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morphine-6-glucuronide is more potent , not less potent than morphine Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-
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Together with [[UGT2B4]], UGT2B7 is capable of glucosidation of [[hyodesoxycholic acid]] in the liver, but, unlike the 2B4 isoform, 2B7 is also able to glucuronidate various [[steroid hormones]] ([[androsterone]], [[epitestosterone]]) and [[fatty acids]].<ref name="pmid12527334">{{cite journal | vauthors = Mackenzie P, Little JM, Radominska-Pandya A | title = Glucosidation of hyodeoxycholic acid by UDP-glucuronosyltransferase 2B7 | journal = Biochem. Pharmacol. | volume = 65 | issue = 3 | pages = 417–21 | date = February 2003 | pmid = 12527334 | doi = 10.1016/S0006-2952(02)01522-8 | url = }}</ref><ref name="pmid17263731">{{cite journal | vauthors = Barre L, Fournel-Gigleux S, Finel M, Netter P, Magdalou J, Ouzzine M | title = Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33 | journal = FEBS J. | volume = 274 | issue = 5 | pages = 1256–64 | date = March 2007 | pmid = 17263731 | doi = 10.1111/j.1742-4658.2007.05670.x }}</ref> It is also able to conjugate major classes of drugs such as analgesics ([[morphine]]), carboxylic nonsteroidal anti-inflammatory drugs ([[ketoprofen]]), and anticarcinogens (''all-trans'' [[retinoic acid]]).<ref name="pmid17263731"/> UGT2B7 is the major enzyme isoform for the metabolism of [[morphine]] to the main metabolites, [[morphine-3-glucuronide]] (M3G) which has no analgesic effect and [[morphine-6-glucuronide]] (M6G),<ref>{{cite journal | vauthors = Coffman BL, Rios GR, King CD, Tephly TR | title = Human UGT2B7 catalyzes morphine glucuronidation | journal = Drug Metab. Dispos. | volume = 25 | issue = 1 | pages = 1–4 | date = 1 January 1997 | pmid = 9010622 | url = http://dmd.aspetjournals.org/cgi/content/abstract/25/1/1 }}</ref> which has analgesic effects more potent than morphine.<ref name="van Dorp">{{cite journal | vauthors = van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A | title = Morphine-6-glucuronide: morphine's successor for postoperative pain relief? | journal = Anesthesia and Analgesia | volume = 102 | issue = 6 | pages = 1789–1797 | year = 2006 | pmid = 16717327 | doi = 10.1213/01.ane.0000217197.96784.c3 | url = http://www.anesthesia-analgesia.org/cgi/content/full/102/6/1789 }}</ref> As a consequence, altered UGT2B7 activity can significantly affect both the effectiveness and side-effects of morphine, as well as some related opiate drugs.<ref>{{cite journal | vauthors = Coller JK, Christrup LL, Somogyi AA | title = Role of active metabolites in the use of opioids. | journal = European journal of clinical pharmacology | volume = 65 | issue = 2 | pages = 121–39 | year = 2009 | pmid = 18958460 | doi = 10.1007/s00228-008-0570-y }}</ref><ref>{{cite journal | vauthors = Fujita K, Ando Y, Yamamoto W, Miya T, Endo H, Sunakawa Y, Araki K, Kodama K, Nagashima F, Ichikawa W, Narabayashi M, Akiyama Y, Kawara K, Shiomi M, Ogata H, Iwasa H, Okazaki Y, Hirose T, Sasaki Y | title = Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer | journal = Cancer chemotherapy and pharmacology | volume = 65 | issue = 2 | pages = 251–8 | year = 2009 | pmid = 19466410 | doi = 10.1007/s00280-009-1029-2 }}</ref><ref>{{cite journal | vauthors = Abildskov K, Weldy P, Garland M | title = Molecular Cloning of the Baboon UDP-Glucuronosyltransferase 2B Gene Family and Their Activity in Conjugating Morphine | journal = Drug metabolism and disposition: the biological fate of chemicals | volume = 38 | issue = 4 | pages = 545–53 | year = 2010 | pmid = 20071451 | pmc = 2845934 | doi = 10.1124/dmd.109.030635 }}</ref><ref>{{cite journal | vauthors = Pergolizzi JV, Raffa RB, Gould E | title = Considerations on the use of oxymorphone in geriatric patients | journal = Expert opinion on drug safety | volume = 8 | issue = 5 | pages = 603–13 | year = 2009 | pmid = 19614559 | doi = 10.1517/14740330903153854 }}</ref><ref>{{cite journal | vauthors = Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P | title = Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes | journal = Drug metabolism and disposition: the biological fate of chemicals | volume = 38 | issue = 1 | pages = 40–5 | year = 2010 | pmid = 19841060 | doi = 10.1124/dmd.109.029546 }}</ref>
