Non-mevalonate pathway

Source: Wikipedia, the free encyclopedia.

The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP).[1][2][3] The currently preferred name for this pathway is the MEP pathway, since MEP is the first committed metabolite on the route to IPP.

Isoprenoid precursor biosynthesis

The mevalonate pathway (MVA pathway or HMG-CoA reductase pathway) and the MEP pathway are metabolic pathways for the biosynthesis of isoprenoid precursors: IPP and DMAPP. Whereas plants use both MVA and MEP pathway, most organisms only use one of the pathways for the biosynthesis of isoprenoid precursors. In plant cells IPP/DMAPP biosynthesis via the MEP pathway takes place in plastid organelles, while the biosynthesis via the MVA pathway takes place in the cytoplasm.[4] Most gram-negative bacteria, the photosynthetic cyanobacteria and green algae use only the MEP pathway.[5] Bacteria that use the MEP pathway include important pathogens such Mycobacterium tuberculosis.[6]

IPP and DMAPP serve as precursors for the biosynthesis of

protein anchoring and N-glycosylation in all three domains of life.[citation needed] In photosynthetic organisms MEP-derived precursors are used for the biosynthesis of photosynthetic pigments, such as the carotenoids and the phytol chain of chlorophyll and light harvesting pigments.[5]

Bacteria such as

isotopomers.[8]

Non-mevalonate pathway reactions in the biosynthesis of isoprenoids. Redrawn verbatim from the scheme of Qidwai and coworkers [Fig. 2.].[9] Note, the enzyme abbreviations in this figure are non-standard (cf. Eisenreich et al.[10]), but are presented here and reproduced in the table to allow the two sets of data to be used together.

Reactions

The reactions of the MEP pathway are as follows, taken primarily from Eisenreich and co-workers, except where the bold labels are additional local abbreviations to assist in connecting the table to the scheme above:[10][9]

Reactants Enzyme Product
Pyruvate (Pyr) and glyceraldehyde 3-phosphate
(G3P)
DOXP synthase
(Dxs; DXP)		 1-Deoxy-D-xylulose 5-phosphate (DOXP; DXP)
DOXP (DXP) DXP reductoisomerase (Dxr, IspC; DXR)
2-C-methylerythritol 4-phosphate
(MEP)
MEP 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (YgbP, IspD; CMS)
4-diphosphocytidyl-2-C-methylerythritol
(CDP-ME)
CDP-ME
4-diphosphocytidyl-2-C-methyl-D-erythritol kinase
(YchB, IspE; CMK)
4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate
(CDP-MEP)
CDP-MEP 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (YgbB, IspF; MCS)
2-C-methyl-D-erythritol 2,4-cyclodiphosphate
(MEcPP)
MEcPP
HMB-PP synthase
(GcpE, IspG; HDS)		 (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP)
HMB-PP
HMB-PP reductase
(LytB, IspH; HDR)		 Isopentenyl pyrophosphate (IPP) and Dimethylallyl pyrophosphate (DMAPP)

Inhibition and other pathway research

Dxs, the first enzyme of the pathway, is

dimer and the precise mechanism of enzyme inhibition has been debated in the field. It has been proposed that IPP/DMAPP are competing the co-factor TPP.[11] A more recent study suggested that IPP/DMAPP trigger monomerisation and subsequent degradation of the enzyme, via interaction with a monomer interaction site that differs from the active site of the enzyme.[12]

DXP reductoisomerase (also known as: DXR, DOXP reductoisomerase, IspC, MEP synthase), is a key enzyme in the MEP pathway. It can be inhibited by the natural product fosmidomycin, which is under study as a starting point to develop a candidate antibacterial or antimalarial drug.[13][14][15]

The intermediate,

Vγ9/Vδ2 T cells, the major γδ T cell population in peripheral blood, and cells that "play a crucial role in the immune response to microbial pathogens".[16]

Metabolic engineering of the MEP/Non-mevalonate pathway

The MEP pathway has been extensively studied and engineered

photo-autotrophic microbes that can assimilate carbon dioxide from the atmosphere into various carbon containing metabolites, including terpenoids.[20][19][21] For biotechnology, cyanobacteria
are, thus, an attractive platform for the sustainable production of high-value compounds.

References

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  4. PMID 15012203
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  5. ^
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  6. PMID 20615187
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  7. S2CID 17214504
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  8. PMID 31843486
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  9. ^
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  17. ^ "Research team reports new class of antibiotics active against a wide range of bacteria". MDLinx. 23 December 2020. Retrieved 23 January 2023.[dead link]
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  21. ^
    PMID 33489752
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  22. ^
    ISSN 2197-4365
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