Biosynthetic pathways of secondary metabolites

Biosynthetic pathway introduction of secondary metabolites in medicinal Plants: During

long period evolution, plants struggling to survive gradually gain the ability to synthesize various
kinds of secondary metabolites with bioactivities. These compounds played important role in
defencing insects, herbivores, microbial pathogens, competing with other plants, and faciliting
pollination and reproduction. Based on the structures, the second metabolites can be classified
into alkaloids, flavonoids, phenylpropanoids, quinones, terpenoids, steroids, tannins and proteins.
These compounds are biosynthesized through series enzyme catalyzed reactions using simple
building blocks in different ways. There are several main biosynthetic pathways in plants,
including shikimic acid pathway (phenylpropanoids), mavalonic acid pathway (quinones), 2-C
methyl-D-erythritol-4-phosphate pathway (quinones), amino acid pathway (alkaloids), acetate-
malonate pathway (fatty acid, phenols and quinones) and combined pathways (flavonoids).

ATROPINE

Introduction
Atropine is a natural alkaloid originally extracted from Atropa belladonna (Figure 1) and then
found in others plants of the family Solanaceae. It is a drug with a wide range of effects in
humans including anesthesia, anti-arhythmia, bronchodilatation, mydriasis and
parasympathicolysis. Brand names of atropine include Atropair, Atropen, Atropine sulfate,
Atropinol and Atropisol (University of Alberta database - DrugBank , Wikipedia)

History
The term “alkaloid” derives from the Arabic al-qali, the plant from which soda was first
obtained. Alkaloids are nitrogenous compounds that constitute the pharmacologically active
principles of several flowering plants. The use of alkaloid-containing plant extracts as potions,
medicines, and poisons date back to the start of civilization. Famous examples include Socrates’
death in 399 B.C. by ingestion of hemlock (scientific name Conium maculatum). Medieval
european women utilized extracts of deadly nightshade (the common name of Atropa
belladonna) for the same purpose, hence the name “belladonna” (Alkaloid biosynthesis - The
basis for metabolic engineering of medicinal plants, 1995)
Biochemistry
Atropine is a racemic mixture of equal parts of D- and L-hyoscyamine (Figure 2). Hyoscyamine
(IUPAC name: (1R,3S,5S)-8-methyl-8azabicyclo [3.2.1] octan-3-yl 3-hydroxy-2-
phenylpropanoate) is a compound with molecular weight of 289 Da and chemical formula C 17 H
23 NO 3

Hereafter the biosynthesis pathway:

I. L-phenylalanine is transaminated to phenylpyruvic acid and then reduced to phenyl-lactic acid
(Figure 3)
II. putrescine-N-methyltransferase catalyzes the transfer of a methyl group from S-adenosyl-L-
methionine to an amino group of putrescine, which is the first committed step in the biosynthesis
of nicotine and tropane alkaloids. This enzyme is expressed in tobacco plant such as in Atropa
belladonna because first steps of nicotine biosynthesis, obtained from tobacco plant, are the same
of atropine biosynthesis. N-methyl-putrescine is then converted to tropinone, whose keto group
is in turn converted by the tropinone reductase-I to the alpha-hydroxyl of tropine (Figure 4)
III. phenyl-lactic acid binds to coenzyme A and reacts with tropine to form littorine, that go
through a radical transposition to make hyoscyamine aldehyde. At last, a dehydrogenase reduces
the aldehyde to alcool forming hyoscyamine (Figure 3)
IV. is also possible to obtain atropine through a chemical synthesis. This process, first discovered
by Richard Willstater, is based on the reaction of tropine with tropic acid while in the presence of
hydrochloric acid (Figure 4) (Synthesis of essential drugs, 1st edition (R. Vardanyan, V. Hruby),
PubChem database, Alkaloid biosynthesis - The basis for metabolic engineering of medicinal
plants, 1995)