Together with [[UGT2B4]], UGT2B7 is capable of glucosidation of [[hyodesoxycholic acid]] in the liver, but, unlike the 2B4 isoform, 2B7 is also able to glucuronidate various [[steroid hormones]] ([[androsterone]], [[epitestosterone]]) and [[fatty acids]].<ref name="pmid12527334">{{cite journal | vauthors = Mackenzie P, Little JM, Radominska-Pandya A | title = Glucosidation of hyodeoxycholic acid by UDP-glucuronosyltransferase 2B7 | journal = Biochem. Pharmacol. | volume = 65 | issue = 3 | pages = 417–21 | date = February 2003 | pmid = 12527334 | doi = 10.1016/S0006-2952(02)01522-8 | url = }}</ref><ref name="pmid17263731">{{cite journal | vauthors = Barre L, Fournel-Gigleux S, Finel M, Netter P, Magdalou J, Ouzzine M | title = Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33 | journal = FEBS J. | volume = 274 | issue = 5 | pages = 1256–64 | date = March 2007 | pmid = 17263731 | doi = 10.1111/j.1742-4658.2007.05670.x }}</ref> It is also able to conjugate major classes of drugs such as analgesics ([[morphine]]), carboxylic nonsteroidal anti-inflammatory drugs ([[ketoprofen]]), and anticarcinogens (''all-trans'' [[retinoic acid]]).<ref name="pmid17263731"/> UGT2B7 is the major enzyme isoform for the metabolism of [[morphine]] to the main metabolites, [[morphine-3-glucuronide]] (M3G) which has no analgesic effect and [[morphine-6-glucuronide]] (M6G),<ref>{{cite journal | vauthors = Coffman BL, Rios GR, King CD, Tephly TR | title = Human UGT2B7 catalyzes morphine glucuronidation | journal = Drug Metab. Dispos. | volume = 25 | issue = 1 | pages = 1–4 | date = 1 January 1997 | pmid = 9010622 | url = http://dmd.aspetjournals.org/cgi/content/abstract/25/1/1 }}</ref> which has analgesic effects more potent than morphine.<ref name="van Dorp">{{cite journal | vauthors = van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A | title = Morphine-6-glucuronide: morphine's successor for postoperative pain relief? | journal = Anesthesia and Analgesia | volume = 102 | issue = 6 | pages = 1789–1797 | year = 2006 | pmid = 16717327 | doi = 10.1213/01.ane.0000217197.96784.c3 | url = http://www.anesthesia-analgesia.org/cgi/content/full/102/6/1789 }}</ref> As a consequence, altered UGT2B7 activity can significantly affect both the effectiveness and side-effects of morphine, as well as some related opiate drugs.<ref>{{cite journal | vauthors = Coller JK, Christrup LL, Somogyi AA | title = Role of active metabolites in the use of opioids. | journal = European journal of clinical pharmacology | volume = 65 | issue = 2 | pages = 121–39 | year = 2009 | pmid = 18958460 | doi = 10.1007/s00228-008-0570-y }}</ref><ref>{{cite journal | vauthors = Fujita K, Ando Y, Yamamoto W, Miya T, Endo H, Sunakawa Y, Araki K, Kodama K, Nagashima F, Ichikawa W, Narabayashi M, Akiyama Y, Kawara K, Shiomi M, Ogata H, Iwasa H, Okazaki Y, Hirose T, Sasaki Y | title = Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer | journal = Cancer chemotherapy and pharmacology | volume = 65 | issue = 2 | pages = 251–8 | year = 2009 | pmid = 19466410 | doi = 10.1007/s00280-009-1029-2 }}</ref><ref>{{cite journal | vauthors = Abildskov K, Weldy P, Garland M | title = Molecular Cloning of the Baboon UDP-Glucuronosyltransferase 2B Gene Family and Their Activity in Conjugating Morphine | journal = Drug metabolism and disposition: the biological fate of chemicals | volume = 38 | issue = 4 | pages = 545–53 | year = 2010 | pmid = 20071451 | pmc = 2845934 | doi = 10.1124/dmd.109.030635 }}</ref><ref>{{cite journal | vauthors = Pergolizzi JV, Raffa RB, Gould E | title = Considerations on the use of oxymorphone in geriatric patients | journal = Expert opinion on drug safety | volume = 8 | issue = 5 | pages = 603–13 | year = 2009 | pmid = 19614559 | doi = 10.1517/14740330903153854 }}</ref><ref>{{cite journal | vauthors = Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P | title = Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes | journal = Drug metabolism and disposition: the biological fate of chemicals | volume = 38 | issue = 1 | pages = 40–5 | year = 2010 | pmid = 19841060 | doi = 10.1124/dmd.109.029546 }}</ref>

