Prenylation

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Skeletal formula of the prenyl group. Prenyl.svg
Skeletal formula of the prenyl group.

Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchors like the GPI anchor, though direct evidence of this has not been observed. Prenyl groups (also called isoprenyl groups, having one hydrogen atom more than isoprene) have been shown to be important for protein–protein binding through specialized prenyl-binding domains.

Contents

Protein prenylation

Protein prenylation involves the transfer of either a farnesyl or a geranylgeranyl moiety to C-terminal cysteine(s) of the target protein. There are three enzymes that carry out prenylation in the cell, farnesyl transferase, Caax protease and geranylgeranyl transferase I. [1]

Farnesylation is a type of prenylation, a post-translational modification of proteins by which an isoprenyl group is added to a cysteine residue. [2] It is an important process to mediate protein–protein interactions and protein–membrane interactions. [3]

Prenylation sites

There are at least 3 types of sites that are recognized by prenylation enzymes. The CaaX motif is found at the COOH-terminus of proteins, such as lamins or Ras. The motif consists of a cysteine (C), two aliphatic amino acids ("aa") and some other terminal amino acid ("X"). If the X position is serine, alanine, or methionine, the protein is farnesylated. For instance, in rhodopsin kinase the sequence is CVLS. If X is leucine, the protein is geranylgeranylated. [4] The second motif for prenylation is CXC, which, in the Ras-related protein Rab3A, leads to geranylgeranylation on both cysteine residues and methyl esterification. [4] The third motif, CC, is also found in Rab proteins, where it appears to direct only geranylgeranylation but not carboxyl methylation. [4] Carboxyl methylation only occurs on prenylated proteins. [4]

Farnesyltransferase and geranylgeranyltransferase I

Farnesyltransferase and geranylgeranyltransferase I are very similar proteins. They consist of two subunits, the α-subunit, which is common to both enzymes, and the β-subunit, whose sequence identity is just 25%. These enzymes recognise the CaaX box at the C-terminus of the target protein. C is the cysteine that is prenylated, a is any aliphatic amino acid, and the identity of X determines which enzyme acts on the protein. Farnesyltransferase recognizes CaaX boxes where X = M, S, Q, A, or C, whereas geranylgeranyltransferase I recognizes CaaX boxes with X = L or E.

Rab geranylgeranyl transferase

Rab geranylgeranyltransferase, or geranylgeranyltransferase II, transfers (usually) two geranylgeranyl groups to the cysteine(s) at the C-terminus of Rab proteins. The C-terminus of Rab proteins varies in length and sequence and is referred to as hypervariable. Thus Rab proteins do not have a consensus sequence, such as the CAAX box, which the Rab geranylgeranyl transferase can recognize. The Rab proteins usually terminate in a CC or CXC motif. Instead, Rab proteins are bound by the Rab escort protein (REP) over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase. Once Rab proteins are prenylated, the lipid anchor(s) ensure that Rabs are no longer soluble. REP, therefore, plays an important role in binding and solubilising the geranylgeranyl groups and delivers the Rab protein to the relevant cell membrane.

Substrates

Both isoprenoid chains, geranylgeranyl pyrophosphate (GGpp) and farnesyl pyrophosphate are products of the HMG-CoA reductase pathway. The product of HMG CoA reductase is mevalonate. By combining precursors with 5 carbons, the pathway subsequently produces geranyl pyrophosphate (10 carbons), farnesyl pyrophosphate (15 carbons) and geranylgeranyl pyrophosphate (20 carbons). Two farnesyl pyrophosphate groups can also be combined to form squalene, the precursor for cholesterol. This means that statins, which inhibit HMG CoA reductase, inhibit the production of both cholesterol and isoprenoids.

Note that, in the HMG-CoA reductase/mevalonate pathway, the precursors already contain a pyrophosphate group, and isoprenoids are produced with a pyrophosphate group. There is no known enzyme activity that can carry out the prenylation reaction with the isoprenoid alcohol. However, enzymatic activity for isoprenoid kinases capable converting isoprenoid alcohols to isoprenoid pyrophosphates have been shown. [5] In accordance with this, farnesol and geranylgeraniol have been shown to be able to rescue effects caused by statins or nitrogenous bisphosphonates, further supporting that alcohols can be involved in prenylation, likely via phosphorylation to the corresponding isoprenoid pyrophosphate.

Proteins that undergo prenylation include Ras, which plays a central role in the development of cancer. This suggests that inhibitors of prenylation enzymes (e.g., farnesyltransferase) may influence tumor growth. In the case of the K- and N-Ras forms of Ras, when cells are treated with FTIs, these forms of Ras can undergo alternate prenylation in the form of geranylgeranylation. [6] Recent work has shown that farnesyltransferase inhibitors (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab prenylation as on Ras prenylation. Inhibitors of prenyltransferase enzymes display different specificity for the prenyltransferases, dependent upon the specific compound being utilized.

In addition to GTPases, the protein kinase GRK1 also known as rhodopsin kinase (RK) has been shown to undergo farnesylation and carboxyl methylation directed by the carboxyl terminal CVLS CaaX box sequence of the protein. [7] The functional consequence of these post-translational modifications have been shown to play a role in regulating the light-dependent phosphorylation of rhodopsin, a mechanism involved in light adaptation. [8]

Inhibitors

FTIs can also be used to inhibit farnesylation in parasites such as Trypanosoma brucei and malaria. Parasites seem to be more vulnerable to inhibition of farnesyltransferase than humans are. In some cases, this may be because they lack geranylgeranyltransferase I. Thus, it may be possible for the development of antiparasitic drugs to 'piggyback' on the development of FTIs for cancer research.

