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Kinetically controlled drug resistance: how Penicillium brevicompactum survives mycophenolic acid

Xin E Sun1, Bjarne Gram Hansen, Lizbeth Hedstrom

  • 1Graduate Program in Biochemistry, Brandeis University, Waltham, Massachusetts 02453, USA.

The Journal of Biological Chemistry
|October 8, 2011
PubMed

Insights

Penicillium brevicompactum produces mycophenolic acid (MPA), an immunosuppressive drug. This study reveals MPA resistance in two IMPDH enzymes due to a rate-limiting intermediate formation, preventing drug accumulation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Mycology

Background:

  • The filamentous fungus *Penicillium brevicompactum* synthesizes mycophenolic acid (MPA), a potent immunosuppressive drug.
  • MPA functions by inhibiting eukaryotic inosine monophosphate dehydrogenases (IMPDHs), crucial enzymes in purine biosynthesis.
  • IMPDH inhibition occurs through trapping a covalent enzyme-intermediate (E-XMP*).

Purpose of the Study:

  • Investigate the mechanism of MPA resistance in two IMPDH enzymes from *P. brevicompactum* (PbIMPDH-A and PbIMPDH-B).
  • Determine why these enzymes exhibit significantly higher resistance to MPA compared to typical IMPDHs.
  • Elucidate the structural and mechanistic basis for MPA resistance in these fungal IMPDH variants.

Main Methods:

  • Enzyme kinetics studies were performed on purified PbIMPDH-A and PbIMPDH-B.
  • Comparative analysis of active site structures between MPA-sensitive and resistant IMPDHs.
  • Characterization of the enzyme-intermediate (E-XMP*) formation and stability.

Main Results:

  • PbIMPDH-A and PbIMPDH-B display 17- and 1000-fold increased resistance to MPA, respectively.
  • The active sites of PbIMPDH-A and PbIMPDH-B are structurally similar to MPA-sensitive IMPDHs.
  • Formation of the E-XMP* intermediate is the rate-limiting step for MPA-resistant PbIMPDHs, unlike MPA-sensitive IMPDHs.

Conclusions:

  • MPA resistance in *P. brevicompactum* IMPDHs is not due to active site alterations.
  • Resistance arises from the inefficient accumulation of the MPA-sensitive E-XMP* intermediate.
  • This finding provides a novel mechanistic explanation for drug resistance in IMPDH enzymes.

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