== Structure ==
No structure of a full human UGT enzyme has been determined yet, however Miley et al resolved a partial UGT2B7 structure showing two dimeric domains with Rossman-like folds in complex.<ref>{{Cite journal|last=Lampe|first=Jed N.|date=2017|title=Advances in the Understanding of Protein-Protein Interactions in Drug Metabolizing Enzymes through the Use of Biophysical Techniques|url=https://www.ncbi.nlm.nih.gov/pubmed/28848438|journal=Frontiers in Pharmacology|volume=8|pages=521|doi=10.3389/fphar.2017.00521|issn=1663-9812|pmc=PMC5550701|pmid=28848438}}</ref><ref>{{Cite journal|last=Miley|first=Michael J.|last2=Zielinska|first2=Agnieszka K.|last3=Keenan|first3=Jeffrey E.|last4=Bratton|first4=Stacie M.|last5=Radominska-Pandya|first5=Anna|last6=Redinbo|first6=Matthew R.|date=2007-06-01|title=Crystal structure of the cofactor-binding domain of the human phase II drug-metabolism enzyme UDP-glucuronosyltransferase 2B7|url=https://www.ncbi.nlm.nih.gov/pubmed/17442341|journal=Journal of Molecular Biology|volume=369|issue=2|pages=498–511|doi=10.1016/j.jmb.2007.03.066|issn=0022-2836|pmc=PMC1976284|pmid=17442341}}</ref> The Rossman fold typically binds nucleotide substrates, in this case the UDP-glucuronic acid cofactor involved in glucuronidation by UGT2B7. Generally, the C-terminus of UGT enzymes is highly conserved and binds the UDP-glucuronic acid cofactor, while the N-terminus is responsible for substrate binding.<ref name=":0">{{Cite journal|last=Yuan|first=Lingmin|last2=Qian|first2=Sainan|last3=Xiao|first3=Yongsheng|last4=Sun|first4=Hongying|last5=Zeng|first5=Su|date=2015-05-01|title=Homo- and hetero-dimerization of human UDP-glucuronosyltransferase 2B7 (UGT2B7) wild type and its allelic variants affect zidovudine glucuronidation activity|url=https://www.ncbi.nlm.nih.gov/pubmed/25770680|journal=Biochemical Pharmacology|volume=95|issue=1|pages=58–70|doi=10.1016/j.bcp.2015.03.002|issn=1873-2968|pmid=25770680}}</ref> This first resolved structure interestingly indicated that the C-terminus of one of the two dimers projected into the UDP-glucuronic acid binding site of the second dimer, thus rendering the second dimer ineffective.

