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Special Issue "Isoprenoid Biosynthesis"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (10 April 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Robert M. Coates

Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA
Website | E-Mail
Interests: terpene and steroid chemistry; isoprenoid biosynthesis; Aza analog inhibitors; organic synthesis; stereochemistry

Special Issue Information

Dear Colleagues,

Isoprenoid compounds comprise a large, diverse family of natural products occurring widely in the plant and animal kingdoms. They exhibit many biological activities and functions, including pheromones, hormones, fragrances, membrane components, and many others. Despite this diversity of structures and functions, their biosynthesis occurs by conversion of relatively few acetate-derived acyclic and cyclic substrates through the action of a novel class of enzymes called terpene synthases. Often the initially formed terpenes are further modified by oxidases and reductases. The objective of this Special Issue is to review the current status of knowledge about isoprenoid biosynthesis by experts in the various relevant areas.

Prof. Dr. Robert M. Coates
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Mevalonate pathway
  • Non-mevalonate pathway
  • Methyl erythritol phosphate pathway
  • Rohmer pathway
  • Isopentenyl diphosphate
  • Dimethylallyl diphosphate
  • Geranyl diphosphate
  • Farnesyl diphsphate
  • Geranylgeranyl diphosphate
  • Squalene
  • Terpenes
  • Isoprene
  • Monoterpenes
  • Irregular monoterpenes
  • Sesquiterpenes
  • Diterpenes
  • Triterpenes
  • Sesterterpenes
  • Phytoene
  • Carotenoids
  • Steroids
  • Cholesterol
  • Dolichol
  • Rubber
  • Hydroxymethylglutaryl CoA
  • Kinase
  • Cyclase
  • Synthase
  • Isomerase
  • Prenyl transferase
  • Isoprene Rule
  • Oxidase
  • Reductase

Published Papers (8 papers)

