Member and Principal Investigator Donald Danforth Plant Science Center Adjunct
Professor M.S.
in Biology (1958) Doctorate
in Plant Science (1959) |
Poppy capsule and brain tissue each contain morphine
Abbreviated biosynthetic
pathway to morphine in human cells
Morphine is a plant-derived alkaloid produced by Papaver somniferum , the opium poppy. Our group has studied the biosynthesis of morphine at the enzyme level, and has found that the process consists of nineteen chemical steps. Morphine is one of the strongest known analgesic compounds and is regarded in medicine as a very reliable and almost never failing pain killer. Morphine, a low molecular weight compound has such a complex structure that the pharmaceutical industry has yet to synthesize it on an industrial scale. Studies over the past two decades have suggested that human tissue and fluids contain trace amounts of morphine. Its presence in mammals has largely been attributed to a dietary origin. Recently, by using isotopic labeled oxygen ( 18 O 2 ), our laboratory unequivocally demonstrated that human cells (neuroblastoma and other cells) synthesize morphine de novo at ca 10 nM concentration, which would be sufficient to modulate the µ-opiate receptor. This was the first experimental proof that morphine occurs by endogenous formation in humans. A very sensitive methodology is being established to quantify morphine and its precursor molecules in mammalian cells and tissue using GC-MSMS and LC-MSMS. The fragmentation pattern of these molecules has been established by using very different mass spectrometer types. The activation by morphine and its precursors of the µ-opioid receptor, present on cells of the nervous and immune systems, is being studied. To explore the function of endogenous morphine in mammals our group studies the location of morphine accumulation in different organs and organelles of the body, especially the brain, spinal cord and blood. The regulation of morphine biosynthesis under stress is being studied through stable isotope-labeled precursor feeding experiments. These application experiments allow the quantitation of de novo endogenous biosynthesis and will yield information as to the turnover of this molecule in vivo . In addition, the inactivation of morphine in the body is being studied. Our goal is to understand the role and function of endogenous morphine in mammals and to develop conditions and drugs that will lead to pain relief through endogenous morphine. |
Nikolaev, V.O., Boettcher, C., Bünemann, M., Lohse, M.J. and Zenk, M.H. (2006) Functional analysis of µ-opoid receptor activation by endogenously occurring morphine biosynthetic precursors. Molecular Pharmacology . Submitted. |
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Boettcher, C., Fischer, W., and Zenk, M.H. (2006) Comment on "Human White Blood Cells Synthesize Morphine: CYP2D6 Modulation". Journal of Immunology. 176: 5703. |
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Schmidt, J., Boettcher, C., Kuhnt, C., Kutchan, T.M. and Zenk, M.H. (2006) Poppy alkaloid profiling by electrospray tandem mass spectrometry and electrospray FT-ICR mass spectrometry after [ ring - 13 C 6 ]-tyramine feeding. Phytochemistry . Submitted. |
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Boettcher, C., Fellermeier, M., Boettcher , Ch. , Dräger, B. and Zenk, M.H. (2005) How human neuroblastoma cells make morphine. Proceedings of the National Academy of Sciences . 102: 8495-8500. |
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Schmidt, J., Raith, K., Boettcher, C. and Zenk, M.H. (2005) Analysis of benzylisoquinoline-type alkaloids by elctrospray tandem mass spectrometry and atmospheric pressure photoionizaiton. European Journal of Mass Spectrometry . 11: 325-333. |
Millgate, A.G., Pogson, B.J., Wilson , I.W., Kutchan, T.M., Zenk, M.H., Gerlach, W.L., Fist, J. and Larkin, P.J. (2004) Analgesia: Morphine-pathway block in top1 poppies. Nature . 431: 413-414. |
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| Poeaknapo, C., Schmidt, J., Brandsch, M., Dräger, B. and Zenk, M.H. (2004) Endogenous formation of morphine in human cells. Proceedings of the National Academy of Science . 101: 14091-14096 |
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Poeaknapo, C., Fisinger, U., Zenk, M.H. and Schmidt, J. (2004) Evaluation of the mass spectrometric fragmentation of codeine and morphine after 13 C-isotope biosynthetic labeling. Phytochemistry . 65: 1413-1420. |
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Hirata, K., Poeaknapo, C., Schmidt, J. and Zenk, M.H. (2004) Dehydroreticuline synthase, the branch point enzyme opening the morphine specific pathway. Phytochemistry . 65: 1039-1046. |
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Raith, K., Neubert, R., Poeaknapo, C., Böttcher, C., Schmidt, J. and Zenk, M.H. (2003) Electrospray tandem mass spectrometric investigations of morphinans. American Society of Mass Spectrometry . 14: 1262-1269. |
