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



01 December 2022 : Editorial  

Editorial: The World Health Organization (WHO) Fungal Priority Pathogens List in Response to Emerging Fungal Pathogens During the COVID-19 Pandemic

Dinah V. Parums
Science Editor, Medical Science Monitor, International Scientific Information, Inc., Melville, NY, USA

DOI: 10.12659/MSM.939088

Med Sci Monit 2022; 28:e939088


29 November 2022 : Clinical Research  

Retrospective Study to Identify Risk Factors for Severe Disease and Mortality Using the Modified Early Warn...

Med Sci Monit In Press; DOI: 10.12659/MSM.938647  

24 November 2022 : Clinical Research  

A Prospective Questionnaire-Based Study to Evaluate Factors Affecting the Decision to Receive COVID-19 Vacc...

Med Sci Monit In Press; DOI: 10.12659/MSM.938665  

01 November 2022 : Clinical Research  

Questionnaire-Based Study of 81 Patients in Poland to Evaluate the Course of Inflammatory Bowel Disease and...

Med Sci Monit 2022; 28:e938243

In Press

05 Dec 2022 : Database Analysis  

Impact of the De Ritis Ratio on the Prognosis of Patients with Stable Coronary Artery Disease Undergoing Pe...

Med Sci Monit In Press; DOI: 10.12659/MSM.937737  

02 Dec 2022 : Clinical Research  

Value of Early Laparoscopic Exploration for Primary Infertile Patients with Patent Fallopian Tubes Complica...

Med Sci Monit In Press; DOI: 10.12659/MSM.938637  

02 Dec 2022 : Clinical Research  

Single-Center Study in Lithuania to Evaluate the Role of Transthoracic Impedance Cardiography in the Diagno...

Med Sci Monit In Press; DOI: 10.12659/MSM.938389  

30 Nov 2022 : Clinical Research  

Retrospective Evaluation of Hematological and Clinical Factors Associated with 30-Day Mortality in 170 Pati...

Med Sci Monit In Press; DOI: 10.12659/MSM.938674  

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

01 Nov 2020 : Review article  

Long-Term Respiratory and Neurological Sequelae of COVID-19

DOI :10.12659/MSM.928996

Med Sci Monit 2020; 26:e928996

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