Geranyltranstransferase

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geranyltranstransferase
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EC no. 2.5.1.10
CAS no. 37277-79-5
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In enzymology, a geranyltranstransferase (EC 2.5.1.10) is an enzyme that catalyzes the chemical reaction

Contents

geranyl diphosphate + isopentenyl diphosphate diphosphate + trans,trans-farnesyl diphosphate

Thus, the two substrates of this enzyme are geranyl diphosphate (a 10 carbon precursor) and isopentenyl diphosphate (a 5 carbon precursor) whereas its two products are diphosphate and trans,trans-farnesyl diphosphate (a 15 carbon product). [1]

This enzyme belongs to the family of transferases, specifically those transferring aryl or alkyl groups other than methyl groups.

Nomenclature

The systematic name of this enzyme class is geranyl-diphosphate:isopentenyl-diphosphate geranyltranstransferase. Other names in common use include:

Common abbreviations include: FPS, FDS, FPPS, and FDPS.

Structure

The structure and mechanism of farnesyl pyrophosphate synthase (FPPS), a type of geranyltranstransferase, is well characterized. FPPS is a ~30 kDa Mg2+ dependent homodimeric enzyme that synthesizes (E, E)-farnesyl pyrophosphate in a successive manner from two equivalents of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). [2]

Crystal structure of the FPPS homodimer with IPP and DMAPP analogue, DMSPP (PDB ID: 1RQI). Monomers are shown in magenta and dark blue. Residues in hydrophobic pocket are highlighted in yellow. The base of the pocket is formed by the residue in green (a phenylalanine). A 90 degree rotated monomer structure is shown in Inset 1 to highlight the hydrophobic pocket. A top view of the active site is shown in Inset 2 along with the aspartate mediated trinuclear Mg (silver spheres) catalytic center. Images generated in PyMOL. Structure of FPPS.jpg
Crystal structure of the FPPS homodimer with IPP and DMAPP analogue, DMSPP (PDB ID: 1RQI). Monomers are shown in magenta and dark blue. Residues in hydrophobic pocket are highlighted in yellow. The base of the pocket is formed by the residue in green (a phenylalanine). A 90 degree rotated monomer structure is shown in Inset 1 to highlight the hydrophobic pocket. A top view of the active site is shown in Inset 2 along with the aspartate mediated trinuclear Mg (silver spheres) catalytic center. Images generated in PyMOL.

FPPS adopts a 3-layered α-helical fold characteristic of many prenyltransferases with 11 helices and flexible loops in between. The centrally located helices (α4 and α8) contain conserved aspartate motifs (DDXXD) that participate in substrate binding and catalysis. [3] Motif aspartate residues, water oxygens, and pyrophosphate coordinate three Mg2+in an octahedral manner. The trinuclear Mg2+ complex is critical for binding DMAPP and stabilizing the pyrophosphate leaving group while the growing hydrocarbon tail wedges into a deep hydrophobic pocket. [2] Site-directed mutagenesis studies have shown that the ultimate length of the isoprenoid product is determined by bulky residues (often phenyalanine) at the hydrophobic pocket's base. [4]

Mechanism

From crystal structures and kinetic assays, it is believed that FPPS catalyzes the condensation reaction in three concerted steps: (1) Ionization, (2) Condensation, and (3) Elimination. [2]

In the first step, three Mg2+stabilize the anionic leaving group, pyrophosphate, on dimethylallyl pyrophosphate (DMAPP). The loss of pyrophosphate forms dimethylallyl cation. In the second step, the reactive C3-C5 double bond in isopentyl pyrophosphate (IPP) performs a nucleophilic attack on the previously formed dimethylallyl cation. The final step involves pyrophosphate held in the trinuclear Mg2+ center acting as a catalytic base in an elimination reaction to form geranyl pyrophosphate. A second consecutive round of geranyl pyrophosphate ionization, condensation with IPP, and elimination forms farnesyl pyrophosphate. [2] [5]

Function

Geranyltranstransferases are an evolutionarily conserved class of enzymes in Archaea, Bacteria, and Eukarya that participate in a broad range of biosynthetic pathways including those of cholesterol, porphyrin, carotenoids, ubiquinone, and isoprenoids. [3] Various studies have located FPPS in chloroplasts, mitochondria, cytosol, and peroxisomes. [6] [7] [8]

FPPS, a geranyltranstransferase, catalyzes reactions (shown with red arrows) central to many biosynthetic pathways. FPPS Biosynthetic Pathways Version 2.png
FPPS, a geranyltranstransferase, catalyzes reactions (shown with red arrows) central to many biosynthetic pathways.

