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Alkaloids, meaning “alkaline-like” or “basic-like”, were previously characterized to be any natural products containing nitrogen within a ring. Since the nineteenth century when this definition came into being, over 10,000 compounds have been distinguished as alkaloids. With this growth, a modern definition of an alkaloid has come into being, which states that an Alkaloid is any natural, non-peptidic, non-nucleosidic compound containing nitrogen. This eliminates the amino acids and nucleobases, but does not eliminate their derivatives, which are still considered alkaloids. Of the 10,000 compounds that have been characterized, one fifth are natural products of plants. Plants undergo a number of alkaloid biosynthesis pathways not commonly found in animals. The alkaloids that plants produce help to fight off predators such as bacteria, fungi, and herbivores. Centuries of trial-and-error coupled with advances in chemistry and pharmacology have allowed us to put many of these alkaloids to good use. Before we discuss the synthesis of alkaloids and some of their functions, let's spend some time tracing the origin of the nitrogen in our biosphere.

Atmospheric Nitrogen and Ammonia

Throughout this course, we have seen how our bodies make use of the so-called "life elements": carbon, oxygen, hydrogen, phosphorous, and nitrogen. We must be able to take these elements from our environment and put them to use if we are to survive.

The hydrogen and oxygen that we use is easy to obtain from water molecules. However, the carbon in our bodies must be fixed in the form of glucose, which we are able to obtain through plants. This works out conveniently for us, since atmospheric CO2 is unreactive, even though it is extremely oxidized, due to its exceedingly strong bonds (totaling about 380 kcal/mol for each molecule). Plants, however, are able to reduce CO2 through the process of photosynthesis, outlined below.

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Note that the carbons in glucose have only one bond to oxygen rather than the four bonds found in carbon dioxide. This form, which is bioreductively activated, is much easier for our bodies to break down and use. As shown above, the products of photosynthesis are subsequently used as the reactants for the process of cellular respiration in our bodies. Cellular respiration is broken into two processes: glycolysis and the Krebs cycle. When you take a look at the glycolysis reaction, you see that the origin of the phosphorus in our bodies is from the phosphate molecules found in ATP. Plants are able to absorb phosphorus directly from the soil, subsequently incorporating it into phosphate molecules. 

*Note that cellular respiration produces the starting materials of photosynthesis, along with the addition of 34 ATP molecules, completing this incredible biological, as well as catalytic, cycle.

Photosynthesis, glycolysis, and the Krebs cycle explain how four of the five "life elements" are made available to the body, but we have yet to discover how nitrogen, arguably the most important of these elements is made available to the body. 60% of the nitrogen in the universe exists in the biosphere as N2 gas, 20% is a result of the Haber process (a synthetic method for converting atmospheric nitrogen to ammonia), 10% comes from lightening and ultraviolet radiation, and the remaining 10% comes from other processes. Even though it is present in many forms, nitrogen gas contains an extremely strong triple bond (approximately 225 kcal/mol per N2 molecule), and therefore must be reduced before our bodies can use it.

Nitrogen fixation, a process comparable to photosynthesis, is the method through which nitrogen becomes available to us in its reduced form of ammonia (NH3). Nitrogen fixation is the work of a particular class of bacteria - the diazatrophs. These bacteria contain two mechanisms that work in tandem to fix atmospheric nitrogen. The reductase mechanism takes 16 ATP molecules and 16 water molecules and converts them to 16 ADP molecules and 16 inorganic phosphate molecules, in the process releasing 8 electrons and 8 protons. These 8 electrons and protons are the driving force for the nitrogenase mechanism, which converts one molecule of N2 to 2 molecules of ammonia and hydrogen gas.

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NH3 in this form is toxic to us, so it is absorbed by legumes (beans, peas, etc.) which is in a form we can now consume. Although this process is chemically expensive, requiring 16 ATP to reduce one molecule of N2 to two NH3 molecules, it is extremely important biologically that we have a nitrogen source, and so nitrogen fixation continues to occur.

