Frankincense and Myrrh, Terpenoids

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Frankencense Resin

 'Tis the season to discuss phytochemicals.  Plants produce a vast array of organic chemicals starting from molecules produced by all organisms, including humans.  Essentially all of these phytochemicals are potent adaptations to kill.  Phytochemicals kill plant pathogens, bacteria and fungi, as well as insects.  Thus, the natural, plant extracts that humans use for flavor enhancers (herbs, spices, and teas), fragrances, recreational/medicinal mind and attitude modifiers (alkaloids, psychopharmaceuticals, etc.), herbal medicines, etc. are present in plants, first and foremost, as antibiotics and insecticides.  Humans have evolved to taste (bitter) and smell phytochemicals to avoid their toxicity, and have adapted culturally to exploit the impact of phytochemicals on body and mind.  In this seasonal post, I focus on the terpenoids in Frankincense and Myrrh, to explore how plant biochemistry contributed to the gifts of the Magi.

It All Starts with Central Metabolism

Phytochemicals are complicated plant chemicals that are produced by a series of enzyme-controlled reactions (Central Metabolism) from the array of chemicals used by plants to convert photosynthetic carbohydrates (fructose and glucose) into the molecules (sugars, amino acids, fatty acids, nucleic acids) used to make the macromolecules of cells (polysaccharides, proteins, fats, DNA/RNA).  Alkaloids and phenolics, e.g. phytoalexins, are made from amino acids (phenylalanine) and terpenoids are made from fatty acids (acetyl CoA/Mevalonate) or other intermediates in glycolysis.  Thus, central metabolism that converts glucose/fructose into pyruvate and the acetyl CoA (see mevalonate pathway left) of mitochondrial fatty acid metabolism, is further converted into amino acids and plant secondary compounds, phytochemicals.  I am going to talk mainly about terpenoids in Frankincense (triterpenoid Boswellic acids) and Myrrh, and many related molecules (steroids) also produced by humans.  

The major thesis here is that carbon dioxide is converted by photosynthesis into either sugars used to build the cell wall polysaccharides (soluble fiber) or larger toxic defensive chemicals, e.g. phytoalexins, resins, essential oils or lignin.  Phytoalexins, e.g. the natural antibiotic resveratrol in wine, are made from phenylalanine along the same biochemical pathway used to produce lignin.  Glyphosate, the herbicide, kills by blocking this unique plant pathway.  Essential oils and resins are another group of natural antibiotics produced by converting acetyl CoA into a five carbon unit, IPP, which is then linked into larger and larger (10, 15, 20 carbons) molecules, terpenoids, that can rearrange into multiple ring structures.  Only the smallest chemicals in the series evaporate to provide identifiable smells, e.g. Frankincense and Myrrh, while larger forms, e.g. cholesterol or testosterone in animals, are odorless solids.

Acetyl CoA to IPP

IPP

For those who enjoy the beauty of biochemistry:  The most abundant enzyme on earth is RibisCo (ribulose bisphosphate carboxylase), the plant enzyme that combines carbon dioxide from air with a five-carbon phosphorylated sugar, ribulose bisphosphate, to produce two, three-carbon intermediates of glycolysis that can be converted into glucose or into acetyl CoA, the starting chemical for fatty acids, the mitochondrial TCA cycle, or via mevalonic acid to isopentanyl pyrophosphate (IPP), the building block for terpenoid synthesis.

In brief:  Photosynthesis uses the energy from sunlight to convert carbon dioxide into sugars (glucose and fructose).  Those sugars can be converted into a five-carbon, molecular building block for terpenoids, IPP.  IPP molecules can then be linked together to make increasingly longer chains and those chains can be ultimately twisted into rings to make resins in plants and steroids in humans.

Five, Ten, Fifteen, Thirty; IPP (5), GPP (10), Sesquiterpenoids (15), Triterpenoids (30)

Terpenoid Polymerization

Terpenoid synthesis begins with IPP, which has five carbons in a branched chain and has a pair of phosphates, pyrophosphate that provide the energy to form chains of 5, 10, 15, etc.  In plants, molecules of each of the incremental lengths are produced together and additional enzymes in different species of plants result in mixtures of molecules with different rings and functional groups.  The smaller molecules evaporate more readily, so that mixtures are extruded from damaged trees as oils and gradually form resins as the remaining larger molecules predominate and solidify.

Shark Livers and the Horn of Africa

IPP with five carbons, an isoprene, is used to make GPP with ten, a monoterpene.  Common monoterpenes are geranol and limonene that make the characteristic odors of geraniums and lemons. Sesquiterpenoids (15 carbons made from three IPPs) include the fragrance of patchouli. Diterpenes, such as sweet steviol, have twenty carbons, which can be chemically twisted into the chemicals that predominate in Myrrh resin, the Balm of Gileade.  The triterpenes with 30 carbons can be rearranged with five rings to form steroids, such as cholesterol in animals or Frankincense.  Linear squalene, is the major component in shark liver oil and provides the same function as a swim bladder in a boney fish.

Essential Oils Are Mixtures of Distilled Terpenoid and Phenylpropanoid Phytoalexins

Boswellic Acid

Phytoalexins and terpenoids have evolved as plant defenses against bacteria, fungi and insects, and they are toxic, because they interact aggressively with proteins through their chemical ring structures that are hydrophobic.  These ring structures make the smaller versions volatile and soluble in organic solvents.  Many of these chemicals have properties similar to petroleum products and may be used as solvents themselves, e.g. paint strippers or thinner.  Steam distillation of plants produces mixtures of phytoalexins and terpenoids commonly called essential oils, which contain the volatile components “essential” for the odor identity of a plant.

Statins Block Cholesterol Synthesis

Statins were identified among a group of fungal antibiotics for their ability to block an early enzyme (marked in the mevalonate pathway above) in the production of cholesterol.  The toxic side effects of statins derive from wholesale disruption of all of the essential pathways (everything below the inhibited enzyme) that are related to cholesterol, such as blood heme A found in hemoglobin, and ubiquinone (CoQ) found in mitochondrial electron transport and needed to reduce oxidative stress and glucose intolerance.  Thus, for these examples, statins would contribute to anemia and type II diabetes/metabolic syndrome.  The side effects are not surprising, since statins are fungal antibiotics that target pathways common to bacteria and human mitochondria.  It is also not surprising that statins have unpredictable impacts on gut flora and the immune system.