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Natural Products


References 1 McKernan, K, Helbert, Y, Kane, LT, Ebling, H, Zhang, L, Liu, B, Eaton, Z, Sun, L, Dimalanta, E, Kingan, S, Baybayan, P, Pres, M, Barbazuk, W and Harkins, T. Cryptocurrencies and Zero Mode Wave guides: An unclouded path to a more contiguous Cannabis sativa L. genome assembly. OSF Preprints (2018) https://osf.io/gf2rv/. 2 Laverty, KU, Stout, JM, Sullivan, MJ, Shah, H, Gill, N, Holbrook, L, Deikus, G, Sebra, R, Hughes, TR, Page, JE, van Bakel, H. A physical and genetic map of Cannabis sativa identifies extensive rearrangements at the THC/CBD acid synthase loci. Genome Res. (2019) doi: 10.1101/gr.242594.118. 3 Shen, Q, Zhang, L, Liao, Z, Wang, S, Yan, T, Shi, P, Liu, M, Fu, X, Pan, Q, Wang, Y, Lv, Z, Lu, X, Zhang, F, Jiang, W, Ma, Y, Chen, M, Hao, X, Li, L, Tang, Y, Lv, G, Zhou, Y, Sun, X, Brodelius, PE, Rose, JKC, Tang, K. The Genome of Artemisia annua Provides Insight into the Evolution of Asteraceae Family and Artemisinin Biosynthesis. Mol Plant. (2018) doi: 10.1016/j.molp.2018.03.015. 4 Kim, JA, Roy, NS, Lee, IH, Choi, AY, Choi, BS, Yu, YS, Park, NI, Park, KC, Kim, S, Yang, HS, Choi, IY. Genome-wide transcriptome profiling of the medicinal plant Zanthoxylum planispinum using a single- molecule direct RNA sequencing approach. Genomics (2018) doi: 10.1016/j.ygeno.2018.06.004. 5 Fan, G, Fu, Y, Yang, B, Liu, M, Zhang, H, Liang, X, Shi, C, Ma, K, Wang, J, Liu, W, Shao, L, Huang, C, Guo, M, Cai, J, Wong, AKC, Li, C, Zhuang, D, Chen, K, Cong, W, Sun, X, Liu, X, Xu, X, Tsui, SK, Chen, W and Lee, SM. Sequencing of Panax notoginseng genome reveals genes involved in disease resistance and ginsenoside biosynthesis. bioRxiv 362046 (2018); doi: 10.1101/362046.


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Icahn School of Medicine at Mount Sinai, New York, resequenced the drug-type strain Purple Kush and the hemp variety ‘Finola’ and created a combined physical and genetic map2 in order to better understand the cannabinoid biosynthesis pathway. One mystery that has stumped cannabis


researchers revolves around the expression of the related enzymes THCA synthase (THCAS) and CBDA synthase (CBDAS), which synthesise the compounds THC (responsible for the well-known psychoactive effects of cannabis consumption) and CBD (responsible for therapeutic properties and investigated as a potential treatment for pain relief, gastrointestinal disorders, schizophrenia and Alzheimer’s Disease). There are two competing theories. In one,


CBDAS and THCAS are mutually exclusive alleles (ie, very different isoforms, as the protein sequences are only 84% identical). The other theo- ry is that THCAS and CBDAS are closely linked (ie, adjacent on a chromosome), and one or the other is inactivated in drug-type or hemp strains. The draft genome and transcriptome of C. sativa described in 2011 (for a female plant of the drug- type strain Purple Kush and the hemp variety ‘Finola’) was unable to resolve these theories due to high fragmentation. Nearly 70% of the C. sativa draft genome is composed of repetitive sequences with a high rate of single-nucleotide variants (SNVs), as well as inter- and intra-cultivar kary- otype polymorphisms (ie, differences in homolo- gous chromosomes), which are not captured well in short read sequencing. To address these complications, the Toronto/NY


team resequenced the two cannabis varieties using SMRT Sequencing which provided new insights into the arrangement of the chromosomes and the cannabinoid biosynthetic genes, including discov- ery of substantial rearrangement and gene duplica- tions at the closely-linked THC and CBD acid syn- thase gene loci. Rather than resolve the THCAS/CBDAS mystery,


however, the genetic map raised more questions. “They are not isoforms at an otherwise equiva-


lent locus, and no equivalent of THCAS (deactivat- ed or not) is found in hemp,” the authors wrote. Their observations suggested that either poly-


morphisms or differential regulation of aromatic prenyltransferase (AP) contributes to cannabinoid production, presumably by controlling substrate concentration for THCAS and CBDAS. Purple Kush has greater than five-fold higher transcript levels of AP than Finola, with no difference in copy number, suggesting that AP enzyme levels may be


higher in drug-type plants partly due to differences in transcript levels. In order to truly understand these mechanisms,


further analysis, ideally at the transcriptome level, is needed. “Comparative sequence analysis of the enzymes


will help ascertain which amino acids are impor- tant in catalysis, and may lead to the rational design of cannabinoid biosynthetic enzymes that produce novel cannabinoids not observed in nature,” the authors write.


Bittersweet success One of herbal genomics’ biggest success stories also illustrates the limits that come with incom- plete genomic and transcriptomic coverage. Chinese scientist Youyou Tu received a Nobel


Prize in Physiology or Medicine in 2015 for her discovery of


the anti-malaria function of


artemisinin, an endoperoxide sesquiterpene lactone isolated from sweet wormwood (Artemisia annua, or Qinghao in Chinese), an annual herb of the Asteraceae family. Artemisinin-based combination therapies


(ACTs), recommended by the World Health Organization for the treatment of uncomplicated malaria caused by the Plasmodium falciparum par- asite, have saved millions of lives. Other therapeu- tic effects have also been reported for artemisinin for diseases such as cancer, tuberculosis and dia- betes, so demand is high for the compound. But plant-based production is struggling to meet the global demand due to the low amount of artemisinin produced in A. annua leaves (0.1%- 1.0% of dry weight). Many have used metabolic engineering in


attempts to increase artemisinin content in A. annua. Their strategies included overexpression of artemisinin biosynthetic pathway genes; overex- pression of transcription factors (TFs) that can enhance the expression of artemisinin biosynthetic genes; and overexpression of the ADP-FPS fusion gene to stimulate substrate channelling. However, by focusing only on modifying the upstream or downstream parts of the artemisinin biosynthetic pathway and overexpressing single genes, they were unable to effectively boost the entire metabol- ic flux toward artemisinin biosynthesis. To get a more complete picture, an international


research team led by Kexuan Tang of Shanghai Jiao Tong University, turned to a combination of long-read genomic and transcriptomic analyses. The result, reported in April 20183, is a high-


quality draft genome assembly of the 1.74-giga- base genome of A. annua, containing 63,226


Drug Discovery World Spring 2019


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