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In summary, the biological ways we obtain life elements are:

  • Hydrogen and oxygen come from water
  • Carbon comes from CO2, which then gets reduced to glucose and broken down into pyruvate
  • Phosphorous comes from phosphate molecules in the soil, which are incorporated into ATP
  • Nitrogen comes from atmospheric N2, which is reduced to ammonia, through nitrogen fixation

Incorporation of Ammonia

After making ammonia, in order to make it biologically useful, it is converted into glutamate, which acts as a portable nitrogen source. Nature uses alpha-ketoglutarate, a byproduct of the Krebs cycle, as the starting material for this transformation.

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Glutamate hydrogenase performs the initial addition/elimination reaction to produce an imine. This imine, which is ready to be converted to glutamate, is the reduced using NADH. Since this reaction is taking place inside of an enzyme, the reduction step is stereoselective, and we observe only one enantiomer of glutamate. The glutamate is the further converted to glutamine after a phosphorylation and another addition/elimination reaction of ammonia.

*Note that the ammonia molecules have been highlighted so that it is easy to see their position in the final molecule.

Pyrimidine Synthesis from Glutamate

As shown above, Glutamine is made from Glutamate. However, if you pay an entropic penalty of using one PPi, the reaction can be reversed from Glutamine to Glutamate (This reaction is shown below). 

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This may not seem reasonable why a reaction would occur that is exactly the reverse of what just happened, PLUS pay an energy penalty of one AMP. However, this reaction generates carbamate along with Glutamate, which can be combined with the Phosphate group used in the reaction to generate Carbamoyl Phosphate NH2CO2PO3. This can then be combined with Aspartate undergoing 4 reactions including reducing agents and ATP, then this reaction (Outlined Below) can produce a Pyrimidine ring!

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Isn't it amazing how our bodies use these basic materials to synthesize other larger materials using principle reagents and amino acids. Speaking of amino acids I'm getting ahead of myself, check out the next section...

Amino Acids Galore

From this glutamate that is formed, we can form a multitude of amino acids and additional metabolites. Most of the amino acids are made in an enzyme known as aspartate transaminase - below is the formation of serine from glutamate, alpha-ketogluterate, and hydroxpyruvate in a PLP-dependent mechanism. Once again, we see the efficiency of our biochemistry as it recycles byproducts of the Krebs cycle for use in amino acid formation in aspartate transaminase.

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*Note that in the hydrolysis reaction that produces alpha-ketogluterate and PAP, the blue nitrogen atom (originally form ammonia) has been transferred from glutamate to PAP. This nitrogen is now ready to be incorporated into any metabolite via another PLP-mediated hydrolysis reaction. The above synthesis outlines this process using hydroxypyruvate to form serine, but one could use any metabolite containing a ketone as your starting material. Another option would be to use oxaloacetate from the kreb's cycle to make aspartate.

Although aspartate transaminase is able to make most of the amino acids, it is not capable of producing all of them. Plants come to our rescue, though, since they are able to form these amino acids that we can’t make ourselves (see the [Shikimic Acid Pathway|Shikimic Acid Pathway] ). These are known as the essential amino acids, and we can get them through ingesting plant products – all the more reason to eat your veggies!

Alkaloid Formation

Now that we understand how our bodies get nitrogen from our environment, we can look at how alkaloids are formed. Given the complex nature of some alkaloids, it may be difficult to believe that they all come from amino acid or nucleobase starting materials. Below are some examples:

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Many of the transformations from amino acid or nucleobase to alkaloid are simply applications of basic cofactor chemistry that we have already encountered in the course. For example, the path from tyrosine to adrenaline: the mechanism begins with PLP-mediated decarboxylation of tryosine coupled with the addition of a hydroxyl group, SAM then methylates the product and following this methylation; oxygen, FAD, and NADH add a second hydroxyl group to the aromatic ring.

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Alkaloids: Endless Variety

Over time, alkaloids have been found to have many pharmacological applications, including use as pain relievers, decongestants, and stimulants. To better understand the transformations that basic amino acids and nucleobases undergo to form alkaloids, let's survey two biosynthetic pathways: psilocybin and cocaine.

Psilocybin

Psilobycin is the active ingredient in so-called "magic mushrooms" or "shrooms". Its biosynthesis begins with the amino acid tryptophan, which, through a series of several cofactor mediated transformations becomes psilobycin. First, the Tryptophan is decarboxylated using a PLP catalysized mechanism. Then following two methylations using SAM and the addition of a hydroxyl with O2, FAD, and NADH (a mechanism previously seen in lecture 16), the final psilocybin is produced.

