Figure 1.

Previously proposed models for PAS activation and methionine-mediated PAS inactivation. As indicated on the left, PAS is an analog of PABA (shown in a dotted box) and is a prodrug that is activated by the M. tuberculosis folate biosynthetic pathway. PAS is incorporated in lieu of PABA by FolP1 and glutamylated by FolC to form the antimetabolite HDHF which inhibits DfrA activity (indicated as red blunted arrows) (Zheng et al., 2013; Zhao et al., 2014; Minato et al., 2015; Dawadi et al., 2017). Previous work has identified N-methyl and N,N-dimethyl PAS species (methyl groups indicated with dotted red boxes) in metabolite extracts from M. tuberculosis treated with PAS (Chakraborty et al., 2013). As N,N-dimethylation of PAS prevents incorporation by FolP1, the resulting metabolite is inactive (shown on the right). This activity is presumed to be dependent upon an as of yet unidentified SAM-dependent methyltransferase(s). Supplementation with methionine may increase SAM pools, which could be utilized by the methyltransferase(s) to inactivate PAS, thereby conferring resistance. PAS, para-aminosalicylic acid; PABA, para-aminobenzoic acid; HDHP, 2′-hydroxy-7,8-dihydropteroate; HDHF, 2′-hydroxy-7,8-dihydrofolate; FolP1, dihydropteroate synthase; FolC, dihydrofolate synthase; DfrA, dihydrofolate reductase; MT, methyltransferase; SAM, S-adenosyl methionine; SAH, S-adenosyl homocysteine.