“Mycophenolic acid acyl-glucuronide esterase”的意思、由来-开放百科全书

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]

Structure

Gene

Protein

Human ABHD10 is a 297 amino acid protein with a MW 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 aa’s 46-47.^[3]

Function

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]

Clinical significance

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]

Interactions

References

1. ^¹²³⁴{{cite journal | vauthors = Iwamura A, Fukami T, Higuchi R, Nakajima M, Yokoi T | title = Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver | journal = The Journal of Biological Chemistry | volume = 287 | issue = 12 | pages = 9240–9 | date = March 2012 | pmid = 22294686 | doi = 10.1074/jbc.M111.271288 | pmc=3308823}}
2. ^{{cite journal | vauthors = Fukami T, Yokoi T | title = The emerging role of human esterases | journal = Drug Metabolism and Pharmacokinetics | volume = 27 | issue = 5 | pages = 466–77 | date = 2012 | pmid = 22813719 | doi=10.2133/dmpk.dmpk-12-rv-042}}
3. ^{{cite journal | vauthors = Li Q, Vande Velde C, Israelson A, Xie J, Bailey AO, Dong MQ, Chun SJ, Roy T, Winer L, Yates JR, Capaldi RA, Cleveland DW, Miller TM | title = ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 49 | pages = 21146–51 | date = December 2010 | pmid = 21078990 | doi = 10.1073/pnas.1014862107 | pmc=3000256}}
4. ^{{cite journal | vauthors = Wieland E, Shipkova M, Schellhaas U, Schütz E, Niedmann PD, Armstrong VW, Oellerich M | title = Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects? | journal = Clinical Biochemistry | volume = 33 | issue = 2 | pages = 107–13 | date = March 2000 | pmid = 10751588 | doi=10.1016/s0009-9120(99)00101-0}}
5. ^{{cite journal | vauthors = Shipkova M, Beck H, Voland A, Armstrong VW, Gröne HJ, Oellerich M, Wieland E | title = Identification of protein targets for mycophenolic acid acyl glucuronide in rat liver and colon tissue | journal = Proteomics | volume = 4 | issue = 9 | pages = 2728–38 | date = September 2004 | pmid = 15352247 | doi = 10.1002/pmic.200300836 }}
6. ^¹²{{cite journal | vauthors = Ito Y, Fukami T, Yokoi T, Nakajima M | title = An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver | journal = Drug Metabolism and Disposition | volume = 42 | issue = 12 | pages = 2109–16 | date = December 2014 | pmid = 25217485 | doi = 10.1124/dmd.114.059485 }}
7. ^{{cite journal | vauthors = Zuhl AM, Mohr JT, Speers AE, Bachovchin DA, Berlin JM, Spicer T, Fernandez-Vega V, Brown SJ, Ferguson J, Fu GC, Cravatt BF, Hodder P, Rosen H | title = Probe Development Efforts to Identify Novel Inhibitors of ABHD10 | journal = Probe Reports from the NIH Molecular Libraries Program | volume = | issue = | pages = | date = 6 December 2011 | pmid = 23762952 | doi = | url = https://www.ncbi.nlm.nih.gov/books/NBK143561/ }}