Biology:Isopentenyl-diphosphate delta isomerase

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Short description: Class of enzymes
isopentenyl-diphosphate Δ-isomerase
1vcf.jpg
Isopentenyl-diphosphate delta isomerase octamer, Thermus thermophilus
Identifiers
EC number5.3.3.2
CAS number9033-27-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Isopentenyl-pyrophosphate Δ isomerase 1
Identifiers
SymbolIDI1
NCBI gene3422
HGNC5387
OMIM604055
RefSeqNM_004508
UniProtQ13907
Other data
EC number5.3.3.2
LocusChr. 10 p15.3

Isopentenyl pyrophosphate isomerase (EC 5.3.3.2, IPP isomerase), also known as Isopentenyl-diphosphate delta isomerase,[1] 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 and the MEP pathway.

isopentenyl diphosphate [math]\displaystyle{ \rightleftharpoons }[/math] dimethylallyl diphosphate

This enzyme belongs to the family of isomerases, specifically those intramolecular oxidoreductases transposing C=C bonds. The systematic name of this enzyme class is isopentenyl-diphosphate Delta3-Delta2-isomerase. Other names in common use include isopentenylpyrophosphate Delta-isomerase, methylbutenylpyrophosphate isomerase, and isopentenylpyrophosphate isomerase.[2][3][4]

Enzyme mechanism

IPP isomerase catalyzes the isomerization of IPP to DMAPP by an antarafacial transposition of hydrogen.[5][6] 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.[7][8] The removal of the pro-R proton from C2 forms the C2-C3 double bond of DMAPP.

IPP isomerase mechanism
The mechanism for the isomerization between IPP and DMAPP. Generic proton donors and acceptors are shown because the identities of the amino acids that carry out these functions have not conclusively been established.

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.[9][10] 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.[9][11] 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.[12] 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.[13]

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+.[9][14] The coordination of the metal cation to the glutamate residue stabilizes the carbiocation intermediate after protonation.

Structural studies

As of late 2007, 25 structures have been solved for this class of enzymes, with PDB accession codes 1HX3, 1HZT, 1I9A, 1NFS, 1NFZ, 1OW2, 1P0K, 1P0N, 1PPV, 1PPW, 1PVF, 1Q54, 1R67, 1VCF, 1VCG, 1X83, 1X84, 2B2K, 2DHO, 2G73, 2G74, 2I6K, 2ICJ, 2ICK, and 2PNY.

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.[15] 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.[16]

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.[17][18][19] 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.[20]

References

  1. ↑ "IDI1 - Isopentenyl-diphosphate Delta-isomerase - Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) - IDI1 gene & protein". UniProt. https://www.uniprot.org/uniprot/P15496. 
  2. ↑ "An unusual isopentenyl diphosphate isomerase found in the mevalonate pathway gene cluster from Streptomyces sp. strain CL190". Proc. Natl. Acad. Sci. U.S.A. 98 (3): 932–7. 2001. doi:10.1073/pnas.020472198. PMID 11158573. 
  3. ↑ Bishop JM (1983). "Cellular oncogenes and retroviruses". Annu. Rev. Biochem. 52: 301–54. doi:10.1146/annurev.bi.52.070183.001505. PMID 6351725. 
  4. ↑ "Biosynthesis of terpenes. VII. Isopentenyl pyrophosphate isomerase". J. Biol. Chem. 235 (2): 326–32. 1960. doi:10.1016/S0021-9258(18)69523-7. PMID 13792054. 
  5. ↑ "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. Sep 1966. doi:10.1016/S0021-9258(18)99800-5. PMID 4288360. 
  6. ↑ Cornforth, R. H.; Popják, G. (1969). "Chemical syntheses of substrates of sterol biosynthesis". in Raymond, B. C.. Methods in Enzymology. 15. Academic Press. pp. 359–390. 
  7. ↑ "Mechanism of action of isopentenyl pyrophosphate isomerase: evidence for a carbonium ion intermediate". Biochemistry 25 (19): 5609–5616. Sep 1986. doi:10.1021/bi00367a040. PMID 3022798. 
  8. ↑ "Hydrogen exchange during the enzyme-catalyzed isomerization of isopentenyl diphosphate and dimethylallyl diphosphate". Journal of the American Chemical Society 112 (23): 8577–8578. 1990. doi:10.1021/ja00179a049. 
  9. ↑ 9.0 9.1 9.2 "Is the relationship between angiogenesis and metastasis in breast cancer real?". Surgical Oncology 1 (3): 223–229. Jun 1992. doi:10.1016/0960-7404(92)90068-v. PMID 1285217. 
  10. ↑ "The crystal structure of human isopentenyl diphosphate isomerase at 1.7 A resolution reveals its catalytic mechanism in isoprenoid biosynthesis". Journal of Molecular Biology 366 (5): 1447–1458. Mar 2007. doi:10.1016/j.jmb.2006.12.055. PMID 17250851. 
  11. ↑ "Identification of Cys139 and Glu207 as catalytically important groups in the active site of isopentenyl diphosphate:dimethylallyl diphosphate isomerase". Biochemistry 33 (14): 4212–4217. Apr 1994. doi:10.1021/bi00180a014. PMID 7908830. 
  12. ↑ "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". The Journal of Biological Chemistry 278 (14): 11903–11908. Apr 2003. doi:10.1074/jbc.M212823200. PMID 12540835. 
  13. ↑ "Crystal structures of human IPP isomerase: new insights into the catalytic mechanism". Journal of Molecular Biology 366 (5): 1437–1446. Mar 2007. doi:10.1016/j.jmb.2006.10.092. PMID 17137593. 
  14. ↑ "Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis". Proceedings of the National Academy of Sciences of the United States of America 98 (23): 12896–12901. Nov 2001. doi:10.1073/pnas.181466998. PMID 11698677. Bibcode: 2001PNAS...9812896B. 
  15. ↑ "Some new aspects of isoprenoid biosynthesis in plants--a review". Lipids 30 (3): 191–202. Mar 1995. doi:10.1007/BF02537822. PMID 7791527. 
  16. ↑ "Isopentenyl diphosphate isomerase: a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function". Natural Product Reports 14 (6): 591–603. Dec 1997. doi:10.1039/np9971400591. PMID 9418296. 
  17. ↑ "Disruption and mapping of IDI1, the gene for isopentenyl diphosphate isomerase in Saccharomyces cerevisiae". Yeast 8 (9): 743–748. Sep 1992. doi:10.1002/yea.320080907. PMID 1441751. 
  18. ↑ "Isopentenyl-diphosphate isomerase is essential for viability of Caenorhabditis elegans". Molecular Genetics and Genomics 273 (2): 158–166. Apr 2005. doi:10.1007/s00438-004-1101-x. PMID 15765206. 
  19. ↑ "Genetic evidence for the role of isopentenyl diphosphate isomerases in the mevalonate pathway and plant development in Arabidopsis". Plant & Cell Physiology 49 (4): 604–616. Apr 2008. doi:10.1093/pcp/pcn032. PMID 18303110. 
  20. ↑ "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. Nov 2010. doi:10.1016/j.bbrc.2010.10.056. PMID 20955688. 

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