Abstract
Methylotrophic yeasts such as Candida boidinii, Hansenula polymorpha, Pichia methanolica and Pichia pastoris are an emerging group of eukaryotic hosts for recombinant protein production with an ever increasing number of applications during the last 30 years. Their applications are linked to the use of strong methanol-inducible promoters derived from genes of the methanol utilisation pathway. These promoters are tightly regulated, highly repressed in presence of non-limiting concentrations of glucose in the medium and strongly induced if methanol is used as carbon source. Several factors involved in this tight control and their regulatory effects have been described so far. This review summarises available data about the regulation of promoters from methanol utilisation pathway genes. Furthermore, the role of cis and trans acting factors (e.g. transcription factors, glucose processing enzymes) in the expression of methanol utilisation pathway genes is reviewed both in the context of the native cell environment as well as in heterologous hosts.
Highlights
The success of methylotrophic yeasts in the production of recombinant proteins is highly linked to the very strong and tightly regulated promoters of some genes of the methanol utilisation pathway (MUT pathway)
Among the reviewed yeasts there are significant differences e.g. in regulation of the alcohol oxidase genes: In C. boidinii and H. polymorpha AOX expression is strongly derepressed by glycerol, at different levels
AOX expression is still repressed in P. pastoris while P. methanolica combines both expression patterns: MOD1 is regulated like the H. polymorpha and C. boidinii alcohol oxidase genes with derepression on glycerol as carbon source while MOD2 is regulated similar to the P. pastoris AOX1/2 genes where no activity is found in glycerol containing media
Summary
The yeast Saccharomyces cerevisiae was used by mankind for millennia, mainly in brewing and baking. In an interesting engineering approach the multi-step pathways to synthesise galactose and sialic acid as well as the respective pathways to add these sugars to glycans was introduced into P. pastoris, providing a battery of individual strains which add specific and homogenous human-like glycan structures to recombinant proteins [45,49,50,51,52,53] This breakthrough has opened the door to increasing applications of this methylotrophic yeast for the production of biopharmaceuticals such as therapeutic antibodies, a market so far dominated by E. coli, S. cerevisiae and mammalian cell lines [53,54,55,56]
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