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-C4double bond resulting in a transient carbocationintermediate.[7][8] The removal of the pro-R proton from C2 forms the C2-C3 double bond of DMAPP.
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 acidside-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 divalentcation 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.
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 mammalianmitochondria.[16]
^Cornforth RH, Popják G (1969). "Chemical syntheses of substrates of sterol biosynthesis". In Raymond BC (ed.). Methods in Enzymology. Vol. 15. Academic Press. pp. 359–390.
^Reardon JE, Abeles RH (Sep 1986). "Mechanism of action of isopentenyl pyrophosphate isomerase: evidence for a carbonium ion intermediate". Biochemistry. 25 (19): 5609–5616. doi:10.1021/bi00367a040. PMID3022798.
^Street IP, Christensen DJ, Poulter CD (1990). "Hydrogen exchange during the enzyme-catalyzed isomerization of isopentenyl diphosphate and dimethylallyl diphosphate". Journal of the American Chemical Society. 112 (23): 8577–8578. doi:10.1021/ja00179a049.
^ abcHall NR, Fish DE, Hunt N, Goldin RD, Guillou PJ, Monson JR (Jun 1992). "Is the relationship between angiogenesis and metastasis in breast cancer real?". Surgical Oncology. 1 (3): 223–229. doi:10.1016/0960-7404(92)90068-v. PMID1285217.
^Zheng W, Sun F, Bartlam M, Li X, Li R, Rao Z (Mar 2007). "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. doi:10.1016/j.jmb.2006.12.055. PMID17250851.
^Street IP, Coffman HR, Baker JA, Poulter CD (Apr 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. PMID7908830.
^Zhang C, Liu L, Xu H, Wei Z, Wang Y, Lin Y, Gong W (Mar 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. PMID17137593.
^Ramos-Valdivia AC, van der Heijden R, Verpoorte R (Dec 1997). "Isopentenyl diphosphate isomerase: a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function". Natural Product Reports. 14 (6): 591–603. doi:10.1039/np9971400591. PMID9418296.
^Mayer MP, Hahn FM, Stillman DJ, Poulter CD (Sep 1992). "Disruption and mapping of IDI1, the gene for isopentenyl diphosphate isomerase in Saccharomyces cerevisiae". Yeast. 8 (9): 743–748. doi:10.1002/yea.320080907. PMID1441751. S2CID19430360.
^Yochem J, Hall DH, Bell LR, Hedgecock EM, Herman RK (Apr 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. PMID15765206. S2CID1637634.
^Kato T, Emi M, Sato H, Arawaka S, Wada M, Kawanami T, Katagiri T, Tsuburaya K, Toyoshima I, Tanaka F, Sobue G, Matsubara K (Nov 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. PMID20955688.