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Research

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Open AccessArticle Production of Putative Diterpene Carboxylic Acid Intermediates of Triptolide in Yeast
Molecules 2017, 22(6), 981; doi:10.3390/molecules22060981
Received: 7 April 2017 / Accepted: 7 June 2017 / Published: 13 June 2017
Cited by 1 | PDF Full-text (1041 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The development of medical applications exploiting the broad bioactivities of the diterpene therapeutic triptolide from Tripterygium wilfordii is limited by low extraction yields from the native plant. Furthermore, the extraordinarily high structural complexity prevents an economically attractive enantioselective total synthesis. An alternative production
[...] Read more.
The development of medical applications exploiting the broad bioactivities of the diterpene therapeutic triptolide from Tripterygium wilfordii is limited by low extraction yields from the native plant. Furthermore, the extraordinarily high structural complexity prevents an economically attractive enantioselective total synthesis. An alternative production route of triptolide through engineered Saccharomyces cerevisiae (yeast) could provide a sustainable source of triptolide. A potential intermediate in the unknown biosynthetic route to triptolide is the diterpene dehydroabietic acid. Here, we report a biosynthetic route to dehydroabietic acid by transient expression of enzymes from T. wilfordii and Sitka spruce (Picea sitchensis) in Nicotiana benthamiana. The combination of diterpene synthases TwTPS9, TwTPS27, and cytochromes P450 PsCYP720B4 yielded dehydroabietic acid and a novel analog, tentatively identified as ‘miltiradienic acid’. This biosynthetic pathway was reassembled in a yeast strain engineered for increased yields of the pathway intermediates, the diterpene olefins miltiradiene and dehydroabietadiene. Introduction in that strain of PsCYP720B4 in combination with two alternative NADPH-dependent cytochrome P450 reductases resulted in scalable in vivo production of dehydroabietic acid and its analog from glucose. Approaching future elucidation of the remaining biosynthetic steps to triptolide, our findings may provide an independent platform for testing of additional recombinant candidate genes, and ultimately pave the way to biotechnological production of the high value diterpenoid therapeutic. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Open AccessArticle Isoprenoids Production from Lipid-Extracted Microalgal Biomass Residues Using Engineered E. coli
Molecules 2017, 22(6), 960; doi:10.3390/molecules22060960
Received: 20 April 2017 / Revised: 1 June 2017 / Accepted: 7 June 2017 / Published: 9 June 2017
PDF Full-text (2364 KB) | HTML Full-text | XML Full-text
Abstract
Microalgae are recognized as a third generation feedstock for biofuel production due to their rapid growth rates and lignin-free characteristics. In this study, a lipid extracted microalgal biomass residues was used as the raw material to produce isoprene, α-pinene and β-pinene with an
[...] Read more.
Microalgae are recognized as a third generation feedstock for biofuel production due to their rapid growth rates and lignin-free characteristics. In this study, a lipid extracted microalgal biomass residues was used as the raw material to produce isoprene, α-pinene and β-pinene with an engineered E. coli strain. We adopted an optimal sulfuric acid hydrolysis method (1:7 ratio of solid to acid solution, 32% (w/v) concentration of sulfuric acid solution at 90 °C for 90 min) to efficiently convert holocellulose into glucose efficiently (6.37 g/L). Futhermore, we explored a novel detoxification strategy (phosphoric acid/calcium hydroxide) to remove inhibitors and notably acetic acid, furfural and 5-hydroxymethylfurfural (5-HMF) were reduced by 5.32%, different number given later 99.19% and 98.22%, respectively. Finally, the fermentation concentrations of isoprene (223.23 mg/L), α-pinene (382.21 μg/L) and β-pinene (17.4 mg/L) were achieved using the detoxified hydrolysate as the carbon source, equivalent to approximately 86.02%, 90.16% and 88.32% of those produced by the engineered E. coli strain fermented on pure glucose, respectively. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Open AccessArticle Sesquiterpene Variation in West Australian Sandalwood (Santalum spicatum)
Molecules 2017, 22(6), 940; doi:10.3390/molecules22060940
Received: 13 April 2017 / Revised: 4 May 2017 / Accepted: 19 May 2017 / Published: 6 June 2017
PDF Full-text (1454 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
West Australian sandalwood (Santalum spicatum) has long been exploited for its fragrant, sesquiterpene-rich heartwood; however sandalwood fragrance qualities vary substantially, which is of interest to the sandalwood industry. We investigated metabolite profiles of trees from the arid northern and southeastern and
[...] Read more.
West Australian sandalwood (Santalum spicatum) has long been exploited for its fragrant, sesquiterpene-rich heartwood; however sandalwood fragrance qualities vary substantially, which is of interest to the sandalwood industry. We investigated metabolite profiles of trees from the arid northern and southeastern and semi-arid southwestern regions of West Australia for patterns in composition and co-occurrence of sesquiterpenes. Total sesquiterpene content was similar across the entire sample collection; however sesquiterpene composition was highly variable. Northern populations contained the highest levels of desirable fragrance compounds, α- and β-santalol, as did individuals from the southwest. Southeastern populations were higher in E,E-farnesol, an undesired allergenic constituent, and low in santalols. These trees generally also contained higher levels of α-bisabolol. E,E-farnesol co-occurred with dendrolasin. Contrasting α-santalol and E,E-farnesol chemotypes revealed potential for future genetic tree improvement. Although chemical variation was evident both within and among regions, variation was generally lower within regions. Our results showed distinct patterns in chemical diversity of S. spicatum across its natural distribution, consistent with earlier investigations into sandalwood population genetics. These results are relevant for plantation tree improvement and conservation efforts. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Open AccessArticle Comprehensive Characterization for Ginsenosides Biosynthesis in Ginseng Root by Integration Analysis of Chemical and Transcriptome