In cholesterol synthesis, the product, farnesyl pyrophosphate, is consumed in a reductive tail-to-tail condensation with another farnesyl pyrophosphate to form a 30-carbon compound called squalene by squalene synthase. [9] Through several more biosynthetic steps, squalene is transformed into lanosterol, a direct precursor for cholesterol. [10] Notably, sterols control FPPS expression through two cis regulatory factors (an inverted CAAT box and SRE-3) in the proximal FPPS promoter. [11] In plants, porphyrin and carotenoids constitute accessory pigments that help capture light in the photosystems. Ubiquinone is a key electron carrier in the electron transport chain of cellular respiration. Isoprenoids are a large group of compounds that serve as biosynthetic precursors for lipids and hormones. [6]

Farnesyl and geranyl pyrophosphate also serve as precursors for prenylated proteins. Prenylation is a common type of covalent post-translational modification at C-terminal CaaX motifs that allows proteins to localize to membranes or bind to one another. A notable example of the former is the farnesylation of small G-proteins including Ras, CDC42, Rho, and Rac. The attachment of a hydrophobic aliphatic chain as those present in farnesyl or geranylgeranyl groups allows small G-proteins to tether from membranes and carry out effector functions. [12]

Drug targeting

FPPS is the target of bisphosphonate drugs such as Fosamax (alendronate) and Actonel (risedronate). Bisphosphonate drugs are commonly prescribed for bone diseases including Paget’s disease, osteolytic metastases, and post-menopausal osteoporosis. Bisphosphonate drugs help maintain bone tissue in osteoporotic patients and reduce blood calcium levels in hypercalcemic patients by inhibiting FPPS in bone-reabsorbing osteoclasts. An FPPS-IPP-risendronate ternary complex demonstrated that risendronate binds to the trinuclear Mg2+ complex and interacts with the hydrophobic pocket in a manner similar to DMAPP. [2] [13]

Related Research Articles

<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.

<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.

Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate (FDP), is an intermediate in the biosynthesis of terpenes and terpenoids such as sterols and carotenoids. It is also used in the synthesis of CoQ, as well as dehydrodolichol diphosphate.

(<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">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.

<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">Isopentenyl-diphosphate delta isomerase</span> Class of enzymes

Isopentenyl pyrophosphate isomerase, also known as 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 and the MEP pathway.

<span class="mw-page-title-main">Dimethylallyltranstransferase</span> Mammalian protein found in Homo sapiens

Dimethylallyltranstransferase (DMATT), also known as farnesylpyrophosphate synthase (FPPS) or as farnesyldiphosphate synthase (FDPS), is an enzyme that in humans is encoded by the FDPS gene and catalyzes the transformation of dimethylallylpyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) into farnesylpyrophosphate (FPP).

<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.

All-trans-nonaprenyl-diphosphate synthase is an enzyme with systematic name geranyl-diphosphate:isopentenyl-diphosphate transtransferase . This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">All-trans-octaprenyl-diphosphate synthase</span> Class of enzymes

All-trans-octaprenyl-diphosphate synthase is an enzyme with systematic name (2E,6E)-farnesyl-diphosphate:isopentenyl-diphosphate farnesyltranstransferase . This enzyme catalyses the following chemical reaction

All-trans-decaprenyl-diphosphate synthase is an enzyme with systematic name (2E,6E)-farnesyl-diphosphate:isopentenyl-diphosphate farnesyltranstransferase . This enzyme catalyses the following chemical reaction

(2Z,6Z)-farnesyl diphosphate synthase is an enzyme with systematic name dimethylallyl-diphosphate:isopentenyl-diphosphate cistransferase . This enzyme catalyses the following chemical reaction

The squalene/phytoene synthase family represents proteins that catalyze the head-to-head condensation of C15 and C20 prenyl units (i.e. farnesyl diphosphate and genranylgeranyl diphosphate). This enzymatic step constitutes part of steroid and carotenoid biosynthesis pathway. Squalene synthase EC (SQS) and Phytoene synthase EC (PSY) are two well-known examples of this protein family and share a number of functional similarities. These similarities are also reflected in their primary structure. In particular three well conserved regions are shared by SQS and PSY; they could be involved in substrate binding and/or the catalytic mechanism. SQS catalyzes the conversion of two molecules of farnesyl diphosphate (FPP) into squalene. It is the first committed step in the cholesterol biosynthetic pathway. The reaction carried out by SQS is catalyzed in two separate steps: the first is a head-to-head condensation of the two molecules of FPP to form presqualene diphosphate; this intermediate is then rearranged in a NADP-dependent reduction, to form squalene:

<span class="mw-page-title-main">Drimentine G</span> Drimentine G and its biosynthesis

Drimentine G belongs to the family of drimentines, which are terpenylated diketopiperazines. As the name suggests, DMT G contains two different parts, one comes from the non-ribosomal peptide synthetase (NRPS) pathway to generate the diketopiperazine ring structure. The other part comes from either the mevalonic acid pathway (MVA) or deoxy xylulose phosphate pathway (MEP) to produce sesquiterpenes needed for interaction with the diketopiperazine. This molecule is said to be useful as an antibiotic to treat bacterial or fungi infections, has therapeutic application to treat animal health, and can serve as a pest control for plants.

