Mycophenolic acid acyl-glucuronide esterase

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

mycophenolic acid O-acyl-glucuronide + H₂O

\rightleftharpoons

mycophenolate + D-glucuronate

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

ABHD10 gene is located at chromosome 3q13.2, consisting of 6 exons.

Protein

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]

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

ABHD10 has also been known to interact with:

References

^ ^a ^b ^c ^d ^e Iwamura A, Fukami T, Higuchi R, Nakajima M, Yokoi T (March 2012). "Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver". The Journal of Biological Chemistry. 287 (12): 9240–9. doi:10.1074/jbc.M111.271288. PMC 3308823. PMID 22294686.
^ Fukami T, Yokoi T (2012). "The emerging role of human esterases". Drug Metabolism and Pharmacokinetics. 27 (5): 466–77. doi:10.2133/dmpk.dmpk-12-rv-042. PMID 22813719.
^ 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 (December 2010). "ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import". Proceedings of the National Academy of Sciences of the United States of America. 107 (49): 21146–51. Bibcode:2010PNAS..10721146L. doi:10.1073/pnas.1014862107. PMC 3000256. PMID 21078990.
^ Wieland E, Shipkova M, Schellhaas U, Schütz E, Niedmann PD, Armstrong VW, Oellerich M (March 2000). "Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects?". Clinical Biochemistry. 33 (2): 107–13. doi:10.1016/s0009-9120(99)00101-0. PMID 10751588.
^ Shipkova M, Beck H, Voland A, Armstrong VW, Gröne HJ, Oellerich M, Wieland E (September 2004). "Identification of protein targets for mycophenolic acid acyl glucuronide in rat liver and colon tissue". Proteomics. 4 (9): 2728–38. doi:10.1002/pmic.200300836. PMID 15352247. S2CID 23631184.
^ ^a ^b ^c Ito Y, Fukami T, Yokoi T, Nakajima M (December 2014). "An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver". Drug Metabolism and Disposition. 42 (12): 2109–16. doi:10.1124/dmd.114.059485. PMID 25217485.
^ 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 (6 December 2011). "Probe Development Efforts to Identify Novel Inhibitors of ABHD10". Probe Reports from the NIH Molecular Libraries Program. PMID 23762952.

External links

Mycophenolic+acid+acyl-glucuronide+esterase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

[pmid22294686-1] Iwamura A, Fukami T, Higuchi R, Nakajima M, Yokoi T (March 2012). "Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver". The Journal of Biological Chemistry. 287 (12): 9240–9. doi:10.1074/jbc.M111.271288. PMC 3308823. PMID 22294686.

[pmid22813719-2] Fukami T, Yokoi T (2012). "The emerging role of human esterases". Drug Metabolism and Pharmacokinetics. 27 (5): 466–77. doi:10.2133/dmpk.dmpk-12-rv-042. PMID 22813719.

[pmid21078990-3] 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 (December 2010). "ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import". Proceedings of the National Academy of Sciences of the United States of America. 107 (49): 21146–51. Bibcode:2010PNAS..10721146L. doi:10.1073/pnas.1014862107. PMC 3000256. PMID 21078990.

[pmid10751588-4] Wieland E, Shipkova M, Schellhaas U, Schütz E, Niedmann PD, Armstrong VW, Oellerich M (March 2000). "Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects?". Clinical Biochemistry. 33 (2): 107–13. doi:10.1016/s0009-9120(99)00101-0. PMID 10751588.

[pmid15352247-5] Shipkova M, Beck H, Voland A, Armstrong VW, Gröne HJ, Oellerich M, Wieland E (September 2004). "Identification of protein targets for mycophenolic acid acyl glucuronide in rat liver and colon tissue". Proteomics. 4 (9): 2728–38. doi:10.1002/pmic.200300836. PMID 15352247. S2CID 23631184.

[pmid25217485-6] Ito Y, Fukami T, Yokoi T, Nakajima M (December 2014). "An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver". Drug Metabolism and Disposition. 42 (12): 2109–16. doi:10.1124/dmd.114.059485. PMID 25217485.

[pmid23762952-7] 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 (6 December 2011). "Probe Development Efforts to Identify Novel Inhibitors of ABHD10". Probe Reports from the NIH Molecular Libraries Program. PMID 23762952.

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)