Abstract

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