Research achievements in the synthetic biology and metabolic engineering of artemisinin

Although the biosynthesis of artemisinin is unique to Artemisia annua L., the upstream pathway is ubiquitous among eukaryotes. Therefore, it should be possible to re-establish the downstream pathway for the de novo biosynthesis of artemisinin in eukaryotic microorganisms such as yeast. In the past decade, artemisinin biosynthetic genes have been cloned and introduced into yeast, resulting in the production of several artemisinin precursors including artemisinic acid and dihydroartemisinic acid. However, because of the lack of a suitable cellular environment, these artemisinin precursors failed to be converted into artemisinin. Consequently, A. annua remains the sole source of artemisinin and, therefore, there is a continuing need for research on the genetic improvement of A. annua germlines. Chinese scientists have obtained high-yielding transgenic A. annua plants or varieties using either the opening carbon flux strategy or the closing carbon flux strategy. These studies have shed light on the accelerated and sustainable production of artemisinin. In addition, the rate-limiting steps of artemisinin biosynthesis, particularly the final reaction mechanism, have been identified and characterized. This information is important to simulate the cellular environment in transgenic systems, to enable the successful production and accumulation of artemisinin. Together, these studies have paved the way towards a solution to the problem of limited artemisinin supply. Finally, we discuss the implications of patents for microorganisms that produce artemisinin precursors, and the ways in which China can avoid patent infringements.