Logo Medical Science Monitor

Call: +1.631.470.9640
Mon - Fri 10:00 am - 02:00 pm EST

Contact Us

Logo Medical Science Monitor Logo Medical Science Monitor Logo Medical Science Monitor

01 October 2006

Morphine synthesis in animals

Richard Kream, George B. Stefano

Med Sci Monit 2006; 12(10): ED1-2 :: ID: 458504


In this month's issue of Medical Science Monitor, Kream and Stefano presentan empirical based model for morphine biosynthesis in animals. Briefly, de novo biosynthesis of morphineboth in Papaver somniferum and in complex animal systems proceeds via chemical modification of two moleculesof L-tyrosine (L-TYR) and ends with the stereoselective expression of biologically active (9R)-morphine.The early stages of morphine biosynthesis in plants and animals utilize the catechol derivatives of L-TYR,L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA), to form benzylisoquinoline (BIQ) alkaloids thatsubsequently undergo sequential O- and N-methylation events, and an additional ring hydroxylation inthe plant pathway, leading to the formation of the essential chemical precursor (S)-reticuline. The importantobservation that both plant and animal systems also utilize the L-TYR-derived trace amine tyramine (TA)for cellular morphine production provides a unifying principle or platform by which to construct ourevidence-based model. TA has previously been established as a key player in the biosynthesis of the BIQalkaloids morphine, sanguinarine, and berberine, in Papaver somniferum. The critical involvement of TAin both plant and animal biosynthetic pathways supports the existence of an active, tyrosine hydroxylase(TH)-independent, cellular pathway of DA expression that may have previously gone unnoticed in higheranimal systems. The essential role of TA as a de novo precursor implicitly links present, historical,and extensive plant data that have established the critical importance of microsomal cytochrome P450(CYP) isoenzymes at early and late stages of morphine biosynthesis. CYP-mediated conversion of severalintermediate BIQ and morphinan precursors within the biosynthetic scheme also indicates that de novo synthesis of morphine is by necessity segregated to enzyme complexes and precursor pools within definedcellular compartments, notably the endoplasmic reticulum (ER) that are independently regulated and distinctfrom those predominantly devoted to TH-dependent synthesis and maintenance of vesicular DA pools. Recentstudies have demonstrated that several key enzymes in the BIQ biosynthetic pathway in Papaver somniferumare associated with the ER. As recently elucidated in plants, the enzyme (S)-norcoclaurine synthase stereoselectivelycatalyzes the condensation and rearrangement of DA and the TA metabolite 4-hydroxyphenylacetaldehydeto form (S)-norcoclaurine as the first committed step in the biosynthesis of BIQ alkaloids such as morphineand berberine. In the opium poppy, pyridoxal phosphate-dependent progenitor isoenzymes with dual L-TYR decarboxylase (TDC) and L-DOPA decarboxylase (DDC) activities generate the L-TYR-derived substrates requiredfor (S)-norcoclaurine formation. Formulation of a cogent model of regulated morphine expression in animalcells requires biochemical elucidation of a similar committed step involving enzyme-catalyzed condensationof DA with aldehyde or ketoacid metabolites of L-DOPA to form the BIQ intermediate precursor tetrahydropapaveroline(THP, also called norlaudanosoline). By analogy to the plant system, the well-established but often overlookedside reaction of mammalian DDC to produce 3, 4-dihydroxyphenylacetaldehyde via pyridoxal phosphate mediated catalysis lends strong support to its essential role as a regulatory enzyme involved in THP formationin vivo. A compelling model of de novo morphine biosynthesis in animals must also include regulatorymechanisms responsible for the compartmentalization and mobilization of essential substrate pools ofL-TYR and L-TYR-derived molecules targeted for BIQ alkaloid production. Previous in vivo pharmacologicaldata indicate reversible transamination of racemic D- and L-DOPA via the alpha-keto acid intermediate3, 4-dihydroxyphenylpyruvate and demonstrate significant L-DOPA sparing effects of co-administered 3,4-dihydroxyphenylpyruvate. Reversible transamination of L-TYR and/or L-DOPA via pyruvic acid intermediatesis proposed as a major mechanism responsible for cellular sorting and/or functional sequestration ofsubstrate pools of L-TYR-derived molecules targeted for endogenous morphine production. Finally, thefunctional implications of endogenous morphine expression as a parallel but independently regulated signalingsystem, confers a major adaptive advantage to an expanding cadre of L-TYR-derived molecular species asautocrine, paracrine, and hormonal regulators of cellular systems involved in immune function, neural-immunecoupling in the mediation of nociception and antinociception, and cardiovascular integrity linked tofunctional recruitment of constitutive nitric oxide (NO). These functional linkages establish an ontogenic/evolutionarybasis for significant cellular adaptation that is dependent on the ability of the aromatic amino acidL-TYR to serve as a pleni-potential precursor capable of significant chemical modification to accommodatean expanding functional circle of cellular regulatory activities.

Keywords: Alkaloids - biosynthesis, Benzylisoquinolines - metabolism, Dihydroxyphenylalanine - metabolism, Morphine - metabolism, Papaver - metabolism, Stereoisomerism, Tyrosine - metabolism

Add Comment 0 Comments

1127 16


01 December 2023 : Editorial  

Editorial: Outbreaks of Post-Pandemic Childhood Pneumonia and the Re-Emergence of Endemic Respiratory Infections

Dinah V. Parums

DOI: 10.12659/MSM.943312

Med Sci Monit 2023; 29:e943312


In Press

08 Dec 2023 : Clinical Research  

Association Between Influenza Vaccine Uptake and Health Awareness: A Cross-Sectional Questionnaire-Based St...

Med Sci Monit In Press; DOI:  

04 Dec 2023 : Animal Research  

Effects of Intrathecal Ketamine on Cerebrospinal Fluid Levels of Brain-Derived Neurotrophic Factor and Mech...

Med Sci Monit In Press; DOI:  

01 Dec 2023 : Clinical Research  

Risk Factors and Clinical Outcomes of COVID-19 Infection in Multiple Sclerosis Patients: A Retrospective St...

Med Sci Monit In Press; DOI:  

30 Nov 2023 : Review article  

Decoding the Neurological Sequelae of General Anesthesia: A Review

Med Sci Monit In Press; DOI:  

Most Viewed Current Articles

13 Nov 2021 : Clinical Research  

Acceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...

DOI :10.12659/MSM.932788

Med Sci Monit 2021; 27:e932788


30 Dec 2021 : Clinical Research  

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis o...

DOI :10.12659/MSM.935379

Med Sci Monit 2021; 27:e935379


14 Dec 2022 : Clinical Research  

Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase Levels

DOI :10.12659/MSM.937990

Med Sci Monit 2022; 28:e937990


08 Mar 2022 : Review article  

A Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Man...

DOI :10.12659/MSM.936292

Med Sci Monit 2022; 28:e936292


Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750