Instruct: Given a question, retrieve passages that answer the question.
Query: What is a 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.
Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam. Most of the drug is metabolised; very little diazepam is excreted unchanged. The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration.
Most of the secondary metabolites of interest to humankind fit into categories which classify secondary metabolites based on their biosynthetic origin. Since secondary metabolites are often created by modified primary metabolite synthases, or "borrow" substrates of primary metabolite origin, these categories should not be interpreted as saying that all molecules in the category are secondary metabolites (for example the steroid category), but rather that there are secondary metabolites in these categories.
Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.
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.
CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans. The primary metabolites are amphetamine and 4-hydroxymethamphetamine; other minor metabolites include: , , , benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine. Among these metabolites, the active sympathomimetics are amphetamine, , , , and norephedrine.
Primary metabolism in a plant comprises all metabolic pathways that are essential to the plant's survival. Primary metabolites are compounds that are directly involved in the growth and development of a plant whereas secondary metabolites are compounds produced in other metabolic pathways that, although important, are not essential to the functioning of the plant. However, secondary plant metabolites are useful in the long term, often for defense purposes, and give plants characteristics such as color. Secondary plant metabolites are also used in signalling and regulation of primary metabolic pathways. Plant hormones, which are secondary metabolites, are often used to regulate the metabolic activity within cells and oversee the overall development of the plant. As mentioned above in the History tab, secondary plant metabolites help the plant maintain an intricate balance with the environment, often adapting to match the environmental needs. Plant metabolites that color the plant are a good example of this, as the coloring of a plant can attract pollinators and also defend against attack by animals.
Dextromethorphan has been found to possess the following actions (<1 μM) using rat tissues:Rather than acting as a direct NMDA receptor antagonist itself, dextromethorphan acts as a prodrug of its much more potent metabolite dextrorphan, and this is the actual mediator of its dissociative effects. What role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects is not entirely clear.
Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours. The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ-spironolactone). These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication. As such, spironolactone is a prodrug. The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite. Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone, as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.
The Human Metabolome Database is a freely available, open-access database containing detailed data on more than 40,000 metabolites that have already been identified or are likely to be found in the human body. The HMDB contains three kinds of information: 1) chemical information, 2) clinical information, and 3) biochemical information. The chemical data includes >40,000 metabolite structures with detailed descriptions, extensive chemical classifications, synthesis information and observed/calculated chemical properties. It also contains nearly 10,000 experimentally measured NMR, GC-MS and LC/MS spectra from more than 1100 different metabolites. The clinical information includes data on >10,000 metabolite-biofluid concentrations, metabolite concentration information on more than 600 different human diseases and pathway data for more than 200 different inborn errors of metabolism. The biochemical information includes nearly 6000 protein (and DNA) sequences and more than 5000 biochemical reactions that are linked to these metabolite entries. The HMDB supports a wide variety of online queries including text searches, chemical structure searches, sequence similarity searches and spectral similarity searches. This makes it particularly useful for metabolomic researchers who are attempting to identify or understand metabolites in clinical metabolomic studies. The first version of the HMDB was released in Jan. 1 2007 and was compiled by scientists at the University of Alberta and the University of Calgary. At that time they reported data on 2,500 metabolites, 1,200 drugs and 3,500 food components. Since then these scientists have greatly expanded the collection. The latest version of the HMDB (version 3.5) contains >16,000 endogenous metabolites, >1500 drugs and >22,000 food constituents or food metabolites.
Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 (CYP P450 or just CYP) enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substrate of the CYP epoxylgenases is arachidonic acid. This polyunsaturated fatty acid is metabolized by cyclooxygenases to various prostaglandin, thromboxane, and prostacyclin metabolites in what has been termed the first pathway of eicosanoid production; it is also metabolized by various lipoxygenases to hydroxyeicosatetraenoic acids (e.g. 5-Hydroxyeicosatetraenoic acid, 12-Hydroxyeicosatetraenoic acid, 15-hydroxyicosatetraenoic acid) and leukotrienes (e.g. leukotriene B4, leukotriene C4) in what has been termed the second pathway of eicosanoid production. The metabolism of arachidonic acid to epoxyeicosatrienoic acids by the CYP epoxygenases has been termed the third pathway of eicosanoid metabolism. Like the first two pathways of eicosanoid production, this third pathway acts as a signaling pathway wherein a set of enzymes (the epoxygenases) metabolize arachidonic acid to a set of products (the eicosatrienoic acid epoxides, abbreviated as EETs, which are classified as nonclassic eicosanoids) that act as secondary signals to work in activating their parent or nearby cells and thereby orchestrate functional responses. However, none of these three pathways is limited to metabolizing arachidonic acid to eicosanoids. Rather, they also metabolize other polyunsaturated fatty acids to products that are structurally analogous to the eicosanoids but often have different bioactivity profiles. This is particularly true for the CYP epoxygenases which in general act on a broader range of polyunsaturated fatty acids to form a broader range of metabolites than the first and second pathways of eicosanoid production. Furthermore, the latter pathways form metabolites many of which act on cells by binding with and thereby activating specific and well-characterized receptor proteins; no such receptors have been fully characterized for the epoxide metabolites. Finally, there are relatively few metabolite-forming lipoxygenases and cyclooxygenases in the first and second pathways and these oxygenase enzymes share similarity between humans and other mammalian animal models. The third pathway consists of a large number of metabolite-forming CYP epoxygenases and the human epoxygenases have important differences from those of animal models. Partly because of these differences, it has been difficult to define clear roles for the epoxygenase-epoxide pathways in human physiology and pathology.
