The functional basis of mycophenolic acid resistance in Candida albicans IMP dehydrogenase

Gerwald Koehler, Xin Gong, Stefan Bentink, Stephanie Theiss, Gina M. Pagani, Nina Agabian, Lizbeth Hedstrom

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Candida albicans is an important fungal pathogen of immunocompromised patients. In cell culture, C. albicans is sensitive to mycophenolic acid (MPA) and mizoribine, both natural product inhibitors of IMP dehydrogenase (IMPDH). These drugs have opposing interactions with the enzyme. MPA prevents formation of the closed enzyme conformation by binding to the same site as a mobile flap. In contrast, mizoribine monophosphate, the active metabolite of mizoribine, induces the closed conformation. Here, we report the characterization of IMPDH from wild-type and MPA-resistant strains of C. albicans. The wild-type enzyme displays significant differences from human IMPDHs, suggesting that selective inhibitors that could be novel antifungal agents may be developed. IMPDH from the MPA-resistant strain contains a single substitution (A251T) that is far from the MPA-binding site. The A251T variant was 4-fold less sensitive to MPA as expected. This substitution did not affect the kcat value, but did decrease the Km values for both substrates, so the mutant enzyme is more catalytically efficient as measured by the value of kcat/ K m. These simple criteria suggest that the A251T variant would be the evolutionarily superior enzyme. However, the A251T substitution caused the enzyme to be 40-fold more sensitive to mizoribine monophosphate. This result suggests that A251T stabilizes the closed conformation, and this hypothesis is supported by further inhibitor analysis. Likewise, the MPA-resistant strain was more sensitive to mizoribine in cell culture. These observations illustrate the evolutionary challenge posed by the gauntlet of chemical warfare at the microbial level.

Original languageEnglish
Pages (from-to)11295-11302
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number12
DOIs
StatePublished - 25 Mar 2005

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IMP Dehydrogenase
Acid resistance
Mycophenolic Acid
Candida
Candida albicans
Enzymes
Conformations
Substitution reactions
Cell culture
Chemical Warfare
Cell Culture Techniques
Chemical warfare
Antifungal Agents
Immunocompromised Host
Pathogens
Metabolites
Biological Products
Binding Sites
bredinin

Cite this

Koehler, G., Gong, X., Bentink, S., Theiss, S., Pagani, G. M., Agabian, N., & Hedstrom, L. (2005). The functional basis of mycophenolic acid resistance in Candida albicans IMP dehydrogenase. Journal of Biological Chemistry, 280(12), 11295-11302. https://doi.org/10.1074/jbc.M409847200
Koehler, Gerwald ; Gong, Xin ; Bentink, Stefan ; Theiss, Stephanie ; Pagani, Gina M. ; Agabian, Nina ; Hedstrom, Lizbeth. / The functional basis of mycophenolic acid resistance in Candida albicans IMP dehydrogenase. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 12. pp. 11295-11302.
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Koehler, G, Gong, X, Bentink, S, Theiss, S, Pagani, GM, Agabian, N & Hedstrom, L 2005, 'The functional basis of mycophenolic acid resistance in Candida albicans IMP dehydrogenase', Journal of Biological Chemistry, vol. 280, no. 12, pp. 11295-11302. https://doi.org/10.1074/jbc.M409847200

The functional basis of mycophenolic acid resistance in Candida albicans IMP dehydrogenase. / Koehler, Gerwald; Gong, Xin; Bentink, Stefan; Theiss, Stephanie; Pagani, Gina M.; Agabian, Nina; Hedstrom, Lizbeth.

In: Journal of Biological Chemistry, Vol. 280, No. 12, 25.03.2005, p. 11295-11302.

Research output: Contribution to journalArticle

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T1 - The functional basis of mycophenolic acid resistance in Candida albicans IMP dehydrogenase

AU - Koehler, Gerwald

AU - Gong, Xin

AU - Bentink, Stefan

AU - Theiss, Stephanie

AU - Pagani, Gina M.

AU - Agabian, Nina

AU - Hedstrom, Lizbeth

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