page_title: Nicotine
section_title: Biosynthesis
hierarchical_section_title: Nicotine / Chemistry / Biosynthesis
caption_attribution_description: English: Agreed biosynthetic pathway of nicotine as of june 2012
context_page_description: Nicotine is a widely used stimulant and potent parasympathomimetic alkaloid that is naturally produced in the nightshade family of plants. It is used for smoking cessation to relieve withdrawal symptoms. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors, except at two nicotinic receptor subunits where it acts as a receptor antagonist.
  Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco. Nicotine is also present at concentrations of millionths of a percent in the edible family Solanaceae, including potatoes, tomatoes, and eggplants, though sources disagree on whether this has any biological significance to human consumers. It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past, and neonicotinoids, such as imidacloprid, are widely used.
  Nicotine is highly addictive, unless used in slow-release forms. An average cigarette yields about 2 mg of absorbed nicotine.
  Higher doses can be fatal. Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence.
context_section_description: The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidine is derived from N-methyl-Δ¹-pyrrollidium cation. Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ¹-pyrrollidium cation.
  The NAD pathway in the genus Nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.
  The N-methyl-Δ¹-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ¹-pyrrollidium cation.
  The final step in the synthesis of nicotine is the coupling between N-methyl-Δ¹-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ¹-pyrrollidium cation to form enantiomerically pure (−)-nicotine.
caption: Nicotine biosynthesis
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