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Para-aminosalicylic acid (PAS) is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis
Zheng, J1; Rubin, EJ2; Bifani, P1; Mathys, V3; Lim, V1; Au, M1; Jang, J4; Nam, J4; Dick, T1; Walker, JR5; Pethe, K4; Camacho, LR1
2013
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
Volume288Issue:32Pages:23447-23456
Abstract

para-Aminosalicylic acid (PAS) is one of the antimycobacterial drugs currently used for multidrug-resistant tuberculosis. Although it has been in clinical use for over 60 years, its mechanism(s) of action remains elusive. Here we report that PAS is a prodrug targeting dihydrofolate reductase (DHFR) through an unusual and novel mechanism of action. We provide evidences that PAS is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity. Interestingly, PAS is recognized by DHPS as efficiently as its natural substrate para-amino benzoic acid. Chemical inhibition of DHPS or mutation in DHFS prevents the formation of the antimetabolite, thereby conferring resistance to PAS. In addition, we identified a bifunctional enzyme (riboflavin biosynthesis protein (RibD)), a putative functional analog of DHFR in a knock-out strain. This finding is further supported by the identification of PAS-resistant clinical isolates encoding a RibD overexpression mutation displaying cross-resistance to genuine DHFR inhibitors. Our findings reveal that a metabolite of PAS inhibits DHFR in the folate pathway. RibD was shown to act as a functional analog of DHFR, and as for DHFS, both were shown to be associated in PAS resistance in laboratory strains and clinical isolates.

DOIhttps://doi.org/10.1074/jbc.M113.475798
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000330598200051
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Cited Times [WOS]:83   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Novartis Inst Trop Dis, Singapore 138670, Singapore
2.Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA
3.Sci Inst Publ Hlth, Inst Pasteur, Lab Mol Pathol TB, B-1050 Brussels, Belgium
4.Inst Pasteur Korea, Songnam 463400, South Korea
5.Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
Recommended Citation
GB/T 7714
Zheng, J,Rubin, EJ,Bifani, P,et al. Para-aminosalicylic acid (PAS) is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2013,288(32):23447-23456.
APA Zheng, J.,Rubin, EJ.,Bifani, P.,Mathys, V.,Lim, V.,...&Camacho, LR.(2013).Para-aminosalicylic acid (PAS) is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis.JOURNAL OF BIOLOGICAL CHEMISTRY,288(32),23447-23456.
MLA Zheng, J,et al."Para-aminosalicylic acid (PAS) is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis".JOURNAL OF BIOLOGICAL CHEMISTRY 288.32(2013):23447-23456.
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