Production of tissue plasminogen activator (t-PA) in Aspergillus niger

Marilyn G. Wiebe, Atul Karandikar, Geoff D. Robson, Anthony P J Trinci, Juana L Flores Candia, Susanne Trappe, Gregg Wallis, Ursula Rinas, Patrick M F Derkx, Susan M. Madrid, Heidi Sisniega, Ignacio Faus, Roy Montijn, Cees A M J J van den Hondel, Peter J. Punt

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    A protease-deficient strain of Aspergillus niger has been used as a host for the production of human tissue plasminogen activator (t-PA). In defined medium, up to 0.07 mg t-PA (g biomass)-1 was produced in batch and fed-batch cultures and production was increased two- to threefold in two-phase batch cultures in which additional glucose was provided as a single pulse at the end of the first batch growth phase. Production was increased [up to 1.9 mg t-PA (g biomass)-1] by the addition of soy peptone to the defined medium. The rate of t-PA production in batch cultures supplemented with soy peptone (0.2 to 0.6 mg t-PA L-1 h-1) was comparable to rates observed previously in high-producing mammalian or insect cell cultures. In glucose-limited chemostat culture supplemented with soy peptone, t-PA was produced at a rate of 0.7 mg t-PA L-1 h-1. Expression of t-PA in A. niger resulted in increased expression of genes (bipA, pdiA, and cypB) involved in the unfolded protein response (UPR). However, when cypB was overexpressed in a t-PA-producing strain, t-PA production was not increased. The t-PA produced in A. niger was cleaved into two chains of similar molecular weight to two-chain human melanoma t-PA. The two chains appeared to be stable for at least 16 h in culture supernatant of the host strain. However, in general,
    Original languageEnglish
    Pages (from-to)164-174
    Number of pages10
    JournalBiotechnology and Bioengineering
    Issue number2
    Publication statusPublished - 2001


    • Aspergillus niger
    • Cyclophilin B
    • Protease-deficient
    • Tissue plasminogen activator (t-PA)
    • Unfolded protein response (UPR)


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