Codeine 3-O-demethylase
| Codeine 3-O-demethylase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 1.14.11.32 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| |||||||||
Codeine 3-O-demethylase (EC 1.14.11.32, codeine O-demethylase, CODM) is an enzyme with systematic name codeine,2-oxoglutarate:oxygen oxidoreductase (3-O-demethylating).[1] It catalyses two of the chemical reactions involved in the pathway to morphine from thebaine. One goes via oripavine and the other via codeine. Both involve the removal of a phenolic methyl group (OCH3) using molecular oxygen as oxidant.[2]
- codeine + α-ketoglutaric acid + O2 morphine + formaldehyde + succinic acid + CO2
This is the reaction from which the enzyme gets its name. However, it also acts on thebaine:
- thebaine + α-ketoglutaric acid + O2 oripavine + formaldehyde + succinic acid + CO2
Conversion of thebaine to oripavine
In this part of the biosynthesis of morphine in the opium poppy Papaver somniferum, the substrate of the enzyme is thebaine and the alkaloid product is oripavine:[3][4]
In this sequence, codeine 3-O-demethylase is responsible for removal of the methyl substituent of the methoxy group attached to the phenyl ring, which is converted to formaldehyde, with the oxidation driven by molecular oxygen.[2] This route to morphine is completed via morphinone.[4] The enzyme is a non-heme iron protein with ferryl active site where Fe(IV)=O is the species that transfers its oxygen to the substrate.[5]
The mechanism used by these 2-oxoglutarate-dependent oxygenases requires 2-oxoglutaric acid to activate the iron oxygen complex, and this gives succinic acid and carbon dioxide when the second atom of the molecular oxygen is removed.[6]
Conversion of codeine to morphine
In the alternative pathway to morphine in which thebaine is first demethylated at its enol ether by the enzyme thebaine 6-O-demethylase giving neopinone and subsequently codeinone and codeine, the final step again involves codeine 3-O-demethylase:[4]
Codeine 3-O-demethylase and thebaine 6-O-demethylase are both α-ketoglutarate/Fe(II)-dependent dioxygenases and as of 2024 were the only enzymes confirmed to use this combination for demethylation.[4]
References
- ^ Hagel, Jillian M.; Facchini, Peter J. (2010). "Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy". Nature Chemical Biology. 6 (4): 273–275. doi:10.1038/nchembio.317. PMID 20228795.
- ^ a b Enzyme 1.14.11.32 at KEGG Pathway Database.
- ^ Mascavage, Linda M.; Jasmin, Serge; Sonnet, Philip E.; Wilson, Michael; Dalton, David R. (2010). "Alkaloids". Ullmann's Encyclopedia of Industrial Chemistry. pp. 46–54. doi:10.1002/14356007.a01_353.pub2. ISBN 978-3-527-30385-4.
- ^ a b c d Tian, Ya; Kong, Lingzhe; Li, Qi; Wang, Yifan; Wang, Yongmiao; An, Zhoujie; Ma, Yuwei; Tian, Lixia; Duan, Baozhong; Sun, Wei; Gao, Ranran; Chen, Shilin; Xu, Zhichao (2024). "Structural diversity, evolutionary origin, and metabolic engineering of plant specialized benzylisoquinoline alkaloids". Natural Product Reports. 41 (11): 1787–1810. doi:10.1039/d4np00029c. PMID 39360417.
- ^ Mbenza, Naasson M.; Vadakkedath, Praveen G.; McGillivray, Duncan J.; Leung, Ivanhoe K.H. (2017). "NMR studies of the non-haem Fe(II) and 2-oxoglutarate-dependent oxygenases". Journal of Inorganic Biochemistry. 177: 384–394. doi:10.1016/j.jinorgbio.2017.08.032. PMID 28893416.
- ^ Clifton, Ian J.; Hsueh, Li-Ching; Baldwin, Jack E.; Harlos, Karl; Schofield, Christopher J. (2001). "Structure of proline 3-hydroxylase". European Journal of Biochemistry. 268 (24): 6625–6636. doi:10.1046/j.0014-2956.2001.02617.x. PMID 11737217.
External links
- Codeine+3-O-demethylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)