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Hansenula polymorpha

Hansenula polymorpha is Pharmedartis’ favourite yeast platform. It is distinghuished by an impressive track record as producer of valuable pharmaceutical proteins, food additives and technical enzymes that have already reached the market. Examples include Insulin, Interferon alpha-2a and HBsAg which is applied to the formulation of several vaccines against hepatitis B. Most of the established processes lean on gene expression under control of strong inducible promoter elements derived from genes of methanol metabolism.

Biology and application

Hansenula polymorpha is a species of the Saccharomycetaceae family like all yeasts applied to biotechnology. It belongs to a limited number of organisms that is able to utilize methanol as sole energy and carbon source. Upon addition of methanol into a culture medium genes of methanol metabolism are strongly induced resulting in a vast production of key enzymes like methanol oxidase (MOX) and formate dehydrogenase (FMD) (see figure). H. polymorpha is a thermo-tolerant organism making it most suited for production of crystalizable proteins. Further attractive characteristics include its robustness and the possibility to produce recombinant proteins in a safe and efficient way: The yeast does not contain pyrogens nor pathogens. In N-glycosylated proteins terminal mannose residues are attached by α1,2 bonds instead of forming allergenic α1,3 linkages observed in S. cerevisiae. H. polymorpha can be fermented to high cell densities in inexpensive synthetic media in a short time.
For heterologous gene production several strong promoter elements are available. MOX and FMD are derived from key genes of the methanol utilization pathway. Strong induction does not exclusively depend on the presence of toxic methanol but can be elicited by limited addition of glycerol or glucose. The strong constitutive TPS1 (trehalose phosphate synthase) promoter is of comparable strength that can further be boosted at elevated temperatures.

Available H. polymorpha strains and genetic elements. Strains, vectors and components of the CoMed™ system, particular strains and elements are:

Strains

Designation

phenotype

characteristics

MedHp1

ura

robust established strain isogenic to RB11 and LR9

MedHp2

leu


MedHp3

leu

strain with increased MOX- and FMD-dependent gene expression Patent protection applied

 

 Vector elements

Promoters


MOX

Established methanol-inducible promoter element, applied to a production process for Hepatitis B vaccines.

FMD

Established methanol-inducible promoter element, applied to the Production process for insulin, IFNalpha-2a and hepatitis B vaccines.

TPSI

Strong constitutive promoter that can be boosted at elevated temperatures.