The enzyme mycophenolic acid acyl-glucuronide esterase (EC 3.1.1.93, mycophenolic acid acyl-glucuronide deglucuronidase; AcMPAG deglucuronidase; systematic name mycophenolic acid O-acyl-glucuronide-ester hydrolase), is in humans encoded by the ABHD10 gene, and catalyses the reaction
This liver enzyme deglucuronidates mycophenolic acid O-acyl-glucuronide. Mycophenolic acid acyl-glucuronide (AcMPAG) is an important product in the metabolism of mycophenolic acid, and ABHD10 is the major esterase responsible for the AcMPAG and probenecid acyl glucuronide deglucuronidation in human liver. [1]
ABHD10 gene is located at chromosome 3q13.2, consisting of 6 exons.
Human ABHD10 is a 297 amino acid protein with a molecular mass of 33 kDa, the mature form of which is a 28-kDa protein and has the nucleophile-His-acid catalytic triad. [2] [1] ABHD10 is a mitochondrial protein with a predicted leader sequence and the proteolytic cleavage site is at residues 46–47. [3]
ABHD10 was identified in 2012, and only two main functions have been reported. First, ABHD10 is involved in the deglucuronidation of AcMPAG in human liver. The activity of this enzyme could attenuate the AcMAPG formation. AcMAPG might be responsible for some adverse effects of mycophenolate mofetil therapy because it promotes the release of TNF-α and IL-6, and it also binds to enzymes that are essential for the control of the energy and redox state of the cells. [4] [5] Thus, the function of ABHD10 could also be regarded as detoxification. [1] Second, ABHD10 counteracts PRAG via deglucuronidation in human liver. As a widely used uricosuric agent, probenecid is mainly metabolized to probenecid acyl glucuronide (PRAG), which is a causal substance of severe allergic or anaphylactoid reaction. The PRAG deglucuronidation catalyzed by ABHD10 could suppress PRAG formation and related adverse reaction. [6]
Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and widely used for the prevention of acute rejection after solid organ transplantation. MPA could be metabolized to AcMPAG, which is responsible for adverse effects of MMF therapy such as leucopenia or gastrointestinal toxicity. Deglucuronidation of AcMPAG may be a detoxification process and human ABHD10 could be a potential therapeutic drug. [1] ABHD10 may also be used to regulate adverse effects of probenecid, because it catalyze the deglucuronidation of PRAG. [6]
ABHD10 has also been known to interact with:
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG.
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Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism 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. The study of drug metabolism is called pharmacokinetics.
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Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.
The enzyme carboxylesterase (or carboxylic-ester hydrolase, EC 3.1.1.1; systematic name carboxylic-ester hydrolase) catalyzes reactions of the following form:
Liver carboxylesterase 1 also known as carboxylesterase 1 is an enzyme that in humans is encoded by the CES1 gene. The protein is also historically known as serine esterase 1 (SES1), monocyte esterase and cholesterol ester hydrolase (CEH). Three transcript variants encoding three different isoforms have been found for this gene. The various protein products from isoform a, b and c range in size from 568, 567 and 566 amino acids long, respectively.
Glycine-N-acyltransferase, also known as GLYAT, is an enzyme which in humans is encoded by the GLYAT gene.
Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.
Acyl-coenzyme A thioesterase 11 also known as StAR-related lipid transfer protein 14 (STARD14) is an enzyme that in humans is encoded by the ACOT11 gene. This gene encodes a protein with acyl-CoA thioesterase activity towards medium (C12) and long-chain (C18) fatty acyl-CoA substrates which relies on its StAR-related lipid transfer domain. Expression of a similar murine protein in brown adipose tissue is induced by cold exposure and repressed by warmth. Expression of the mouse protein has been associated with obesity, with higher expression found in obesity-resistant mice compared with obesity-prone mice. Alternative splicing results in two transcript variants encoding different isoforms.
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UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the UGT1A9 gene.
Acyl-CoA thioesterase 9 is a protein that is encoded by the human ACOT9 gene. It is a member of the acyl-CoA thioesterase superfamily, which is a group of enzymes that hydrolyze Coenzyme A esters. There is no known function, however it has been shown to act as a long-chain thioesterase at low concentrations, and a short-chain thioesterase at high concentrations.
Anthony Clifford Allison was a South African geneticist and medical scientist who made pioneering studies on the genetic resistance to malaria. Clark completed his primary schooling in Kenya, completed his higher education in South Africa, and obtained a BSc in medical science from the University of the Witwatersrand in 1947. He earned his PhD from the University of Oxford in 1950. After working at the Radcliffe Infirmary for two years, he worked as post-doctoral student to Linus Pauling in 1954. After teaching medicine for three years at Oxford, he worked at the Medical Research Council in London. In 1978 he simultaneously worked at the International Laboratory for Research on Animal Diseases (ILRAD) as its Director, and at the World Health Organization's (WHO) Immunology Laboratory, both in Nairobi. He later became the Vice President for Research at Syntex Corporation (1981-1994).
Bartolomeo Gosio was an Italian medical scientist. He discovered a toxic fume, eponymously named "Gosio gas", which is produced by microorganisms, that killed many people. He identified the chemical nature of the gas as an arsenic compound (arsine), but incorrectly named it as diethylarsine. He also discovered an antibacterial compound called mycophenolic acid from the mould Penicillium brevicompactum. He demonstrated that the novel compound was effective against the deadly anthrax bacterium, Bacillus anthracis. This was the first antibiotic compound isolated in pure and crystallised form. Though the original compound was abandoned in clinical practice due to its adverse effects, its chemical derivative mycophenolate mofetil became the drug of choice as an immunosuppressant in kidney, heart, and liver transplantations.
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