Who needs poppies? A brief overview of morphine biosynthesis in mammals.

Who needs poppies?  A brief overview of morphine biosynthesis in mammals.

     The presence of opiate receptors in the human body led to the search for and subsequent discovery of peptides believed to be the natural ligands.  These peptides were named endorphins, a contraction of the words endogenous morphine.  This was widely hailed as a great advance in neuroscience and the concept of endorphins has gone mainstream, invoked provide a biological basis for some people's tendency to enjoy opiate drugs ("endorphin deficiency") and mood elevation following aerobic exertion ("runner's high").  Within the last ten years or so sophisticated chemical analyses have detected minute quantities morphine in mammalian tissue, cow and human milk as well as a host of plants.
Using isotopically labeled precursors researchers have conclusively proven that human neuroblastoma cells can produce their own morphine in a series of reactions that are remarkably similar to those that occur in the opium poppy.  The reaction starts with two molecules of the amino acid L-tyrosine and proceeds through at least 19 steps before becoming morphine.
Work on identifying the enzymes responsible for each of the 19 steps in converting L-tyrosine to morphine is underway and the picture is mostly complete.  Identification of the genes responsible is the next logical step.  Once all the genes are identified it is a small step to develop a cDNA library and introduce the genetic material into a bacterium.  Fast growing bacterial cultures could then be developed which, when fed a L-tyrosine rich diet, produce morphine.  This would eliminate the need for growing poppies and allow morphine to be produced anywhere in the world at any time.  Some cultures would almost certainly make their way to the black market and into the welcome arms of opiophiles and drug trafficking organizations.  The cost of production would probably be lower than currently methods of refining morphine from opium.  At the very least bacterial cultures would be more resistant to fluctuations in growing conditions and periodic eradication campaigns.  This is not likely to have much effect on prices at the retail level since nearly all the markup on heroin is due to price inflation due to prohibition and not cost of production.  Still if the prohibitionists succeed in eliminating the opium poppy from the world, which would be a great crime against nature, it is nice to know the world will not be dependent on synthetic opioid drugs.
There is also a larger issue of criminalizing the possession of a naturally occurring substance in the human body.  After all the amount of drug does not matter as the weight of the drug includes all adulterants and packaging.  For example a gram of black-market heroin is almost never pure, with mean purity in the US around 30%.  And yet the unfortunate individual charged with possession of a gram of 30% pure heroin is charged as though the mixture containing some heroin and a lot of adulterants was all drug.  Given the low standards used in fighting the war on drugs, we are all guilty of "possession" of "pounds" of morphine at all times!

"Even more shocking and fraudulent is the established American practice of regarding one gram of 10% heroin to be one gram of heroin (when in reality only one-tenth gram of heroin is involved) in considering sentencing or the charge (simple possession is distinguished from "possession with intent to sell," which carries much stiffer penalties, by the quantity of the drug seized as evidence). This is especially absurd when doses of LSD are seized, which may contain only 25 or 50 mcg of the drug on a piece of paper or gelatin weighing tens or hundreds of milligrams (Shulgin & Shulgin 1991).  Imagine the innocent farmer wending a weary way to the barn in a bucolic setting with a couple of tons of hay on the truck. Hay which contains morphine (Hazum et al. 1981) in trace quantities ... by this standard (s)he could be arrested for possession of a couple of tons of morphine, and go down in history as one of the all-time great narcotraficantes. How about an Untouchables type raid on the pasteurization plant, to bust the nefarious pushers of tons and tons of "morphine"-milk containing traces of the drug, that is? "
Jonathan Ott, Pharmacotheon. p. 38

The specific reactions involved in the transformation of L-tyrosine to morphine are detailed below.  This is likely to be only of interest to chemists, but for those with a background in organic chemistry the following exerpt from Boettcher et al, 2005 provides a good overview of the specifics.


On the basis of these and our previous results (1) of classical precursor feeding experiments, we are now capable of providing a detailed picture of the pathway to morphine in human cells starting from two molecules of tyrosine (Fig. 5). L-tyrosine is hydroxylated to yield L-dopa, which can undergo either decarboxylation to dopamine or a possible deamination to 3,4-dihydroxyphenylpyruvate, which, in turn, is assumed to be decarboxylated to 3,4-dihydroxyphenylacetaldehyde. The product of the stereospecific enzymatic condensation of dopamine and the aldehyde, resembling a Pictet-Spengler-type reaction, is (S)-norlaudanosoline [(S)-tetrahydropapaveroline]. This first tetraoxygenated isoquinoline alkaloid of the morphine pathway in mammals is subject to three methylation reactions involving S-adenosylmethionine as a methyl group donor to yield (S)-reticuline (33, 34). The sequence of methylation reactions remains to be established. The (R)-configured enantiomer of norlaudanosoline is biologically inactive. The necessary change of configuration to furnish the biological active (9R)-configuration of (-) morphine is accomplished at the level of (S)-reticuline by means of a stereoselective oxidation-reduction process and the intermediate 1,2-dehydroreticulinium ion. (R)-reticuline is the substrate for the intramolecular C12-C13 phenol oxidative coupling, catalyzed by a cytochrome P450-dependent enzyme (28), to yield salutaridine. Salutaridinol is formed from salutaridine by stereospecific enzymatic reduction of the carbonyl group. Ring closure to form the ether linkage in thebaine is the result of a nucleophilic substitution reaction. This cyclization step requires the acetylation of salutaridinol by an acetyl-CoA transferase to improve the nature of the leaving hydroxyl. Thebaine can undergo either an enol-ether (C-6) or phenol-ether (C-3) demethylation reaction to form codeine or oripavine, respectively. Both codeine and oripavine serve as substrates in a final demethylation step to produce the (-)morphine.  We have unequivocally shown that human neuroblastoma cells are able to synthesize morphine. The metabolic route starting from L-tyrosine involving at least 19 chemical steps shares remarkable similarities with the morphine biosynthesis in opium poppy. In the future, the identification of the respective genes and enzymes in humans and animals will provide information on the evolution of this pathway in the animal kingdom. The function of endogenous morphine is still a matter of discussion. In contrast to plants, where morphine is a highly specific secondary metabolite providing protection against herbivores, presumptions indicate that morphine in animals and humans may play a role as a general regulator and/or transmitter. Once these functions are identified, the genes and enzymes of morphine biosynthesis may become attractive targets for the modulation of pain, immune response, cell death, and behavioral phenomena.


How human neuroblastoma cells make morphine. Chotima Boettcher, Monika Fellermeier, Christian Boettcher, Birgit Drager, and Meinhart H. Zenk. PNAS June 14, 2005 vol. 102 no. 24 8495-8500