Metabolites are the intermediates and products of metabolism. Within the context of metabolomics, a metabolite is usually defined as any molecule less than 1 kDa in size. However, there are exceptions to this depending on the sample and detection method. For example, macromolecules such as lipoproteins and albumin are reliably detected in NMR-based metabolomics studies of blood plasma. In plant-based metabolomics, it is common to refer to "primary" and "secondary" metabolites. A primary metabolite is directly involved in the normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important ecological function. Examples include antibiotics and pigments. By contrast, in human-based metabolomics, it is more common to describe metabolites as being either endogenous (produced by the host organism) or exogenous. Metabolites of foreign substances such as drugs are termed xenometabolites.
A compound's toxicological property has been linked to metabolic pathways, which often differ in various species. For that reason the correlation between toxicity and metabolism has been observed to obtain a clear insight into cellular metabolism, both in vitro and in vivo conditions. 
In vitro studies on liver preparations from rats and other rodents revealed that hydroxylation is the major process during the metabolism of NRB. Furthermore, the metabolites between the sexes of the rat seemed to deviate from one another. First and foremost when NRB had been incubated with the liver S9 fraction, a few metabolic products were observed. The S9 fraction has been defined as "Supernatant fraction obtained from an organ (usually liver) homogenate by centrifuging at 9000 g for 20 minutes in a suitable medium; this fraction contains cytosol and microsomes." The S9 fraction consists of two components: the microsomes component which incorporates cytochrome P450 isoforms (phase I metabolism) and the cytosolic component which contains transferases (phase II metabolism).
A mixture of four active endo-isomers of NRB (U, V, W en Y) formed four major metabolites in rat liver S9 and cytosolic preparations after incubation. The isomers are separately not pure compounds, but research with pure V isomer and a mixture of U and V isomers pointed out that each isomer undergoes metabolism to be formed into a single product in rat. Mass spectrometry confirmed that all metabolites had a mass consistent with a hydroxylated metabolite of NRB. Because female rats are more sensitive to NRB than the male species, the level of metabolites are higher in females than in males.
The same metabolites were found in guinea pigs, although the levels of metabolism in these rodents are considerately lower compared to those in rats. In mice two metabolites were detected: one metabolite of the V isomer (V1) which was also found in the rat preparations and another, new metabolite of the V isomer (V2). (Figure 7.1) These data acknowledge the link between the susceptibility to NRB and the production of different types and different levels of metabolites. 
After collecting blood from rats 10 and 30 minutes after oral administration, plasma and red blood cell fractions were analyzed in search for either parent compounds or hydroxylated metabolites. However, neither were found, which either means that the absorption did not take place or the compounds underwent a quick clearance from the body. Whole blood samples certainly showed traces of the parent compound and a metabolite (M3) with molecular mass of 226, in samples from both female and male rats. The level in which this metabolite occurred, appeared to be once again higher in the female rats than in the male species. M3 was not found in any other rat or mouse tissue. This suggests that M3 may be formed by gut microflora in rats.
After NRB had orally been administered, an examination of both rat and mouse liver revealed traces of the parent compound. Comparing the metabolite levels in both sexes and species, a significantly higher amount was discovered in the female rats than in the male rats or the mice. HPLC chromatograms liver preparations from female of and male rats, display the detection of four metabolites (U1, V1, M1, M2). (Figure 7.2) Mass spectrometry had been used to identify these and easily so, because the hydroxylated metabolites were +16 amu higher than NRB. These studies confirmed that the metabolites were identical to those found in the in vitro preparations.
The metabolites were not found in mouse liver preparations. Moreover, neither NRB parent compound nor its metabolites were discovered in the heart after oral administration in rats as well as mice. This lack of detectable metabolites implies that NRB is able to induce a lethal effect at extremely low levels.
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.
