is expressed in these patients. The studies propose that in the islets of Langerhans ALOX12 and its 12("S")-HETE product cause excessive production of reactive oxygen species and inflammation which lead to losses in insulin-secreting beta cells and thereby types 1 and 2 diabetes and that in adipose tissue the excess in AlOX12, 12("S")-HETE, reactive oxygen species, and inflammation lead to fat cell dysfunction (also see 12-HETE#Inflammation and inflammatory diseases and 12-HETE#Diabetes). Indeed, in one study a Single-nucleotide polymorphism, rs2073438, located in an intron region of the "ALOX12" gene was significantly associated with total and percentage fat mass of obese compared to non-obese young Chinese men. ALOX12 and 12("S")-HETE are likewise implicated in essential hypertension (see next section). Hence, ALOX12 and its metabolite(s) may contribute to the development and/or progression of obesity, diabetes, hypertension, and/or the metabolic syndrome.
Primary metabolite
A primary metabolite is a kind of metabolite that is directly involved in normal growth, development, and reproduction. It usually performs a physiological function in the organism (i.e. an intrinsic function). A primary metabolite is typically present in many organisms or cells. It is also referred to as a central metabolite, which has an even more restricted meaning (present in any autonomously growing cell or organism). Some common examples of primary metabolites include: lactic acid, and certain amino acids.
Note: Primary metabolites do not show any pharmacological actions or effects.
Norgestimate
Norgestimate is extensively metabolized into its active metabolites during first-pass metabolism in the liver and intestines. The major metabolite of norgestimate is norelgestromin and is formed from norgestimate via deacetylation in the liver and intestines. A more minor metabolite of norgestimate is levonorgestrel, which accounts for 20 to 25% (22 ± 6%) of an administered dose or about 40 to 70 µg norgestimate, and a very minor metabolite of norgestimate is levonorgestrel 17β-acetate. Both of these metabolites are active similarly to norgelstromin. With a typical oral contraceptive dosage of norgestimate of 200 to 250 µg/day, an amount of 50 to 60 µg/day levonorgestrel may be produced. This is similar to the ovulation-inhibiting dosage of levonorgestrel, and suggests that norgestimate may act in considerable part as a prodrug specifically of levonorgestrel. Following their formation, the active metabolites of norgestimate are inactivated via reduction, hydroxylation, and conjugation into levonorgestrel metabolites. The terminal half-life of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 to 32 hours. The metabolites of norgestimate are eliminated 47% in urine and 37% in feces. Unchanged norgestimate is undetectable in urine.
Acetamiprid
The metabolism of acetamiprid has been primarily studied in plants and soil. However, a recent study (2005) focussed on the metabolism of acetamiprid in honey bees. The honey bees in this study were fed a sucrose solution that contained acetamiprid. Seven different metabolites were discovered, of which two could not be identified. The five most abundant of these metabolites were found in the abdomen of the bee. Within the first hour of ingestion, acetamiprid concentrations were highest in tissues with a high nicotinic acetylcholine receptor density such as the abdomen, thorax and head.
Combination
which gives
Muscle fatigue
Metabolites are the substances (generally waste products) produced as a result of muscular contraction. They include chloride, potassium, lactic acid, ADP, magnesium (Mg), reactive oxygen species, and inorganic phosphate. Accumulation of metabolites can directly or indirectly produce metabolic fatigue within muscle fibers through interference with the release of calcium (Ca) from the sarcoplasmic reticulum or reduction of the sensitivity of contractile molecules actin and myosin to calcium.
Metabolome
Scientists at the University of Alberta have been systematically characterizing specific biofluid metabolomes including the serum metabolome, the urine metabolome, the cerebrospinal fluid (CSF) metabolome and the saliva metabolome. These efforts have involved both experimental metabolomic analysis (involving NMR, GC-MS, ICP-MS, LC-MS and HPLC assays) as well as extensive literature mining. According to their data, the human serum metabolome contains at least 4200 different compounds (including many lipids), the human urine metabolome contains at least 3000 different compounds (including 100s of volatiles and gut microbial metabolites), the human CSF metabolome contains nearly 500 different compounds while the human saliva metabolome contains approximately 400 different metabolites, including many bacterial products.
Norhydrocodone
Norhydrocodone is the major metabolite of the opioid analgesic hydrocodone. It is formed from hydrocodone in the liver via N-demethylation predominantly by CYP3A4. Unlike hydromorphone, a minor metabolite of hydrocodone, norhydrocodone is described as inactive. However, norhydrocodone is actually an agonist of the μ-opioid receptor with similar potency to hydrocodone, but has been found to produce only minimal analgesia when administered peripherally to animals. This is likely due to poor blood-brain-barrier and thus central nervous system penetration.
Inborn errors of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders.
The term "inborn errors of metabolism" was coined by a British physician, Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, "Inborn Errors of Metabolism" was published in 1923.
METLIN
METLIN is a metabolomics database and, , contains over 64,727 structures. It serves as a data management system to assist in metabolite research and metabolite identification by providing public access to its repository of comprehensive MS/MS metabolite data. An annotated list of known metabolites and their mass, chemical formula, and structure are available on the METLIN website. Each metabolite is linked to outside resources such as the "Kyoto Encyclopedia of Genes and Genomes" (KEGG) for further reference and inquiry. Available MS/MS data are expanding continuously as more metabolite information is being deposited and discovered. The METLIN database was developed and is maintained by the Siuzdak laboratory at The Scripps Research Institute.