References

  1. ↑ Lynen F, Agranoff BW, Eggerer H, Henning U, Möslein EM (1959). "Zur Biosynthese der Terpene. VI gamma,gamma-Dimethyl-allyl-pyrophosphat und Geranyl-pyrophosphat, biologische Vorstufen des Squalens". Angew. Chem. 71 (21): 657–663. doi:10.1002/ange.19590712102.
  2. 1 2 3 4 5 6 Hosfield DJ, Zhang Y, Dougan DR, Broun A, Tari LW, Swanson RV, Finn J (Mar 2004). "Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis". The Journal of Biological Chemistry. 279 (10): 8526–9. doi: 10.1074/jbc.C300511200 . PMID   14672944.
  3. 1 2 Chen A, Kroon PA, Poulter CD (Apr 1994). "Isoprenyl diphosphate synthases: protein sequence comparisons, a phylogenetic tree, and predictions of secondary structure". Protein Science. 3 (4): 600–7. doi:10.1002/pro.5560030408. PMC   2142870 . PMID   8003978.
  4. ↑ Tarshis LC, Proteau PJ, Kellogg BA, Sacchettini JC, Poulter CD (Dec 1996). "Regulation of product chain length by isoprenyl diphosphate synthases". Proceedings of the National Academy of Sciences of the United States of America. 93 (26): 15018–23. Bibcode:1996PNAS...9315018T. doi: 10.1073/pnas.93.26.15018 . PMC   26348 . PMID   8986756.
  5. ↑ Tarshis LC, Yan M, Poulter CD, Sacchettini JC (Sep 1994). "Crystal structure of recombinant farnesyl diphosphate synthase at 2.6-A resolution". Biochemistry. 33 (36): 10871–7. doi:10.1021/bi00202a004. PMID   8086404.
  6. 1 2 3 Dhar MK, Koul A, Kaul S (Jan 2013). "Farnesyl pyrophosphate synthase: a key enzyme in isoprenoid biosynthetic pathway and potential molecular target for drug development". New Biotechnology. 30 (2): 114–23. doi:10.1016/j.nbt.2012.07.001. PMID   22842101.
  7. ↑ Sanmiya K, Ueno O, Matsuoka M, Yamamoto N (Mar 1999). "Localization of farnesyl diphosphate synthase in chloroplasts". Plant & Cell Physiology. 40 (3): 348–54. doi:10.1093/oxfordjournals.pcp.a029549. PMID   10353221.
  8. ↑ Martín D, Piulachs MD, Cunillera N, Ferrer A, Bellés X (Mar 2007). "Mitochondrial targeting of farnesyl diphosphate synthase is a widespread phenomenon in eukaryotes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1773 (3): 419–26. doi:10.1016/j.bbamcr.2006.11.015. PMID   17198737.
  9. ↑ Tansey TR, Shechter I (2001). "Squalene synthase: structure and regulation". Prog. Nucleic Acid Res. Mol. Biol. Progress in Nucleic Acid Research and Molecular Biology. 65: 157–95. doi:10.1016/S0079-6603(00)65005-5. ISBN   9780125400657. PMID   11008488.
  10. ↑ Liang PH, Ko TP, Wang AH (2002). "Structure, mechanism and function of prenyltransferases". Eur. J. Biochem. 269 (14): 3339–54. doi:10.1046/j.1432-1033.2002.03014.x. PMID   12135472.
  11. ↑ Ericsson J, Jackson SM, Edwards PA (Oct 1996). "Synergistic binding of sterol regulatory element-binding protein and NF-Y to the farnesyl diphosphate synthase promoter is critical for sterol-regulated expression of the gene". The Journal of Biological Chemistry. 271 (40): 24359–64. doi: 10.1074/jbc.271.40.24359 . PMID   8798690.
  12. ↑ Sebti SM (Apr 2005). "Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy". Cancer Cell. 7 (4): 297–300. doi: 10.1016/j.ccr.2005.04.005 . PMID   15837619.
  13. ↑ Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH (Jun 2007). "Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10022–7. Bibcode:2007PNAS..10410022G. doi: 10.1073/pnas.0702254104 . PMC   1877987 . PMID   17535895.
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