Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Feb 1;28(3):1403.
doi: 10.3390/molecules28031403.

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

Alizée Allamand  1 , Teresa Piechowiak  1   2 , Didier Lièvremont  1 , Michel Rohmer  1 , Catherine Grosdemange-Billiard  1
Affiliations
Review

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

Alizée Allamand et al. Molecules. .

Abstract

Isoprenoids, a diverse class of natural products, are present in all living organisms. Their two universal building blocks are synthesized via two independent pathways: the mevalonate pathway and the 2-C-methyl-ᴅ-erythritol 4-phosphate (MEP) pathway. The presence of the latter in pathogenic bacteria and its absence in humans make all its enzymes suitable targets for the development of novel antibacterial drugs. (E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), the last intermediate of this pathway, is a natural ligand for the human Vγ9Vδ2 T cells and the most potent natural phosphoantigen known to date. Moreover, 5-hydroxypentane-2,3-dione, a metabolite produced by Escherichia coli 1-deoxy-ᴅ-xylulose 5-phosphate synthase (DXS), the first enzyme of the MEP pathway, structurally resembles (S)-4,5-dihydroxy-2,3-pentanedione, a signal molecule implied in bacterial cell communication. In this review, we shed light on the diversity of potential uses of the MEP pathway in antibacterial therapies, starting with an overview of the antibacterials developed for each of its enzymes. Then, we provide insight into HMBPP, its synthetic analogs, and their prodrugs. Finally, we discuss the potential contribution of the MEP pathway to quorum sensing mechanisms. The MEP pathway, providing simultaneously antibacterial drug targets and potent immunostimulants, coupled with its potential role in bacterial cell-cell communication, opens new therapeutic perspectives.

Keywords: MEP pathway; antibacterial drug; immunostimulant; isoprenoids; laurencione; phosphoantigen; prodrug; quorum sensing.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
The multifaceted MEP pathway. ThDP: thiamine diphosphate; PLP: pyridoxal phosphate; ᴅ-G3P: ᴅ-glyceraldehyde 3-phosphate; DXS: 1-deoxy-ᴅ-xylulose 5-phosphate synthase; DXP ; IspC: 1-deoxy-ᴅ-xylulose 5-phosphate reductoisomerase; MEP: 2-C-methyl-ᴅ-erythritol 4-phosphate; IspD: 2-C-methyl-ᴅ-erythritol 4-phosphate cytidyl transferase; CDP-ME: 4-diphosphocytidyl-2-C-methyl-ᴅ-erythritol; IspF: 2-C-methyl-ᴅ-erythritol 2,4-cyclodiphosphate synthase; MEcPP: 2-C-methyl-ᴅ-erythritol-2,4 cyclodiphosphate; IspG: 2-C-methyl-ᴅ-erythritol 2,4-cyclodiphosphate reductase; HMBPP: (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate; IspH: 4-hydroxy-3-methylbut-2-enyl diphosphate reductase; DMAPP: dimethylallyl diphosphate; IPP: isopentenyl diphosphate.
Figure 1
Figure 1
Representative inhibitors of DXS. IC50: half maximal inhibitory concentration; MIC: minimum inhibitory concentration; Ki: inhibitory constant.
Figure 2
Figure 2
Representative inhibitors of DXR.
Figure 3
Figure 3
Representative prodrug of fosmidomycin analogs.
Figure 4
Figure 4
Representative inhibitors of IspD.
Figure 5
Figure 5
Representative inhibitors of IspE.
Figure 6
Figure 6
Representative inhibitors of IspF and IspDF.
Figure 7
Figure 7
Representative inhibitors of IspG and IspH.
Figure 8
Figure 8
Natural phosphoantigens from the isoprenoid biosynthesis and aminobisphosphonates. MVA: mevalonate; EC50: half maximal effective concentration.
Figure 9
Figure 9
Synthetic phosphoantigens (PAgs).
Figure 10
Figure 10
Prodrugs of phosphoantigens.
Scheme 2
Scheme 2
(A) DPD as a precursor to AI-2 S-(tetrahydroxytetrahydrofuran)-borate diester (S-THMF-borate) (B) DPD analogs.
Scheme 3
Scheme 3
Proposed pathway to laurencione.
Figure 11
Figure 11
Signal molecules identified in E. coli JB525 mutant.
See this image and copyright information in PMC

References

    1. Rohmer M., Knani M., Simonin P., Sutter B., Sahm H. Isoprenoid biosynthesis in bacteria: A novel pathway for the early steps leading to isopentenyl diphosphate. Biochem. J. 1993;295:517–524. doi: 10.1042/bj2950517. - DOI - PMC - PubMed
    1. Lombard J., Moreira D. Origins and early evolution of the mevalonate pathway of isoprenoid biosynthesis in the three domains of Life. Mol. Biol. Evol. 2011;28:87–99. doi: 10.1093/molbev/msq177. - DOI - PubMed
    1. Rohmer M. The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat. Prod. Rep. 1999;16:565–574. doi: 10.1039/a709175c. - DOI - PubMed
    1. Frank A., Groll M. The methylerythritol phosphate pathway to isoprenoids. Chem. Rev. 2017;117:5675–5703. doi: 10.1021/acs.chemrev.6b00537. - DOI - PubMed
    1. Cane D.E., Du S., Robinson J.K., Hsiung Y., Spenser I.D. Biosynthesis of vitamin B6: Enzymatic conversion of 1-deoxy-ᴅ-xylulose-5-phosphate to pyridoxol phosphate. J. Am. Chem. Soc. 1999;121:7722–7723. doi: 10.1021/ja9914947. - DOI

MeSH terms

LinkOut - more resources