Pregabalin
Pregabalin undergoes little or no metabolism. In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The main metabolite is "N"-methylpregabalin.
Phthalate
There may be a link between the obesity epidemic and endocrine disruption and metabolic interference. Studies conducted on mice exposed to phthalates in utero did not result in metabolic disorder in adults. However, "in a national cross-section of U.S. men, concentrations of several prevalent phthalate metabolites showed statistically significant correlations with abnormal obesity and insulin resistance." Mono-ethylhexyl-phthalate (MEHP), a metabolite of DEHP, has been found to interact with all three peroxisome proliferator-activated receptors (PPARs). PPARs are members of the nuclear receptor superfamily. The author of the study stated "The roles of PPARs in lipid and carbohydrate metabolism raise the question of their activation by a sub-class of pollutants, tentatively named metabolic disrupters." Phthalates belong to this class of metabolic disruptors. It is a possibility that, over many years of exposure to these metabolic disruptors, they are able to deregulate complex metabolic pathways in a subtle manner.
4-Methylthioamphetamine
4-MTA undergoes limited biotransformation, the metabolic pathways of the metabolites in humans is postulated in the following steps:
The main metabolite was identified as 4-methylthiobenzoic acid. This compound leads to bioactivation (toxification), since the metabolite increases dramatically the sensitivity to the reduction in ATP content. The biotransformation shows great similarities to the metabolic pathway of the structurally related 4-methoxyamphetamine
Metabolite damage
Damage repair is the conversion of a damaged metabolite back to its original state via one or more enzymatic reactions; the concept is similar to DNA repair and protein repair. For example, the promiscuous activity of malate dehydrogenase causes reduction of alpha-ketoglutarate to L-2-hydroxyglutarate. This compound is a dead-end metabolite and is not a substrate for any other enzyme in central metabolism, and its accumulation in humans causes L-2-Hydroxyglutaric aciduria. The repair enzyme L-2-hydroxyglutarate dehydrogenase oxidizes L-2-hydroxyglutarate back to alpha-ketoglutarate, thus repairing this metabolite. In humans, L-2-hydroxyglutarate dehydrogenase uses FAD as the cofactor, while the "E. coli" enzyme reduces molecular oxygen.
Dihydroxy-E,Z,E-PUFA
Dihydroxy-"E","Z","E"-PUFA are metabolites of a) docosahexaenoic acid (DHA, i.e. 4"Z",7"Z",10"Z",13"Z",16"Z",19"Z"-docosahexaenoic acid), b) α-Linolenic acid (ALA, i.e. "9"Z,12"Z",15"Z"-octadecatrienoic acid), an c) arachidonic acid (AA); "E","Z","E"-DHA and "E","Z","E" AA metabolites are termed poxytrins; ALA metabolites are termed linotrins. The first and perhaps most prominent member of this class of metabolites is protectin DX (PDX; i.e. 10"R",17"S"-dihydroxy-4"Z",7"Z",11"E",13"Z",15"E",19"Z"-docosahexaenoic acid). PDX is an isomer of (and sometimes confused with) neuroprotectin D1 (NPD1; i.e. 10"R",17"S"-dihydroxy-4"Z",7"Z",11"E",13"E",15"Z",19"Z"-doxahexaenoic acid; also termed protectin D1 [PD1]). NPD1 is structurally identical to PDX except that its three conjugated double bonds have the "E","E","Z" configuration as opposed to the "E","Z","E" configuration of PDX. Both compounds are members of the specialized proresolving mediators class of PUFA metabolites in that they possess potent anti-inflammatory activity; however, only PDX inhibited human platelet aggregation responses. Subsequent studies found that various other dihydroxy-"E","Z","E"-double bound-configured PUFA but not those with "E","E","E" or "E","E","Z" double bond configurations share with PDX anti-platelet activity. Cells make PDX by metabolizing DHA by double oxygenation a 15-lipoxygenase to form the 10"R",17"S"-hydroxperoxy intermediated which is reduced its 10"R",17"S"-hydroxyl product, PDX, probably by cytosolic GPX1 (i.e. glutathione peroxidase 1). Serial metabolism two different lipoxygenases or a lipoxygenase and a cytochrome P45) on PUFA possessing three double bonds in a 1"Z",4"Z",7"Z" configuration may also make a 1,7-dihydroxy 2"E",4"Z",6"E" product.
Pharmacometabolomics
Following identification and quantification of metabolites in individual patient samples, NMR and mass spectrometry (MS) output is compiled into a dataset. These datasets include information on the identity and levels of individual metabolites detected within processed samples, as well as characteristics of each metabolite during the detection process (e.g. mass-to-charge ratios for mass spectrometry (MS)-based analysis). Multiple datasets can be created and compiled into large databases for individual patients in order to monitor varying metabolic profiles over a treatment course (i.e. pre- and post-treatment profiles). Each database is then processed through a type of informatics platform with software designed to characterize and analyze the data to generate an overall metabolic profile for the patient. To generate this overall profile, computational programs are designed to:
Metabolic intermediate
Metabolic intermediates are molecules which are the precursors or metabolites of biologically significant molecules.