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. 2022 Nov 30;13:6557. doi: 10.1038/s41467-022-34243-3

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Orange arrows are specific to bacteria. Blue arrows are pathways specific to mammals. Black arrows are common to both bacteria and mammals. Mammalian dihydrofolate reductase (mDHFR) is able to reduce folic acid to DHF, while bacterial dihydrofolate reductase enzymes are unable to perform this reaction²³. Mammalian exogenous folate uptake pathways can accommodate multiple reduced folate substrates (RFC and hFR) or folic acid in addition to reduced folates (PCFT)⁴². RFC is the major transporter in systemic tissues while hFR and PCFT are tissue-specific. RFC reduced folate carrier, hFR human folate receptor, PCFT proton-coupled folate transporter, GTP guanosine triphosphate, DHP dihydropteroate, DHF dihydrofolate, THF tetrahydrofolate, PABA para-aminobenzoic acid, dUMP deoxyuridine monophosphate, dTMP deoxythymidine monophosphate, TMP trimethoprim, SMX sulfamethoxazole, DHFR dihydrofolate reductase (mammalian). Created with BioRender.com.