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]
Contents
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
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- ↑ Lua error in package.lua at line 80: module 'strict' not found.
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