What is a galactose challenge? The goal of a galactose challenge is to learn whether a child is able to metabolize dietary galactose sufficiently to prevent the abnormal accumulation of galactose metabolites, generally measured as Gal-1P in the blood or galactitol in the urine. For infants with DG who showed elevated galactose metabolites at diagnosis, this test can be used to see if the child's ability to process galactose has improved.
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.
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.
At 1 hour after dosing, one metabolite (A) was found in plasma using HPLC. The retention times of parent compound citrinin (C) and this metabolite (A) were 270 and 176 seconds, respectively. The metabolite was more polar than citrinin. Urine samples at different times yielded two metabolites at 180 (A) and 140 (B) seconds, which were both more polar than CTN. Bile samples taken 3 hours after dosing yielded a retention time of 140 seconds, indicating metabolite B. Uterus extracts yielded metabolite A (retention time: 180 seconds) and fetus yielded no metabolite, only the parent compound citrinin. These results suggest that only the parent compound, which is found in plasma and uterus, can enter the fetus and the metabolite (A), also present in plasma and uterus, does not. This can be because the metabolite was more polar and can thereby not cross the placental barrier.
Rabeprazole is extensively metabolized by the liver. 90% of the drug is rendered into metabolites by the liver, which are then excreted by the kidneys. 10% of the dose is excreted in the feces. The drug metabolizing enzymes primarily responsible for rabeprazole's metabolism are CYP2C19 and CYP3A4. However, rabeprazole is mainly metabolized through non-enzymatic reduction to a thioether metabolite. Some of rabeprazole's metabolites include the following: a thioether carboxylic acid metabolite, a thioether glucuronide metabolite, and a sulfone metabolite. The most common metabolites excreted in the urine are the mercapturic acid conjugate and carboxylic acid. A diagram of rabeprazole's phase I metabolism is shown below.
The aromatic amino acids produced by the shikimate acid pathway are used by higher plants as protein building blocks and as precursors for several secondary metabolites. Examples of such secondary metabolites are plant pigments and compounds to defend against herbivores, insects, and UV light. The specific aromatic secondary metabolites produced, as well as when and in what quantities they are produced in, varies across different types of plants. Mammals consume essential amino acids in their diets, converting them to precursors for important substances such as neurotransmitters.
The molecular target of the active metabolite of ADP receptor inhibitors is the P2Y receptor. P2Y receptor is a G-coupled receptor and is activated by adenosine diphosphate. ADP binds to the P2Y receptor that leads to inhibition of adenyl cyclase and thereby decreases the intracellular levels of cAMP. This reduction of cAMP reduces phosphorylation of vasodilator stimulated phosphoprotein that leads to the activation of the glycoprotein IIb/IIIa receptors. Activation of the glycoprotein IIb/IIIa receptors increases thromboxane production and prolonged platelet aggregation. Ticlopidine, clopidogrel and prasugrel are thienopyridine prodrugs that are irreversible platelet inhibitors of the P2Y receptor. Cangrelor and ticagrelor are direct –acting P2Y inhibitors that change the conformation of the P2Y receptor and therefore, results in reversible platelet inhibition of the receptor. Thienopyridines are metabolized in the liver and the intestinal to active metabolites.
Ticlopidine is a prodrug and is metabolized by at least five main pathways. There is one active metabolite that has been identified and shown to have antiplatelet activity. This active metabolite is formed by a CYP-dependent pathway. CYP2C19 and CYP2B6 are enzymes suggested to contribute to the metabolic transformation of ticlopidine to the thiolactone intermediate, 2-oxo-ticlopidine in the liver. The thiolactone intermediate is then converted to ticlopidine active metabolite via CYP oxidation where oxidation activation occurs. However the CYP enzymes that are involved in this pathway are unknown. In the formation of the active metabolite additional metabolites have been identified and they are dihydrothienopyridinium (M5) and thienodihydropyridinium metabolites (M6). These metabolites may be responsible for the toxic side effects of ticlopidine.
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.
Robert L. Last is a plant biochemical genomicist who studies metabolic processes that protect plants from the environment and produce products important for animal and human nutrition. His research has covered (1) production and breakdown of essential amino acids, (2) the synthesis and protective roles of Vitamin C (ascorbic acid) and Vitamin E (tocopherols) as well as identification of mechanisms that protect photosystem II from damage, and (3) synthesis and biological functions of plant protective specialized metabolites (plant secondary metabolites). Four central questions are: (i) how are leaf and seed amino acids levels regulated, (ii.) what mechanisms protect and repair photosystem II from stress-induced damage, (iii.) how do plants produce protective metabolites in their glandular secreting trichomes (iv.) and what are the evolutionary mechanisms that contribute to the tremendous diversity of specialized metabolites that protect plants from insects and pathogens and are used as therapeutic agents.
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.
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.