Publications

• Structural and Chemical Biology of Terpenoid Cyclases.

  Christianson D.W.

  The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpeno ... >> More

  The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpenoid natural products. Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that more than half of the substrate carbon atoms undergo changes in bonding and hybridization during a single enzyme-catalyzed cyclization reaction. The past two decades have witnessed structural, functional, and computational studies illuminating the modes of substrate activation that initiate the cyclization cascade, the management and manipulation of high-energy carbocation intermediates that propagate the cyclization cascade, and the chemical strategies that terminate the cyclization cascade. The role of the terpenoid cyclase as a template for catalysis is paramount to its function, and protein engineering can be used to reprogram the cyclization cascade to generate alternative and commercially important products. Here, I review key advances in terpenoid cyclase structural and chemical biology, focusing mainly on terpenoid cyclases and related prenyltransferases for which X-ray crystal structures have informed and advanced our understanding of enzyme structure and function. << Less

  Chem Rev 117:11570-11648(2017) [PubMed] [EuropePMC]

• A geranylfarnesyl diphosphate synthase provides the precursor for sesterterpenoid (C25) formation in the glandular trichomes of the mint species Leucosceptrum canum.

  Liu Y., Luo S.-H., Schmidt A., Wang G.-D., Sun G.-L., Grant M., Kuang C., Yang M.-J., Jing S.-X., Li C.-H., Schneider B., Gershenzon J., Li S.-H.

  Plant sesterterpenoids, an important class of terpenoids, are widely distributed in various plants, including food crops. However, little is known about their biosynthesis. Here, we cloned and functionally characterized a plant geranylfarnesyl diphosphate synthase (Lc-GFDPS), the enzyme producing ... >> More

  Plant sesterterpenoids, an important class of terpenoids, are widely distributed in various plants, including food crops. However, little is known about their biosynthesis. Here, we cloned and functionally characterized a plant geranylfarnesyl diphosphate synthase (Lc-GFDPS), the enzyme producing the C25 prenyl diphosphate precursor to all sesterterpenoids, from the glandular trichomes of the woody plant Leucosceptrum canum. GFDPS catalyzed the formation of GFDP after expression in Escherichia coli. Overexpressing GFDPS in Arabidopsis thaliana also gave an extract catalyzing GFDP formation. GFDPS was strongly expressed in glandular trichomes, and its transcript profile was completely in accordance with the sesterterpenoid accumulation pattern. GFDPS is localized to the plastids, and inhibitor studies indicated its use of isoprenyl diphosphate substrates supplied by the 2-C-methyl-D-erythritol 4-phosphate pathway. Application of a jasmonate defense hormone induced GFDPS transcript and sesterterpenoid accumulation, while reducing feeding and growth of the generalist insect Spodoptera exigua, suggesting that these C25 terpenoids play a defensive role. Phylogenetic analysis suggested that GFDPS probably evolved from plant geranylgeranyl diphosphate synthase under the influence of positive selection. The isolation of GFDPS provides a model for investigating sesterterpenoid formation in other species and a tool for manipulating the formation of this group in plants and other organisms. << Less

  Plant Cell 28:804-822(2016) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties.

  Yan D., Arakelyan J., Wan T., Raina R., Chan T.K., Ahn D., Kushnarev V., Cheung T.K., Chan H.C., Choi I., Ho P.Y., Hu F., Kim Y., Lau H.L., Law Y.L., Leung C.S., Tong C.Y., Wong K.K., Yim W.L., Karnaukhov N.S., Kong R.Y.C., Babak M.V., Matsuda Y.

  A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin (<b>1</b>) and variecolactone (<b>2</b>) was identified in <i>Aspergillus aculeatus</i> ATCC 16872. Heterologous production of <b>1</b> and <b>2</b> was achieved in <i>Aspergillus oryzae</i> by expressing the sesterte ... >> More

  A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin (<b>1</b>) and variecolactone (<b>2</b>) was identified in <i>Aspergillus aculeatus</i> ATCC 16872. Heterologous production of <b>1</b> and <b>2</b> was achieved in <i>Aspergillus oryzae</i> by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues (<b>5</b>-<b>7</b>). Analysis of the compounds' anticancer activity <i>in vitro</i> and <i>in vivo</i> revealed that although <b>5</b> and <b>1</b> had comparable activities, <b>5</b> was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities. << Less

  Acta Pharm. Sin. B (APSB) 14:421-432(2024) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.