(E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate explained

(E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP or HMB-PP) is an intermediate of the MEP pathway (non-mevalonate pathway) of isoprenoid biosynthesis.[1] [2] The enzyme HMB-PP synthase (GcpE, IspG) catalyzes the conversion of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP) into HMB-PP. HMB-PP is then converted further to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).

HMB-PP is an essential metabolite in most pathogenic bacteria including Mycobacterium tuberculosis as well as in malaria parasites, but is absent from the human host.[3]

HMB-PP is the physiological activator ("phosphoantigen") for human Vγ9/Vδ2 T cells, the major γδ T cell population in peripheral blood. With a bioactivity of 0.1 nM it is 10,000-10,000,000 times more potent than any other natural compound, such as IPP or alkyl amines. HMB-PP functions in this capacity by binding the B30.2 domain of BTN3A1.[4]

Notes and References

  1. Rohmer . M . The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants . Natural Product Reports . 16 . 5 . 565–74 . 1999 . 10584331 . 10.1039/a709175c . Rohmer . Michel.
  2. Fox . DT . Poulter . CD . Synthesis of (E)-4-hydroxydimethylallyl diphosphate. An intermediate in the methyl erythritol phosphate branch of the isoprenoid pathway . The Journal of Organic Chemistry . 67 . 14 . 5009–10 . 2002 . 12098326 . 10.1021/jo0258453.
  3. Eisenreich . W . Bacher . A . Arigoni . D . Rohdich . F . Biosynthesis of isoprenoids via the non-mevalonate pathway . Cellular and Molecular Life Sciences . 61 . 12 . 1401–26 . 2004 . 15197467 . 10.1007/s00018-004-3381-z . 24558920 . 11138651 .
  4. Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor Periplakin. Rhodes DA, Chen HC, Price AJ, Keeble AH, Davey MS, James LC, Eberl M, Trowsdale J. 2015. J Immunol. 10.4049/jimmunol.1401064. 25637025. 4337483. 194. 5. 2390–8.

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