Proposed biosynthetic routes leading from L-phenylalanine to amphetamine-type alkaloids in khat and <i>Ephedra sinica</i>.

<p>A CoA-independent, non-β-oxidative pathway of L-phenylalanine side chain-shortening is shown in blue, whereas a CoA-dependent, β-oxidative route is shown in purple. Benzaldehyde, benzoic acid and/or benzoyl-CoA undergo condensation with pyruvate, a reaction putatively catalyzed by a ThDP-dependent carboligase. 1-Phenylpropane-1,2-dione undergoes transamination to yield (<i>S</i>)-cathinone, which is reduced to cathine and (1<i>R</i>,2<i>S</i>)-norephedrine. <i>N</i>-Methylation is restricted to <i>Ephedra</i> spp. and does not occur in khat. Activity has been detected for enzymes highlighted in yellow, and corresponding genes are available for enzymes highlighted in green. Enzymes highlighted in red have not been isolated, although database mining revealed numerous potential candidates (Tables <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119701#pone.0119701.t002" target="_blank">2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119701#pone.0119701.t003" target="_blank">3</a>). Abbreviations: CoA, Coenzyme A; NAD(H), nicotinamide adenine dinucleotide; NADP(H), nicotinamide adenine dinucleotide phosphate. PAL, phenylalanine ammonia lyase; ThDP, thiamine diphosphate.