In addition, FTIs have shown some promise in treating a mouse model of progeria, and in May 2007 a phase II clinical trial using the FTI lonafarnib was started for children with progeria. [9]

In signal transduction via G protein, palmitoylation of the α subunit, prenylation of the γ subunit, and myristoylation is involved in tethering the G protein to the inner surface of the plasma membrane so that the G protein can interact with its receptor. [10]

Prenylation of small molecules

Small molecules can also undergo prenylation, such as in the case of prenylflavonoids and other meroterpenoids. Prenylation of a vitamin B2 derivative (flavin mononucleotide) was recently described. [11]

Longevity and cardiac effects

A 2012 study found that statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation. The study concluded, "These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related) health effects of statins." [12]

A 2012 clinical trial explored the approach of inhibiting protein prenylation with some degree of success in the treatment of Hutchinson–Gilford progeria syndrome, a multisystem disorder which causes failure to thrive and accelerated atherosclerosis leading to early death. [13] [14]

See also

Related Research Articles

<span class="mw-page-title-main">Lipid-anchored protein</span> Membrane protein

Lipid-anchored proteins are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilayer structure of the membrane alongside the similar fatty acid tails. The lipid-anchored protein can be located on either side of the cell membrane. Thus, the lipid serves to anchor the protein to the cell membrane. They are a type of proteolipids.

The C-terminus is the end of an amino acid chain, terminated by a free carboxyl group (-COOH). When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus. The convention for writing peptide sequences is to put the C-terminal end on the right and write the sequence from N- to C-terminus.

<span class="mw-page-title-main">Farnesyltransferase inhibitor</span> Class of experimental cancer drugs

The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in cancer.

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

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

Farnesyltransferase is one of the three enzymes in the prenyltransferase group. Farnesyltransferase (FTase) adds a 15-carbon isoprenoid called a farnesyl group to proteins bearing a CaaX motif: a four-amino acid sequence at the carboxyl terminus of a protein. Farnesyltransferase's targets include members of the Ras superfamily of small GTP-binding proteins critical to cell cycle progression. For this reason, several FTase inhibitors are undergoing testing as anti-cancer agents. FTase inhibitors have shown efficacy as anti-parasitic agents, as well. FTase is also believed to play an important role in development of progeria and various forms of cancers.

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

Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products.

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.

Geranylgeranyltransferase type 1 or simply geranylgeranyltransferase is one of the three enzymes in the prenyltransferase group. In specific terms, Geranylgeranyltransferase adds a 20-carbon isoprenoid called a geranylgeranyl group to proteins bearing a CaaX motif: a four-amino acid sequence at the carboxyl terminal of a protein. Geranylgeranyltransferase inhibitors are being investigated as anti-cancer agents.

<span class="mw-page-title-main">Rab geranylgeranyltransferase</span> Class of enzyme complexes

Rab geranylgeranyltransferase also known as (protein) geranylgeranyltransferase II is one of the three prenyltransferases. It transfers (usually) two geranylgeranyl groups to the cystein(s) at the C-terminus of Rab proteins.

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

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

<span class="mw-page-title-main">Mevalonate kinase deficiency</span> Medical condition

Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a very rare genetic disease.

Geranylgeranylation is a form of prenylation, which is a post-translational modification of proteins that involves the attachment of one or two 20-carbon lipophilic geranylgeranyl isoprene units from geranylgeranyl diphosphate to one or two cysteine residue(s) at the C-terminus of specific proteins. Prenylation is thought to function, at least in part, as a membrane anchor for proteins.

<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.

The isoprenylcysteine o-methyltransferase carries out carboxyl methylation of cleaved eukaryotic proteins that terminate in a CaaX motif. In Saccharomyces cerevisiae this methylation is carried out by Ste14p, an integral endoplasmic reticulum membrane protein. Ste14p is the founding member of the isoprenylcysteine carboxyl methyltransferase (ICMT) family, whose members share significant sequence homology.

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

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

<span class="mw-page-title-main">FNTA</span> Protein-coding gene in the species Homo sapiens

Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha is an enzyme that in humans is encoded by the FNTA gene.

<span class="mw-page-title-main">FNTB</span> Protein-coding gene in the species Homo sapiens

Protein farnesyltransferase subunit beta is an enzyme that in humans is encoded by the FNTB gene.

<span class="mw-page-title-main">Protein geranylgeranyltransferase type I subunit beta</span> Protein-coding gene in the species Homo sapiens

Protein geranylgeranyltransferase type I subunit beta is a protein that in humans is encoded by the PGGT1B gene.

Channing Joseph Der is an American scientist and educator, and Sarah Graham Kenan Distinguished Professor of Pharmacology, at UNC Lineberger Comprehensive Cancer Center. Der is a Fellow of the American Association for the Advancement of Science, He is recognized for his work with the Ras oncoprotein and its role in human oncogenesis.

References

  1. ↑ P. J. Casey & M. C. Seabra (1996). "Protein Prenyltransferases". Journal of Biological Chemistry. 271 (10): 5289–5292. doi: 10.1074/jbc.271.10.5289 . PMID   8621375.
  2. ↑ Maltese WA (December 1990). "Posttranslational modification of proteins by isoprenoids in mammalian cells". FASEB J. 4 (15): 3319–28. doi: 10.1096/fasebj.4.15.2123808 . PMID   2123808. S2CID   17511637.
  3. ↑ G. Novelli & M. R. D'Apice (2012). "Protein farnesylation and disease". Journal of Inherited Metabolic Disease. 35 (5): 917–926. doi:10.1007/s10545-011-9445-y. PMID   22307208. S2CID   11555502.
  4. 1 2 3 4 Marshall, C. J. (26 March 1993). "Protein prenylation: a mediator of protein-protein interactions". Science. 259 (5103): 1865–1866. