"Isopentenyl pyrophosphate isomerase"

Isopentenyl-pyrophosphate delta isomerase 1
Identifiers
Symbol IDI1
Entrez 3422
HUGO 5387
OMIM 604055
RefSeq NM_004508
UniProt Q13907
Other data
EC number 5.3.3.2
Locus Chr. 10 p15.3

Isopentenyl pyrophosphate isomerase (IPP isomerase) (incorrectly, Isopentenyl-diphosphate delta isomerase) is an isomerase that catalyzes the conversion of the relatively un-reactive isopentenyl pyrophosphate (IPP) to the more-reactive electrophile dimethylallyl pyrophosphate (DMAPP). This isomerization is a key step in the biosynthesis of isoprenoids through the mevalonate pathway.

Enzyme Mechanism

IPP isomerase catalyzes the isomerization of IPP to DMAPP by an antarafacial transposition of hydrogen.[1][2] The empirical evidence suggests that this reaction proceeds by a protonation/deprotonation mechanism, with the addition of a proton to the re-face of the inactivated C3-C4 double bond resulting in a transient carbocation intermediate.[3][4] The removal of the pro-R proton from C2 forms the C2-C3 double bond of DMAPP.

IPP isomerase mechanism

Enzyme Structure

A cartoon diagram of human IPP isomerase with the catalytic cysteine residue (Cys87) in red and the catalytic glutamic acid residue (Glu149) in blue (RCSB Protein Data Bank accession number 2ICJ).

Crystallographic studies have observed that the active form of IPP isomerase is a monomer with alternating α-helices and β-sheets.[5][6] The active site of IPP isomerase is deeply buried within the enzyme and consists of a glutamic acid residue and a cysteine residue that interact with opposite sides of the IPP substrate, consistent with the antarafacial stereochemistry of isomerization.[5][7] The origin of the initial protonation step has not been conclusively established. Recent evidence suggests that the glutamic acid residue is involved in the protonating step despite the observation that its carboxylic acid side-chain is stabilized in its carboxylate form.[8] This discrepancy has been addressed by the discovery of a water molecule in the active site of human IPP isomerase, suggesting a mechanism where the glutamine residue polarizes the double bond of IPP and makes it more susceptible to protonation by water.[9]

IPP isomerase also requires a divalent cation to fold into its active conformation. The enzyme contains several amino acids, including the catalytic glutamate, that are involved in coordinating with Mg2+ or Mn2+.[5][10] The coordination of the metal cation to the glutamate residue stabilizes the carbiocation intermediate after protonation.

Biological Function

The protonation of an inactivated double bond is rarely seen in nature, highlighting the unique catalytic mechanism of IPP isomerase. The isomerization of IPP to DMAPP is a crucial step in the synthesis of isoprenoids and isoprenoid-derivatives, compounds that play vital roles in the biosynthetic pathways of all living organisms.[11] Because of the importance of the melavonate pathway in isoprenoid biosynthesis, IPP isomerase is found in a variety of different cellular compartments, including plastids and mammalian mitochondria.[12]

Mevalonate pathway

Disease Relevance

Mutations in IDI1, the gene that codes for IPP isomerase 1, have been implicated in decreased viability in a number of organisms, including the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans and the plant Arabidopsis thaliana.[13][14][15] While there have been no evidence directly implicating IDI1 mutations in human disease, genomic analysis has identified a copy-number gain near two IPP isomerase genes in a substantial proportion of patients with sporadic amyotrophic lateral sclerosis, suggesting that the isomerase may play a role in this disease.[16]

