Isopentenyl-diphosphate delta isomerase

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isopentenyl-diphosphate Δ-isomerase
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Isopentenyl-diphosphate delta isomerase octamer, Thermus thermophilus
Identifiers
EC no. 5.3.3.2
CAS no. 9033-27-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
Isopentenyl-pyrophosphate Δ isomerase 1
Identifiers
SymbolIDI1
NCBI gene 3422
HGNC 5387
OMIM 604055
RefSeq NM_004508
UniProt Q13907
Other data
EC number 5.3.3.2
Locus Chr. 10 p15.3
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Structures Swiss-model
Domains InterPro

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.

Contents

isopentenyl diphosphate 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.

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. IPP Delta Isomerase Mechanism.png
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). IPP isomerase structure with active sites highlighted.png
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 Mevalonate pathway.png
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]

Related Research Articles

Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. It is produced by many plants and animals (including humans) and its polymers are the main component of natural rubber. C. G. Williams named the compound in 1860 after obtaining it from the pyrolysis of natural rubber; he correctly deduced the empirical formula C5H8.

<span class="mw-page-title-main">Terpene</span> Class of oily organic compounds found in plants

Terpenes are a class of natural products consisting of compounds with the formula (C5H8)n for n ≥ 2. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. Terpenes are further classified by the number of carbons: monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), as examples. The terpene alpha-pinene is a major component of the common solvent, turpentine.

Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids that regulate many aspects of insect physiology. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction, diapause, and polyphenisms. The chemical formula for juvenile hormone is .

Isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. The general form of such a reaction is as follows:

<span class="mw-page-title-main">Mevalonate pathway</span>

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

<span class="mw-page-title-main">Dimethylallyl pyrophosphate</span> Chemical compound

Dimethylallyl pyrophosphate is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynthesis. It is an isomer of isopentenyl pyrophosphate (IPP) and exists in virtually all life forms. The enzyme isopentenyl pyrophosphate isomerase catalyzes isomerization between DMAPP and IPP.

<span class="mw-page-title-main">Sabinene</span> Chemical compound

Sabinene is a natural bicyclic monoterpene with the molecular formula C10H16. It is isolated from the essential oils of a variety of plants including Marjoram, holm oak (Quercus ilex) and Norway spruce (Picea abies). It has a strained ring system with a cyclopentane ring fused to a cyclopropane ring.

<span class="mw-page-title-main">Isopentenyl pyrophosphate</span> Chemical compound

Isopentenyl pyrophosphate is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway and in the non-mevalonate MEP pathway of isoprenoid precursor biosynthesis. Isoprenoid precursors such as IPP, and its isomer DMAPP, are used by organisms in the biosynthesis of terpenes and terpenoids.

(<i>E</i>)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate Chemical compound

(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).

The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The currently preferred name for this pathway is the MEP pathway, since MEP is the first committed metabolite on the route to IPP.

<span class="mw-page-title-main">Steviol</span> Chemical compound

Steviol is a diterpene first isolated from the plant Stevia rebaudiana in 1931. Its chemical structure was not fully elucidated until 1960.

<span class="mw-page-title-main">Andrographolide</span> Chemical compound

Andrographolide is a labdane diterpenoid that has been isolated from the stem and leaves of Andrographis paniculata. Andrographolide is an extremely bitter substance.

CRT is the gene cluster responsible for the biosynthesis of carotenoids. Those genes are found in eubacteria, in algae and are cryptic in Streptomyces griseus.

<span class="mw-page-title-main">Farnesyl-diphosphate farnesyltransferase</span> Class of enzymes

Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH. Catalysis by SQS is the first committed step in sterol synthesis, since the squalene produced is converted exclusively into various sterols, such as cholesterol, via a complex, multi-step pathway. SQS belongs to squalene/phytoene synthase family of proteins.

<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase, is an enzyme that catalyzes the chemical reaction

In enzymology, a geranyltranstransferase is an enzyme that catalyzes the chemical reaction

4-Hydroxy-3-methylbut-2-enyl diphosphate reductase (EC 1.17.1.2, isopentenyl-diphosphate:NADP+ oxidoreductase, LytB, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate reductase, HMBPP reductase, IspH, LytB/IspH) is an enzyme in the non-mevalonate pathway. It acts upon (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (or "HMB-PP").