Further studies have investigated dimerization of UGT enzyme polymorphisms and found both homodimer and heterodimer formation are possible, with some combinations having an effect on enzyme activity.<ref name=":0" />


== References ==
== References ==

Revision as of 02:05, 8 March 2018

UGT2B7
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesUGT2B7, UDPGT 2B9, UDPGT2B7, UDPGTH2, UGT2B9, UDP glucuronosyltransferase family 2 member B7, UDPGT 2B7, UDPGTh-2
External IDsOMIM: 600068; MGI: 3576103; HomoloGene: 128251; GeneCards: UGT2B7; OMA:UGT2B7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7364

231396

Ensembl

ENSG00000171234

ENSMUSG00000070704

UniProt

P16662

n/a

RefSeq (mRNA)

NM_001074
NM_001330719
NM_001349568

NM_001029867

RefSeq (protein)

NP_001065
NP_001317648
NP_001336497

n/a

Location (UCSC)Chr 4: 69.05 – 69.11 MbChr 5: 87.21 – 87.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltransferase-2B7 is encoded by the UGT2B7 gene.[5][6]

Function

The UGTs serve a major role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. UGT2B7 has unique specificity for 3,4-catechol estrogens and estriol, suggesting that it may play an important role in regulating the level and activity of these potent estrogen metabolites.

This enzyme is located on the endoplasmic reticulum and nuclear membranes of cells. Its function is to catalyse the conjugation of a wide variety of lipophilic aglycon substrates with glucuronic acid, using uridine diphosphate glucuronic acid.

Together with UGT2B4, UGT2B7 is capable of glucosidation of hyodesoxycholic acid in the liver, but, unlike the 2B4 isoform, 2B7 is also able to glucuronidate various steroid hormones (androsterone, epitestosterone) and fatty acids.[7][8] It is also able to conjugate major classes of drugs such as analgesics (morphine), carboxylic nonsteroidal anti-inflammatory drugs (ketoprofen), and anticarcinogens (all-trans retinoic acid).[8] UGT2B7 is the major enzyme isoform for the metabolism of morphine to the main metabolites, morphine-3-glucuronide (M3G) which has no analgesic effect and morphine-6-glucuronide (M6G),[9] which has analgesic effects more potent than morphine.[10] As a consequence, altered UGT2B7 activity can significantly affect both the effectiveness and side-effects of morphine, as well as some related opiate drugs.[11][12][13][14][15]

Structure

No structure of a full human UGT enzyme has been determined yet, however Miley et al resolved a partial UGT2B7 structure showing two dimeric domains with Rossman-like folds in complex.[16][17] The Rossman fold typically binds nucleotide substrates, in this case the UDP-glucuronic acid cofactor involved in glucuronidation by UGT2B7. Generally, the C-terminus of UGT enzymes is highly conserved and binds the UDP-glucuronic acid cofactor, while the N-terminus is responsible for substrate binding.[18] This first resolved structure interestingly indicated that the C-terminus of one of the two dimers projected into the UDP-glucuronic acid binding site of the second dimer, thus rendering the second dimer ineffective.

