Super yeast is a first-class penicillin factory
17 December 2009
Hansenula polymorpha gets new genes
Dutch researchers have rebuilt the yeast Hansenula polymorpha to become a first-class penicillin factory. Penicillin is still one of the most commonly used antibiotics in the world. However, the medicine is produced by a fungus, which makes large-scale production far from easy. Using the yeast instead will allow a far easier and more sustainable production of penicillin in the future. The journal PLoS ONE recently published the results of the study.
The yeast H. polymorpha is already widely used for the production of medicines such as insulin and hepatitis B vaccines. PhD researcher Loknath Gidijala has found out how to construct the unicellular fungus so that it can make the commonly used penicillin. He did this by transferring genes from Penicillium chrysogenum, the fungus that naturally releases penicillin, to H. polymorpha. After transfer of the genes, the cell not only produced penicillin but did so in a highly efficient manner. The investigators did not need to use any other devices to obtain penicillin from the yeast.
Genetic wonder
The production of penicillin requires specific enzymes. Penicillium chrysogenum possesses these naturally, but the modest yeast H. polymorpha does not. The researchers therefore placed genes in the yeast that code for the necessary enzymes. However, Loknath Gidijala did not transfer just a few loose genes, but an entire 'biochemical pathway' of genes that mediate the effect of each other. This was the first time that this entire pathway has been copied from Penicillium chrysogenum.
To make it even more challenging, the biochemical pathway did not just have to work in one part of the cell, but in several: the first stages had to take place in the cytosol (the fluid containing all the cell organelles), and the other two stages in so-called peroxisomes, rugby ball-shaped organelles that deal with the cell’s specific breakdown processes. In H. polymorpha, the enzymes that had to go to a specific place did this themselves, after which the end product was also produced of its own accord.
Crammed with peptides
Although the results of Gidijala’s study are very promising, things almost went amiss. At one of the very first stages, a rather large protein – the so-called non-ribosomal peptide synthetase – had to be produced in the small yeast cells. Such proteins occur in moulds and bacteria, but not in yeasts. Initially the protein was not active in the yeast, but by linking an extra enzyme to the protein Gidijala and his colleagues were able to activate it. This technique offers many possibilities for the production of other medicines.
New, sustainable antibiotics
As yeasts are easier to culture and genetically modify than moulds, they might be used in the future to produce new cheaper antibiotics. Furthermore, penicillin is economical to produce using H. polymorpha, which grows very well on inexpensive biofuels such as methanol.
The study by Loknath Gidijala and his colleagues was part of B-BASIC (Bio-based Sustainable Industrial Chemistry). This is an NWO-ACTS (Advanced Chemical Technologies for Sustainability) research consortium in which Dutch universities, research institutes and industrial partners work together. The programme focuses on the development of new concepts for the sustained production of energy and chemicals. The technologies generated by B-BASIC offer considerable advantages for society such as cleaner production, waste recycling and greater competition. DSM, the world market leader in penicillin production, collaborated on this project. The study group is led by Ida van der Klei. The article can be freely accessed via the PLoS ONE website.
About NWO
The Netherlands Organisation for Scientific Research (NWO) is the principal Dutch science funding body and its mission is to facilitate excellent scientific research in the Netherlands by means of national competition. Each year NWO spends more than 700 million euro on grants for top researchers, on innovative instruments and equipment, and on institutes where top research is performed. NWO funds the research of more than 5300 talented researchers at universities and institutes. Independent experts select proposals by means of a peer review system. NWO facilitates the transfer of knowledge to society.
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Further information:
- Ida van der Klei (University of Groningen)
- t.: + 31 (0)50 363 21 79, i.j.van.der.klei@rug.nl
Publication details:
An Engineered Yeast Efficiently Secreting Penicillin, Loknath Gidijala, Jan A. K. W. Kiel, Rutger D. Douma, Reza M. Seifar, Walter M. van Gulik, Roel A. L. Bovenberg, Marten Veenhuis, Ida J. van der Klei
