Terpene Moiety Enhancement by Overexpression of Geranyl(geranyl) Diphosphate Synthase and Geraniol Synthase Elevates Monomeric and Dimeric Monoterpene Indole Alkaloids in Transgenic Catharanthus roseus

Current approaches for the production of high-value compounds in microorganisms mostly use the cytosol as a general reaction vessel. However, competing pathways and metabolic cross-talk frequently prevent efficient synthesis of target compounds in the cytosol. Eukaryotic cells control the complexity of their metabolism by harnessing organelles to insulate biochemical pathways. Inspired by this concept, herein we transform yeast peroxisomes into microfactories for geranyl diphosphate-derived compounds, focusing on monoterpenoids, monoterpene indole alkaloids, and cannabinoids. We introduce a complete mevalonate pathway in the peroxisome to convert acetyl-CoA to several commercially important monoterpenes and achieve up to 125-fold increase over cytosolic production. Furthermore, peroxisomal production improves subsequent decoration by cytochrome P450s, supporting efficient conversion of (S)-(-)-limonene to the menthol precursor trans-isopiperitenol. We also establish synthesis of 8-hydroxygeraniol, the precursor of monoterpene indole alkaloids, and cannabigerolic acid, the cannabinoid precursor. Our findings establish peroxisomal engineering as an efficient strategy for the production of isoprenoids.

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Enzyme inhibitors cause multiple effects on accumulation of monoterpene indole alkaloids in Catharanthus roseus cambial meristematic cell cultures

Pharmacognosy Magazine ◽

10.4103/0973-1296.218121 ◽

2017 ◽

Vol 13 (52) ◽

pp. 732

Author(s):

Yu Rongmin ◽

Zi Jiachen ◽

Zhou Pengfei ◽

Zhu Jianhua

Keyword(s):

Cell Cultures ◽

Catharanthus Roseus ◽

Enzyme Inhibitors ◽

Indole Alkaloids ◽

Meristematic Cell ◽

Monoterpene Indole Alkaloids

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Monoterpene indole alkaloids from the leaves of Tabernaemontana elegans induce apoptosis activity in human hepatoma cells

Planta Medica ◽

10.1055/s-0029-1234593 ◽

2009 ◽

Vol 75 (09) ◽

Author(s):

TA Mansoor ◽

RM Ramalho ◽

CMP Rodrigues ◽

S Mulhovo ◽

MJU Ferreira

Keyword(s):

Indole Alkaloids ◽

Hepatoma Cells ◽

Human Hepatoma ◽

Human Hepatoma Cells ◽

Monoterpene Indole Alkaloids

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Apoptosis inducing activity of hydrazone derivatives of monoterpene indole alkaloids in human colon (HCT116) and liver (HepG2) carcinoma cells

Planta Medica ◽

10.1055/s-0034-1394659 ◽

2014 ◽

Vol 80 (16) ◽

Author(s):

A Paterna ◽

PM Borralho ◽

SE Gomes ◽

S Mulhovo ◽

CMP Rodrigues ◽

...

Keyword(s):

Indole Alkaloids ◽

Human Colon ◽

Carcinoma Cells ◽

Monoterpene Indole Alkaloids ◽

Derivatives Of

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Chemical Diversity and Bioactivities of Monoterpene Indole Alkaloids (MIAs) from Six Apocynaceae Genera

Molecules ◽

10.3390/molecules26020488 ◽

2021 ◽

Vol 26 (2) ◽

pp. 488

Author(s):

Afrah E. Mohammed ◽

Zainab H. Abdul-Hameed ◽

Modhi O. Alotaibi ◽

Nahed O. Bawakid ◽

Tariq R. Sobahi ◽

...

Keyword(s):

Biological Activities ◽

Indole Alkaloids ◽

Natural Compounds ◽

Molecular Target ◽

Chemical Diversity ◽

Drug Lead ◽

The Family ◽

Monoterpene Indole Alkaloids ◽

Drug Leads ◽

Anti Hiv

By the end of the twentieth century, the interest in natural compounds as probable sources of drugs has declined and was replaced by other strategies such as molecular target-based drug discovery. However, in the recent times, natural compounds regained their position as extremely important source drug leads. Indole-containing compounds are under clinical use which includes vinblastine and vincristine (anticancer), atevirdine (anti-HIV), yohimbine (erectile dysfunction), reserpine (antihypertension), ajmalicine (vascular disorders), ajmaline (anti-arrhythmic), vincamine (vasodilator), etc. Monoterpene Indole Alkaloids (MIAs) deserve the curiosity and attention of researchers due to their chemical diversity and biological activities. These compounds were considered as an impending source of drug-lead. In this review 444 compounds, were identified from six genera belonging to the family Apocynaceae, will be discussed. These genera (Alstonia, Rauvolfia, Kopsia, Ervatamia, and Tabernaemontana, and Rhazya) consist of 400 members and represent 20% of Apocynaceae species. Only 30 (7.5%) species were investigated, whereas the rest are promising to be investigated. Eleven bioactivities, including antibacterial, antifungal, anti-inflammatory and immunosuppressant activities, were reported. Whereas cytotoxic effect represents 47% of the reported activities. Convincingly, the genera selected in this review are a wealthy source for future anticancer drug lead.

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Biosynthesis of pinene in purple non-sulfur photosynthetic bacteria

Microbial Cell Factories ◽

10.1186/s12934-021-01591-6 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Xiaomin Wu ◽

Guang Ma ◽

Chuanyang Liu ◽

Xin-yuan Qiu ◽

Lu Min ◽

...

Keyword(s):

Fusion Protein ◽

Heterologous Expression ◽

Rhodobacter Sphaeroides ◽

Photosynthetic Bacteria ◽

Fine Chemicals ◽

Isopentenyl Diphosphate ◽

Isopentenyl Diphosphate Isomerase ◽

Geranyl Diphosphate ◽

Ribosome Binding ◽

Geranyl Diphosphate Synthase

Abstract Background Pinene is a monoterpene, that is used in the manufacture of fragrances, insecticide, fine chemicals, and renewable fuels. Production of pinene by metabolic-engineered microorganisms is a sustainable method. Purple non-sulfur photosynthetic bacteria belong to photosynthetic chassis that are widely used to synthesize natural chemicals. To date, researches on the synthesis of pinene by purple non-sulfur photosynthetic bacteria has not been reported, leaving the potential of purple non-sulfur photosynthetic bacteria synthesizing pinene unexplored. Results Rhodobacter sphaeroides strain was applied as a model and engineered to express the fusion protein of heterologous geranyl diphosphate synthase (GPPS) and pinene synthase (PS), hence achieving pinene production. The reaction condition of pinene production was optimized and 97.51 μg/L of pinene was yielded. Then, genes of 1-deoxy-d-xylulose 5-phosphate synthase, 1-deoxy-d-xylulose 5-phosphate reductoisomerase and isopentenyl diphosphate isomerase were overexpressed, and the ribosome binding site of GPPS-PS mRNA was optimized, improving pinene titer to 539.84 μg/L. Conclusions In this paper, through heterologous expression of GPPS-PS, pinene was successfully produced in R. sphaeroides, and pinene production was greatly improved by optimizing the expression of key enzymes. This is the first report on pinene produce by purple non-sulfur photosynthetic bacteria, which expands the availability of photosynthetic chassis for pinene production.

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