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

(E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate
Chemical structure of HMB-PP
Chemical structure of HMB-PP
Ball-and-stick model, shown here as a 3- ion
Ball-and-stick model, shown here as a 3- ion
Names
Preferred IUPAC name
(2E)-4-Hydroxy-3-methylbut-2-en-1-yl trihydrogen diphosphate
Other names
(E)-4-hydroxy-dimethylallyl pyrophosphate
HDMAPP
(E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate
HMBDP
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
  • InChI=1S/C5H12O8P2/c1-5(4-6)2-3-12-15(10,11)13-14(7,8)9/h2,6H,3-4H2,1H3,(H,10,11)(H2,7,8,9)/b5-2+ checkY
    Key: MDSIZRKJVDMQOQ-GORDUTHDSA-N checkY
  • O=P(O)(O)OP(=O)(O)OCC=C(C)CO
Properties
C5H12O8P2
Molar mass 262.091 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

(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. 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).

Biochemical role

HMB-PP is an intermediate in the non-mevalonate pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Most gram-negative bacteria, the photosynthetic cyanobacteria and green algae use only this pathway, while higher plants also use the mevalonate pathway.

The enzyme 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase uses two reduced ferredoxin proteins per molecule of the precursor MEcPP to convert it to HMB-PP:

2D representation of the chemical structure of Q27103069.

MEcPP

+ 2 oxidised ferredoxin
 
 
 
H2O
Rightward reaction arrow with minor product(s) to top right
 
 
 

2D representation of the chemical structure of Q76285996.

HMB-PP

+ 2 reduced ferredoxin
 

The final step in the non-mevalonate pathway is carried out by the enzyme 4-hydroxy-3-methylbut-2-enyl diphosphate reductase, which gives a mixture of dimethylallyl pyrophosphate and isopentenyl pyrophosphate in the ratio of five to one.

HMB-PP +
2 reduced ferredoxin
 
 
2 H+
H2O
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right
 
 
 

2D representation of the chemical structure of dimethylallyl pyrophosphate .

dimethylallyl pyrophosphate

+ 2 oxidised ferredoxin
 
HMB-PP +
2 reduced ferredoxin
 
 
2 H+
H2O
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right
 
 
 

2D representation of the chemical structure of isopentenyl pyrophosphate .

isopentenyl pyrophosphate

+ 2 oxidised ferredoxin
 

The products are then used in terpenoid biosynthesis.

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.

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.

References

  1. 1 2 Rohmer, M; Rohmer, Michel (1999). "The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants". Natural Product Reports. 16 (5): 565–74. doi:10.1039/a709175c. PMID 10584331.
  2. ↑ Fox, DT; Poulter, CD (2002). "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. doi:10.1021/jo0258453. PMID 12098326.
  3. 1 2 3 Eisenreich, W; Bacher, A; Arigoni, D; Rohdich, F (2004). "Biosynthesis of isoprenoids via the non-mevalonate pathway". Cellular and Molecular Life Sciences. 61 (12): 1401–26. doi:10.1007/s00018-004-3381-z. PMC 11138651. PMID 15197467. S2CID 24558920.
  4. ↑ Hunter, WN (2007). "The Non-mevalonate Pathway of Isoprenoid Precursor Biosynthesis". Journal of Biological Chemistry. 282 (30): 21573–21577. doi:10.1074/jbc.R700005200. PMID 17442674.
  5. ↑ Vranová, Eva; Coman, Diana; Gruissem, Wilhelm (2013-04-29). "Network Analysis of the MVA and MEP Pathways for Isoprenoid Synthesis". Annual Review of Plant Biology. 64 (1): 665–700. Bibcode:2013AnRPB..64..665V. doi:10.1146/annurev-arplant-050312-120116. ISSN 1543-5008. PMID 23451776.
  6. ↑ Hecht, Stefan; Eisenreich, Wolfgang; Adam, Petra; Amslinger, Sabine; Kis, Klaus; Bacher, Adelbert; Arigoni, Duilio; Rohdich, Felix (2001). "Studies on the nonmevalonate pathway to terpenes: The role of the GcpE (IspG) protein". Proceedings of the National Academy of Sciences. 98 (26): 14837–14842. doi:10.1073/pnas.201399298. PMC 64945. PMID 11752431.
  7. ↑ Okada, Ken; Hase, Toshiharu (2005). "Cyanobacterial Non-mevalonate Pathway". Journal of Biological Chemistry. 280 (21): 20672–20679. doi:10.1074/jbc.M500865200. PMID 15792953.
  8. ↑ Charon, L.; Pale-Grosdemange, C.; Rohmer, M. (1999). "On the reduction steps in the mevalonate independent 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis in the bacterium Zymomonas mobilis". Tetrahedron Lett. 40 (40): 7231–7234. doi:10.1016/s0040-4039(99)01531-2.
  9. ↑ Röhrich RC, Englert N, Troschke K, Reichenberg A, Hintz M, Seeber F, Balconi E, Aliverti A, Zanetti G, Köhler U, Pfeiffer M, Beck E, Jomaa H, Wiesner J (November 2005). "Reconstitution of an apicoplast-localised electron transfer pathway involved in the isoprenoid biosynthesis of Plasmodium falciparum". FEBS Letters. 579 (28): 6433–8. doi:10.1016/j.febslet.2005.10.037. PMID 16289098.
  10. ↑ Rhodes DA, Chen HC, Price AJ, Keeble AH, Davey MS, James LC, Eberl M, Trowsdale J (2015). "Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor Periplakin". J Immunol. 194 (5): 2390–8. doi:10.4049/jimmunol.1401064. PMC 4337483. PMID 25637025.