Further studies have investigated dimerization of UGT enzyme polymorphisms and found both homodimer and heterodimer formation are possible, with some combinations having an effect on enzyme activity.[18]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000171234 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000070704 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Ritter JK, Sheen YY, Owens IS (May 1990). "Cloning and expression of human liver UDP-glucuronosyltransferase in COS-1 cells. 3,4-catechol estrogens and estriol as primary substrates". J. Biol. Chem. 265 (14): 7900–6. PMID 2159463.
  6. ^ Monaghan G, Clarke DJ, Povey S, See CG, Boxer M, Burchell B (September 1994). "Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4q13". Genomics. 23 (2): 496–9. doi:10.1006/geno.1994.1531. PMID 7835904.
  7. ^ Mackenzie P, Little JM, Radominska-Pandya A (February 2003). "Glucosidation of hyodeoxycholic acid by UDP-glucuronosyltransferase 2B7". Biochem. Pharmacol. 65 (3): 417–21. doi:10.1016/S0006-2952(02)01522-8. PMID 12527334.
  8. ^ a b Barre L, Fournel-Gigleux S, Finel M, Netter P, Magdalou J, Ouzzine M (March 2007). "Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33". FEBS J. 274 (5): 1256–64. doi:10.1111/j.1742-4658.2007.05670.x. PMID 17263731.
  9. ^ Coffman BL, Rios GR, King CD, Tephly TR (1 January 1997). "Human UGT2B7 catalyzes morphine glucuronidation". Drug Metab. Dispos. 25 (1): 1–4. PMID 9010622.
  10. ^ van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A (2006). "Morphine-6-glucuronide: morphine's successor for postoperative pain relief?". Anesthesia and Analgesia. 102 (6): 1789–1797. doi:10.1213/01.ane.0000217197.96784.c3. PMID 16717327.
  11. ^ Coller JK, Christrup LL, Somogyi AA (2009). "Role of active metabolites in the use of opioids". European journal of clinical pharmacology. 65 (2): 121–39. doi:10.1007/s00228-008-0570-y. PMID 18958460.
  12. ^ Fujita K, Ando Y, Yamamoto W, Miya T, Endo H, Sunakawa Y, Araki K, Kodama K, Nagashima F, Ichikawa W, Narabayashi M, Akiyama Y, Kawara K, Shiomi M, Ogata H, Iwasa H, Okazaki Y, Hirose T, Sasaki Y (2009). "Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer". Cancer chemotherapy and pharmacology. 65 (2): 251–8. doi:10.1007/s00280-009-1029-2. PMID 19466410.
  13. ^ Abildskov K, Weldy P, Garland M (2010). "Molecular Cloning of the Baboon UDP-Glucuronosyltransferase 2B Gene Family and Their Activity in Conjugating Morphine". Drug metabolism and disposition: the biological fate of chemicals. 38 (4): 545–53. doi:10.1124/dmd.109.030635. PMC 2845934. PMID 20071451.
  14. ^ Pergolizzi JV, Raffa RB, Gould E (2009). "Considerations on the use of oxymorphone in geriatric patients". Expert opinion on drug safety. 8 (5): 603–13. doi:10.1517/14740330903153854. PMID 19614559.
  15. ^ Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P (2010). "Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes". Drug metabolism and disposition: the biological fate of chemicals. 38 (1): 40–5. doi:10.1124/dmd.109.029546. PMID 19841060.
  16. ^ Lampe, Jed N. (2017). "Advances in the Understanding of Protein-Protein Interactions in Drug Metabolizing Enzymes through the Use of Biophysical Techniques". Frontiers in Pharmacology. 8: 521. doi:10.3389/fphar.2017.00521. ISSN 1663-9812. PMC 5550701. PMID 28848438.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  17. ^ Miley, Michael J.; Zielinska, Agnieszka K.; Keenan, Jeffrey E.; Bratton, Stacie M.; Radominska-Pandya, Anna; Redinbo, Matthew R. (2007-06-01). "Crystal structure of the cofactor-binding domain of the human phase II drug-metabolism enzyme UDP-glucuronosyltransferase 2B7". Journal of Molecular Biology. 369 (2): 498–511. doi:10.1016/j.jmb.2007.03.066. ISSN 0022-2836. PMC 1976284. PMID 17442341.{{cite journal}}: CS1 maint: PMC format (link)
  18. ^ a b Yuan, Lingmin; Qian, Sainan; Xiao, Yongsheng; Sun, Hongying; Zeng, Su (2015-05-01). "Homo- and hetero-dimerization of human UDP-glucuronosyltransferase 2B7 (UGT2B7) wild type and its allelic variants affect zidovudine glucuronidation activity". Biochemical Pharmacology. 95 (1): 58–70. doi:10.1016/j.bcp.2015.03.002. ISSN 1873-2968. PMID 25770680.

Further reading

External links

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