Non-mevalonate pathway

The non-mevalonate pathway or 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway (MEP/DOXP pathway) of isoprenoid biosynthesis is an alternative metabolic pathway leading to the formation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP).^[1][2][3]

Diversity of isoprenoid biosynthesis

The classical mevalonate pathway or HMG-CoA reductase pathway is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria. It is important for the production of IPP and DMAPP that serve as the basis for the biosynthesis of molecules used in processes as diverse as protein prenylation, cell membrane maintenance, hormones, protein anchoring and N-glycosylation.

In contrast to the classical mevalonate pathway of isoprenoid biosynthesis, plants and apicomplexan protozoa such as malaria parasites have the ability to produce their isoprenoids (terpenoids) using an alternative pathway, the non-mevalonate pathway, which takes place in their plastids.^[4] In addition, most bacteria including important pathogens such Mycobacterium tuberculosis synthesize IPP and DMAPP via the non-mevalonate pathway.^[5]

Reactions

The reactions are as follows:^[6]

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

Inhibition

Fosmidomycin specifically inhibits DOXP reductoisomerase, a key enzyme in the non-mevalonate pathway, and therefore represents an attractive candidate as antibiotic or antimalarial drug.^[7][8]

T cell activation

The intermediate HMB-PP is the natural activator for human Vγ9/Vδ2 T cells, the major γδ T cell population in peripheral blood.^[9]

References

1. Rohmer M; Rohmer, Michel (1999). "The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants". Nat Prod Rep. 16 (5): 565–574. doi:10.1039/a709175c. PMID 10584331.
2. W. Eisenreich, A. Bacher, D. Arigoni and F. Rohdich (2004). "Review Biosynthesis of isoprenoids via the non-mevalonate pathway". Cellular and Molecular Life Sciences. 61 (12): 1401–1426. doi:10.1007/s00018-004-3381-z. PMID 15197467.
3. William N. Hunter (2007). "The Non-mevalonate Pathway of Isoprenoid Precursor Biosynthesis". The Journal of Biological Chemistry. 282 (30): 21573–21577. doi:10.1074/jbc.R700005200. PDF
4. Lichtenthaler H (1999). "The 1-Deoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants". Annu Rev Plant Physiol Plant Mol Biol. 50: 47–65. doi:10.1146/annurev.arplant.50.1.47. PMID 15012203.
5. Wiemer, AJ; Hsiao, CH; Wiemer, DF (2010). "Isoprenoid metabolism as a therapeutic target in gram-negative pathogens.". Current topics in medicinal chemistry. 10 (18): 1858–71. PMID 20615187.
6. Eisenreich W, Bacher A, Arigoni D, Rohdich F (June 2004). "Biosynthesis of isoprenoids via the non-mevalonate pathway". Cell. Mol. Life Sci. 61 (12): 1401–26. doi:10.1007/s00018-004-3381-z. PMID 15197467.
7. Jomaa H, Wiesner J, Sanderbrand S, et al. (September 1999). "Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs". Science. 285 (5433): 1573–6. doi:10.1126/science.285.5433.1573. PMID 10477522.
8. C. Zinglé, L. Kuntz, D. Tritsch, C. Grosdemange-Billiard and M. Rohmer (2010). "Isoprenoid Biosynthesis via the Methylerythritol Phosphate Pathway: Structural Variations around Phosphonate Anchor and Spacer of Fosmidomycin, a Potent Inhibitor of Deoxyxylulose Phosphate Reductoisomerase". J. Org. Chem. 75 (10): 3203–3207. doi:10.1021/jo9024732.
9. Eberl M, Hintz M, Reichenberg A, Kollas AK, Wiesner J, Jomaa H (June 2003). "Microbial isoprenoid biosynthesis and human gammadelta T cell activation". FEBS Lett. 544 (1-3): 4–10. doi:10.1016/S0014-5793(03)00483-6. PMID 12782281.