Molecules 2017, 22(6), 889; doi:10.3390/molecules22060889
Received: 9 April 2017 / Revised: 9 May 2017 / Accepted: 23 May 2017 / Published: 31 May 2017
Cited by 1 | PDF Full-text (1718 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Herbgenomics provides a global platform to explore the genetics and biology of herbs on the genome level. Panax ginseng C.A. Meyer is an important medicinal plant with numerous pharmaceutical effects. Previous reports mainly discussed the transcriptome of ginseng at the organ level. However,
[...] Read more.
Herbgenomics provides a global platform to explore the genetics and biology of herbs on the genome level. Panax ginseng C.A. Meyer is an important medicinal plant with numerous pharmaceutical effects. Previous reports mainly discussed the transcriptome of ginseng at the organ level. However, based on mass spectrometry imaging analyses, the ginsenosides varied among different tissues. In this work, ginseng root was separated into three tissues—periderm, cortex and stele—each for five duplicates. The chemical analysis and transcriptome analysis were conducted simultaneously. Gene-encoding enzymes involved in ginsenosides biosynthesis and modification were studied based on gene and molecule data. Eight widely-used ginsenosides were distributed unevenly in ginseng roots. A total of 182,881 unigenes were assembled with an N50 contig size of 1374 bp. About 21,000 of these unigenes were positively correlated with the content of ginsenosides. Additionally, we identified 192 transcripts encoding enzymes involved in two triterpenoid biosynthesis pathways and 290 transcripts encoding UDP-glycosyltransferases (UGTs). Of these UGTs, 195 UGTs (67.2%) were more highly expressed in the periderm, and that seven UGTs and one UGT were specifically expressed in the periderm and stele, respectively. This genetic resource will help to improve the interpretation on complex mechanisms of ginsenosides biosynthesis, accumulation, and transportation. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Open AccessArticle Strengthening Triterpene Saponins Biosynthesis by Over-Expression of Farnesyl Pyrophosphate Synthase Gene and RNA Interference of Cycloartenol Synthase Gene in Panax notoginseng Cells
Molecules 2017, 22(4), 581; doi:10.3390/molecules22040581
Received: 21 February 2017 / Revised: 20 March 2017 / Accepted: 30 March 2017 / Published: 5 April 2017
Cited by 1 | PDF Full-text (3109 KB) | HTML Full-text | XML Full-text
Abstract
To conform to the multiple regulations of triterpene biosynthesis, the gene encoding farnesyl pyrophosphate synthase (FPS) was transformed into Panax notoginseng (P. notoginseng) cells in which RNA interference (RNAi) of the cycloartenol synthase (CAS) gene had been accomplished. Transgenic cell lines
[...] Read more.
To conform to the multiple regulations of triterpene biosynthesis, the gene encoding farnesyl pyrophosphate synthase (FPS) was transformed into Panax notoginseng (P. notoginseng) cells in which RNA interference (RNAi) of the cycloartenol synthase (CAS) gene had been accomplished. Transgenic cell lines showed both higher expression levels of FPS and lower expression levels of CAS compared to the wild-type (WT) cells. In the triterpene and phytosterol analysis, transgenic cell lines provided a higher accumulation of total triterpene saponins, and a lower amount of phytosterols in comparison with the WT cells. Compared with the cells in which RNAi of the CAS gene was achieved, the cells with simultaneously over-expressed FPS and silenced CAS showed higher triterpene contents. These results demonstrate that over-expression of FPS can break the rate-limiting reaction catalyzed by FPS in the triterpene saponins biosynthetic pathway; and inhibition of CAS expression can decrease the synthesis metabolic flux of the phytosterol branch. Thus, more precursors flow in the direction of triterpene synthesis, and ultimately promote the accumulation of P. notoginseng saponins. Meanwhile, silencing and over-expressing key enzyme genes simultaneously is more effective than just manipulating one gene in the regulation of saponin biosynthesis. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Open AccessArticle Combination of Morroniside and Diosgenin Prevents High Glucose-Induced Cardiomyocytes Apoptosis
Molecules 2017, 22(1), 163; doi:10.3390/molecules22010163
Received: 6 December 2016 / Revised: 13 January 2017 / Accepted: 16 January 2017 / Published: 19 January 2017
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Abstract
Cornus officinalis and Dioscorea opposita are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic cardiomyopathy. Morroniside (Mor) of Cornus officinalis and diosgenin (Dio) of Dioscorea opposita formed an innovative formula named M +
[...] Read more.
Cornus officinalis and Dioscorea opposita are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic cardiomyopathy. Morroniside (Mor) of Cornus officinalis and diosgenin (Dio) of Dioscorea opposita formed an innovative formula named M + D. The aims of the present study were to investigate myocardial protective effect of M + D on diabetic cardiomyopathy (DCM) through the inhibition of expression levels of caspase-3 protein, and identify the advantage of M + D compared with Mor, Dio, and the positive drug metformin (Met). We detected cell viability, cell apoptosis, intracellular reactive oxygen species (ROS) levels, and the expression levels of Bcl-2, Bax, and caspase-3 protein in rat cardiomyocytes. In result, Mor, Dio, and M + D increased cell viability, inhibited cell apoptosis and decreased ROS levels. Additionally, the expression of Bax and Bcl-2 protein was modulated and the expression levels of caspase-3 protein were markedly decreased. Among the treatment groups, M + D produced the most prominent effects. In conclusion, our data showed for the first time that Mor, Dio, and M + D prevented high glucose (HG)-induced myocardial injury by reducing oxidative stress and apoptosis in rat cardiomyocytes. Among all the groups, M + D produced the strongest effect, while Mor and Dio produced weaker effects. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Review