<span class="mw-page-title-main">Aucubin</span> Chemical compound

Aucubin is an iridoid glycoside. Iridoids are commonly found in plants and function as defensive compounds. Iridoids decrease the growth rates of many generalist herbivores.

<span class="mw-page-title-main">Juvabione</span> Chemical compound

Juvabione, historically known as the paper factor, is the methyl ester of todomatuic acid. Both are sesquiterpenes (C15) found in the wood of true firs of the genus Abies. They occur naturally as part of a mixture of sesquiterpenes based upon the bisabolane scaffold. Sesquiterpenes of this family are known as insect juvenile hormone analogues (IJHA) because of their ability to mimic juvenile activity in order to stifle insect reproduction and growth. These compounds play important roles in conifers as the second line of defense against insect induced trauma and fungal pathogens.

<span class="mw-page-title-main">Polyprenyl synthetase</span>

Polyprenyl synthetases are a class of enzymes responsible for synthesis of isoprenoids. Isoprenoid compounds are synthesized by various organisms. For example, in eukaryotes the isoprenoid biosynthetic pathway is responsible for the synthesis of a variety of end products including cholesterol, dolichol, ubiquinone or coenzyme Q. In bacteria this pathway leads to the synthesis of isopentenyl tRNA, isoprenoid quinones, and sugar carrier lipids. Among the enzymes that participate in that pathway, are a number of polyprenyl synthetase enzymes which catalyze a 1'4-condensation between 5-carbon isoprene units. It has been shown that all the above enzymes share some regions of sequence similarity. Two of these regions are rich in aspartic-acid residues and could be involved in the catalytic mechanism and/or the binding of the substrates.

References

  1. ↑ "IDI1 - Isopentenyl-diphosphate Delta-isomerase - Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) - IDI1 gene & protein". UniProt. Retrieved 6 June 2016.
  2. ↑ Kaneda K, Kuzuyama T, Takagi M, Hayakawa Y, Seto H (2001). "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. doi: 10.1073/pnas.020472198 . PMC   14687 . 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. ↑ Agranoff BW, Eggerer H, Henning U, Lynen F (1960). "Biosynthesis of terpenes. VII. Isopentenyl pyrophosphate isomerase". J. Biol. Chem. 235 (2): 326–32. doi: 10.1016/S0021-9258(18)69523-7 . PMID   13792054.
  5. ↑ Cornforth JW, Cornforth RH, Popják G, Yengoyan L (Sep 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. doi: 10.1016/S0021-9258(18)99800-5 . PMID   4288360.
  6. ↑ 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.
  7. ↑ 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. PMID   3022798.
  8. ↑ 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.
  9. 1 2 3 Hall 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. PMID   1285217.
  10. ↑ 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. PMID   17250851.
  11. ↑ 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. PMID   7908830.
  12. ↑ Wouters J, Oudjama Y, Barkley SJ, Tricot C, Stalon V, Droogmans L, Poulter CD (Apr 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". The Journal of Biological Chemistry. 278 (14): 11903–11908. doi: 10.1074/jbc.M212823200 . PMID   12540835.
  13. ↑ 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. PMID   17137593.
  14. ↑ Bonanno JB, Edo C, Eswar N, Pieper U, Romanowski MJ, Ilyin V, Gerchman SE, Kycia H, Studier FW, Sali A, Burley SK (Nov 2001). "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. Bibcode:2001PNAS...9812896B. doi: 10.1073/pnas.181466998 . PMC   60796 . PMID   11698677.
  15. ↑ Bach TJ (Mar 1995). "Some new aspects of isoprenoid biosynthesis in plants--a review". Lipids. 30 (3): 191–202. doi:10.1007/BF02537822. PMID   7791527. S2CID   3999323.
  16. ↑ 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. PMID   9418296.
  17. ↑ 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. PMID   1441751. S2CID   19430360.
  18. ↑ 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. PMID   15765206. S2CID   1637634.
  19. ↑ Okada K, Kasahara H, Yamaguchi S, Kawaide H, Kamiya Y, Nojiri H, Yamane H (Apr 2008). "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. doi: 10.1093/pcp/pcn032 . PMID   18303110.
  20. ↑ 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. PMID   20955688.
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