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Adaptive evolution of drug targets in producer and non-producer organisms

Bjarne G Hansen1, Xin E Sun, Hans J Genee

  • 1Technical University of Denmark, Department of Systems Biology, Center for Microbial Biotechnology, 2800 Kgs Lyngby, Denmark.

The Biochemical Journal
|September 16, 2011
PubMed

Insights

Gene duplication in Penicillium fungi allowed for the evolution of mycophenolic acid (MPA) production. This adaptation led to resistant IMPDH enzymes, though with reduced catalytic efficiency, suggesting a trade-off for survival.

Area of Science:

  • Biochemistry
  • Mycology
  • Evolutionary Biology

Background:

  • Mycophenolic acid (MPA) is an immunosuppressive drug produced by Penicillium fungi.
  • MPA inhibits IMP dehydrogenase (IMPDH), a crucial enzyme in nucleotide biosynthesis.
  • Penicillium subgenus Penicillium fungi possess genes for both IMPDH-A and IMPDH-B types.

Purpose of the Study:

  • To investigate the evolutionary relationship between IMPDH gene duplication and MPA biosynthesis in Penicillium.
  • To understand the biochemical basis of MPA resistance in IMPDH enzymes.
  • To explore the functional consequences of MPA resistance on IMPDH catalytic activity.

Main Methods:

  • Comparative analysis of IMPDH genes across Penicillium species.
  • Biochemical assays to determine MPA resistance and catalytic efficiency (kcat/Km) of IMPDH variants.
  • Site-directed mutagenesis to identify structural determinants of MPA resistance.

Main Results:

  • IMPDH gene duplication preceded MPA cluster acquisition and occurred independently.
  • Both P. brevicompactum IMPDHs exhibit MPA resistance, while non-producers' IMPDHs are sensitive.
  • MPA-resistant IMPDH-B shows significantly reduced catalytic efficiency (>1000-fold resistance, 0.5% of normal kcat/Km).
  • The C-terminal segment is a key determinant of MPA resistance, while the MPA-binding site is conserved.

Conclusions:

  • IMPDH gene duplication was a prerequisite for MPA production in Penicillium.
  • MPA production imposed selective pressure, driving the evolution of resistant IMPDHs with compromised catalytic function.
  • MPA resistance may have protected IMPDH-B from genetic drift, highlighting an evolutionary trade-off.

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