References

  1. ↑ Cornforth, J.; Cornforth, R.; Popják, G.; Yengoyan, L. (1966). "Studies on the biosynthesis of cholesterol. XX. Steric course of decarboxylation of 5-pyrophosphomevalonate and of the carbon to carbon bond formation in the biosynthesis of farnesyl pyrophosphate". The Journal of Biological Chemistry 241 (17): 3970–3987. PMID 4288360.
  2. ↑ Cornforth, R. H. and G. Popják (1969). Chemical syntheses of substrates of sterol biosynthesis. Methods in Enzymology. B. C. Raymond, Academic Press. Volume 15: 359-390.
  3. ↑ Reardon, J.; Abeles, R. (1986). "Mechanism of action of isopentenyl pyrophosphate isomerase: Evidence for a carbonium ion intermediate". Biochemistry 25 (19): 5609–5616. doi:10.1021/bi00367a040. PMID 3022798.
  4. ↑ Street, I. P., D. J. Christensen, et al. (1990). "Hydrogen exchange during the enzyme-catalyzed isomerization of isopentenyl diphosphate and dimethylallyl diphosphate." Journal of the American Chemical Society 112(23): 8577-8578.
  5. ↑ 5.0 5.1 5.2 Hall, N.; Fish, D.; Hunt, N.; Goldin, R.; Guillou, P.; Monson, J. (1992). "Is the relationship between angiogenesis and metastasis in breast cancer real?". Surgical oncology 1 (3): 223–229. PMID 1285217.
  6. ↑ Zheng, W.; Sun, F.; Bartlam, M.; Li, X.; Li, R.; Rao, Z. (2007). "The Crystal Structure of Human Isopentenyl Diphosphate Isomerase at 1.7 Å Resolution Reveals its Catalytic Mechanism in Isoprenoid Biosynthesis". Journal of Molecular Biology 366 (5): 1447–1458. doi:10.1016/j.jmb.2006.12.055. PMID 17250851.
  7. ↑ Street, I.; Coffman, H.; Baker, J.; Poulter, C. (1994). "Identification of Cys139 and Glu207 as catalytically important groups in the active site of isopentenyl diphosphate:dimethylallyl diphosphate isomerase". Biochemistry 33 (14): 4212–4217. doi:10.1021/bi00180a014. PMID 7908830.
  8. ↑ Wouters, J.; Oudjama, Y.; Barkley, S.; Tricot, C.; Stalon, V.; Droogmans, L.; Poulter, C. (2003). "Catalytic Mechanism of Escherichia coli Isopentenyl Diphosphate Isomerase Involves Cys-67, Glu-116, and Tyr-104 as Suggested by Crystal Structures of Complexes with Transition State Analogues and Irreversible Inhibitors". Journal of Biological Chemistry 278 (14): 11903–11908. doi:10.1074/jbc.M212823200. PMID 12540835.
  9. ↑ Zhang, C.; Liu, L.; Xu, H.; Wei, Z.; Wang, Y.; Lin, Y.; Gong, W. (2007). "Crystal Structures of Human IPP Isomerase: New Insights into the Catalytic Mechanism". Journal of Molecular Biology 366 (5): 1437–1446. doi:10.1016/j.jmb.2006.10.092. PMID 17137593.
  10. ↑ Bonanno, J. B.; Edo, C.; Eswar, N.; Pieper, U.; Romanowski, M.; Ilyin, V.; Gerchman, S.; Kycia, H.; Studier, F.; Sali, A.; Burley, S. K. (2001). "Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis". Proceedings of the National Academy of Sciences 98 (23): 12896–12901. doi:10.1073/pnas.181466998. PMC 60796. PMID 11698677.
  11. ↑ Bach, T. (1995). "Some new aspects of isoprenoid biosynthesis in plants--a review". Lipids 30 (3): 191–202. doi:10.1007/BF02537822. PMID 7791527.
  12. ↑ Ramos-Valdivia, A.; Van Der Heijden, R.; Verpoorte, R. (1997). "Isopentenyl diphosphate isomerase: A core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function". Natural product reports 14 (6): 591–603. PMID 9418296.
  13. ↑ Mayer, M. P.; Hahn, F. M.; Stillman, D. J.; Poulter, C. D. (1992). "Disruption and mapping ofIDI1, the gene for isopentenyl diphosphate isomerase inSaccharomyces cerevisiae". Yeast 8 (9): 743–748. doi:10.1002/yea.320080907. PMID 1441751.
  14. ↑ Yochem, J.; Hall, D. H.; Bell, L. R.; Hedgecock, E. M.; Herman, R. K. (2005). "Isopentenyl-diphosphate isomerase is essential for viability of Caenorhabditis elegans". Molecular Genetics and Genomics 273 (2): 158–166. doi:10.1007/s00438-004-1101-x. PMID 15765206.
  15. ↑ Okada, K.; Kasahara, H.; Yamaguchi, S.; Kawaide, H.; Kamiya, Y.; Nojiri, H.; Yamane, H. (2008). "Genetic Evidence for the Role of Isopentenyl Diphosphate Isomerases in the Mevalonate Pathway and Plant Development in Arabidopsis". Plant and Cell Physiology 49 (4): 604–616. doi:10.1093/pcp/pcn032. PMID 18303110.
  16. ↑ Kato, T.; Emi, M.; Sato, H.; Arawaka, S.; Wada, M.; Kawanami, T.; Katagiri, T.; Tsuburaya, K.; Toyoshima, I.; Tanaka, F.; Sobue, G.; Matsubara, K. (2010). "Segmental copy-number gain within the region of isopentenyl diphosphate isomerase genes in sporadic amyotrophic lateral sclerosis". Biochemical and Biophysical Research Communications 402 (2): 438–442. doi:10.1016/j.bbrc.2010.10.056. PMID 20955688.

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