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Below is a comparison between serotonin and psilocybin. Serotonin is a neurotransmitter that is produced in our bodies and that, among other things, is responsible for the regulation of mood and social behavior. You can see that psilocybin greatly resembles the structure of serotonin. As a result your seratonin receptors can be fooled into binding psilocybin which acts as an antagonist and will block these receptors from binding serotonin. When humans ingest these mushrooms, they are known to cause hallucinations. However, plants originally produced psilobycin as a defense mechanism to fight off microorganism invaders who are not able to tolerate the blocking of the serotonin receptors like humans are.

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Cocaine

Cocaine, however, follows a much more complex pathway which results in a molecule bearing little similarity to its starting material. The biosynthesis of cocaine begins with glutamate, which then undergoes a series of cofactor mediated transformations. Specifically glutamate will undergo a phosphorylation, a reduction, a reductive amination, decarboxylation, and methylation (in terms of an acronym, it is a P, R, RA, D and M) before it performs and addition/elimination to create the N-methyl pyrrolinium cation (highlighted in blue), which is a very common intermediate produced by plants. This molecule is then attacked by acetyl-CoA. A second attack on the acetyl-CoA by a second molecule of acetyl-CoA results in the final beta-keto-thio-ester:

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At the end of this mechanism though, we still don't have cocaine. We begin the second half of the process with the final molecule we created, just shown in a product-like conformation. The main bond that needs to be created is shown as a dashed red line in the first structure. To create this bond, the mechanism begins with an oxidiation, followed by an aldol addition. Attack by water in a protease-like mechanism methylation, reduction and a final esterification all take place, culminating in the production of cocaine.

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Other Notable Alkaloids

Given the large number of transformations that a simple amino acid or nucleobase can undergo to form an alkaloid, it is easy to understand the large number and varied makeup of alkaloids. Here are a few more alkaloids that you may recognize:

Coniine

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Coniine is an alkaloid found in poison hemlock and other plants. The molecule works by blocking a particular neuroreceptor and inducing paralysis. The victim remains conscious until respiratory paralysis causes suffocation. Coniine was what cause Socrates' death by hemlock and it was the first alkaloid to be synthesized in 1826. Due to lack of modern spectroscopy to identify cells, coniine was identified using an analysis of the combustion of the compound and its empirical formula.

Quinine

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Quinine was a common antimalarial drug used until the mid-20th century. Today, it is used to treat lupus and arthritis, among other conditions. The molecule is derived from the cinchona tree and is available by prescription and in small amounts in tonic water. Because quinine fluoresces when exposed to ultraviolet light, it is may be used as an indicator in photochemistry.

Ephedrine

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Ephedrine is isolated from the ephedra plant and is commonly used as a stimulant and decongestant. It may also be used recreationally, both on its own and as a precursor to methamphetamines. In chemistry labs, ephedrine may be used to create chiral auxiliary groups.

Codeine

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Codeine is found in the opium poppy. Codeine, like most opiates, is used as an analgesic, anti-tussive and anti-diarrheal. Codeine is currently the most widely-used opiate in the world, and probably the most commonly used drug overall according to numerous reports by organizations including the World Health Organization

Chiral auxiliary is the process of incorporating a compound into organic syntheisis, so that it may introduce chirality into the racemic compounds. A chiral auxiliary also aids the selective formation of one of the two enantiomers. These compounds are optically active.

Just as a note: Pseudoephedrine is a diastereomer of Ephedrine, and has similar medical effects as ephedrine. Pseudoephedrine has less of a stimulant and fatburning effect, but has a more noticeable effect on serotonin and appetite suppression. Pseudoephedrine is used in the production of methamphetamines, because of its use of a Selective Serotonin Reuptake Inhibitor (SSRI), where the drug blocks the reuptake of dopamine to the presynaptic cleft of a neuron. This leaves the dopamine free to bind to the postsynaptic neuron multiple times, causing an andronergic effect.

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2010-F-SCK-Vincristine.cdx

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d34-1.cdx

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d34-3.cdx

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d34-2.cdx

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2010-S-GCP-Vincristine.cdx

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