Global metabolic rewiring of the nonconventional yeast Ogataea polymorpha for biosynthesis of the sesquiterpenoid β-elemene

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Abstract

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" id="d8593627e83">Bioproduction of natural products via microbial cell factories is a promising alternative to traditional plant extraction. Recently, nonconventional microorganisms have emerged as attractive chassis hosts for biomanufacturing. One such microorganism, Ogataea polymorpha is an industrial yeast used for protein expression with numerous advantages, such as thermal-tolerance, a wide substrate spectrum and high-density fermentation. Here, we systematically rewired the cellular metabolism of O. polymorpha to achieve high-level production of the sesquiterpenoid β-elemene by optimizing the mevalonate pathway, enhancing the supply of NADPH and acetyl-CoA, and downregulating competitive pathways. The engineered strain produced 509 mg/L and 4.7 g/L of β-elemene under batch and fed-batch fermentation, respectively. Therefore, this study identified the potential industrial application of O. polymorpha as a good microbial platform for producing sesquiterpenoids. </p>

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High-level semi-synthetic production of the potent antimalarial artemisinin.

C Paddon, P. J. Westfall, D Pitera … (2013)

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

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Computational Method to Predict Mitochondrially Imported Proteins and their Targeting Sequences

Manuel G. Claros, Pierre Vincens (1996)

Most of the proteins that are used in mitochondria are imported through the double membrane of the organelle. The information that guides the protein to mitochondria is contained in its sequence and structure, although no direct evidence can be obtained. In this article, discriminant analysis has been performed with 47 parameters and a large set of mitochondrial proteins extracted from the SwissProt database. A computational method that facilitates the analysis and objective prediction of mitochondrially imported proteins has been developed. If only the amino acid sequence is considered, 75-97% of the mitochondrial proteins studied have been predicted to be imported into mitochondria. Moreover, the existence of mitochondrial-targeting sequences is predicted in 76-94% of the analyzed mitochondrial precursor proteins. As a practical application, the number of unknown yeast open reading frames that might be mitochondrial proteins has been predicted, which revealed that many of them are clustered.

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Haematococcus astaxanthin: applications for human health and nutrition.

Martin Guerin, Mark Huntley, Miguel Olaizola (2003)

The carotenoid pigment astaxanthin has important applications in the nutraceutical, cosmetics, food and feed industries. Haematococcus pluvialis is the richest source of natural astaxanthin and is now cultivated at industrial scale. Astaxanthin is a strong coloring agent and a potent antioxidant - its strong antioxidant activity points to its potential to target several health conditions. This article covers the antioxidant, UV-light protection, anti-inflammatory and other properties of astaxanthin and its possible role in many human health problems. The research reviewed supports the assumption that protecting body tissues from oxidative damage with daily ingestion of natural astaxanthin might be a practical and beneficial strategy in health management.