Comparative functional analysis of CYP71AV1 natural variants reveals an important residue for the successive oxidation of amorpha‐4,11‐diene
Abstract
Artemisinin is an antimalarial sesquiterpenoid isolated from the aerial parts of the plant Artemisia annua. CYP71AV1, a cytochrome P450 monooxygenase was identified in the artemisinin biosynthetic pathway. CYP71AV1 catalyzes three successive oxidation steps at the C12 position of amorpha‐4,11‐diene to produce artemisinic acid. In this study, we isolated putative CYP71AV1 orthologs in different species of Artemisia. Comparative functional analysis of CYP71AV1 and its putative orthologs, together with homology modeling, enabled us to identify an amino acid residue (Ser479) critical for the second oxidation reaction catalyzed by CYP71AV1. Our results clearly show that a comparative study of natural variants is useful to investigate the structure–function relationships of CYP71AV1.
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Compared to WT and heterozygous material, the juvenile leaves of cyp71av1-1 contain significantly elevated levels of amorpha-4,11-diene (A-4,11-D).
“Compared to WT and heterozygous material, the juvenile leaves of cyp71av1-1 contain significantly elevated levels of the first committed metabolite in the artemisinin pathway, amorpha4,11-diene (A-4,11-D; Fig. 1A i), Supplemental T ables 2 and 4), consistent with the reported in vitro activity of CYP71AV1 (13, 26, 27).”
From <i>Artemisia annua</i> mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [27]
CYP71AV1 catalyses the three-step conversion of amorpha-4,11-diene to artemisinic acid.
“We have chosen to target CYP71AV1, which catalyses the three-step conversion of amorpha-4,11-diene to artemisinic acid (13, 26, 27).”
From <i>Artemisia annua</i> mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism (2016) · cites this paper as [27]
Cites
Schmid, G., & Hofheinz, W. (1983) · Journal of the American Chemical Society · doi:10.1021/ja00341a054 · Cited by 329 · cited 1× · see citing works
“Many valuable contributions to the total synthesis of artemisinin have been reported [2–4], but the industrialization of total chemical synthesis has not yet been achieved due to the high cost of the multistep synthesis process.”
BackgroundBertea, C. M., Freije, J. R., van der Woude, H., Verstappen, F. W., Perk, L., Marquez, V., De Kraker, J.-W., Posthumus, M. A., Jansen, B. J., de Groot, A., et al. (2005) · Planta Medica · doi:10.1055/s-2005-837749 · Cited by 205 · see citing works
The Total synthesis of (+)-artemisinin and (+)-9-desmethyltemesinin
Avery, M. A., Jennings-White, C., & Chong, W. K. M. (1987) · Tetrahedron Letters · doi:10.1016/s0040-4039(00)96582-1 · Cited by 114 · see citing works
Picaud, S., Mercke, P., He, X., Sterner, O., Brodelius, M., Cane, D. E., & Brodelius, P. E. (2006) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2005.07.015 · Cited by 79 · cited 1× · see citing works
“All compounds were identified by a comparison of proton nuclear magnetic resonance spectroscopy ((1)H NMR), carbon nuclear magnetic resonance spectroscopy ((13)C NMR), and gas chromatography–mass spectrometry (GC–MS) with reference data [11,17,18].”
BackgroundBioconversion of arteannuin B to artemisinin
Nair, M. S. R., & Basile, D. V. (1993) · Journal of Natural Products · doi:10.1021/np50099a015 · Cited by 62 · cited 1× · see citing works
“In an earlier study, artemisinic acid was proposed as a precursor of artemisinin [9].”
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Czechowski, T., Larson, T. R., Catania, T. M., Harvey, D., Brown, G. D., & Graham, I. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611567113 · Cited by 94 · see citing works
- Authors
- Komori, A., Suzuki, M., Seki, H., Nishizawa, T., Meyer, J. J. M., Shimizu, H., Yokoyama, S., & Muranaka, T.
- Affiliations
- Kihara Institute for Biological Research (JP)
- RIKEN (JP)
- University of Pretoria (ZA)
- ORCID
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2012-12-13
- Volume
- 587
- Issue
- 3
- Pages
- 278-284
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2126658049
- Cited by
- 24
- References
- 5
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 1 · 2013: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- RIKEN
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- CYP71AV1, cytochrome P450 monooxygenase, artemisinin biosynthesis, artemisinic acid, structure-function relationship, Artemisia, natural variants, homology modeling, sesquiterpene biosynthesis
- MeSH terms
- Polycyclic Sesquiterpenes, Amino Acid Sequence, Cytochrome P-450 Enzyme System, Models, Molecular, Molecular Sequence Data, Mutation, Oxidation-Reduction, Protein Conformation, Sequence Homology, Nucleic Acid, Sesquiterpenes, Species Specificity, Mutagenesis, Site-Directed, Artemisia absinthium, Artemisia annua, Biocatalysis
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