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Open AccessReview Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors
Molecules 2017, 22(6), 886; doi:10.3390/molecules22060886
Received: 4 April 2017 / Revised: 24 May 2017 / Accepted: 24 May 2017 / Published: 27 May 2017
Cited by 1 | PDF Full-text (1171 KB) | HTML Full-text | XML Full-text
Abstract
The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein
[...] Read more.
The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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Open AccessReview Solanesol Biosynthesis in Plants
Molecules 2017, 22(4), 510; doi:10.3390/molecules22040510
Received: 1 March 2017 / Revised: 18 March 2017 / Accepted: 22 March 2017 / Published: 23 March 2017
PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
Solanesol is a non-cyclic terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants. Solanesol plays an important role in the interactions between plants and environmental factors such as pathogen infections and moderate-to-high temperatures. Additionally, it is a key intermediate
[...] Read more.
Solanesol is a non-cyclic terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants. Solanesol plays an important role in the interactions between plants and environmental factors such as pathogen infections and moderate-to-high temperatures. Additionally, it is a key intermediate for the pharmaceutical synthesis of ubiquinone-based drugs such as coenzyme Q10 and vitamin K2, and anti-cancer agent synergizers such as N-solanesyl-N,N′-bis(3,4-dimethoxybenzyl) ethylenediamine (SDB). In plants, solanesol is formed by the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway within plastids. Solanesol’s biosynthetic pathway involves the generation of C5 precursors, followed by the generation of direct precursors, and then the biosynthesis and modification of terpenoids; the first two stages of this pathway are well understood. Based on the current understanding of solanesol biosynthesis, we here review the key enzymes involved, including 1-deoxy-d-xylulose 5-phosphate synthase (DXS), 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), isopentenyl diphosphate isomerase (IPI), geranyl geranyl diphosphate synthase (GGPPS), and solanesyl diphosphate synthase (SPS), as well as their biological functions. Notably, studies on microbial heterologous expression and overexpression of key enzymatic genes in tobacco solanesol biosynthesis are of significant importance for medical uses of tobacco. Full article
(This article belongs to the Special Issue Isoprenoid Biosynthesis)
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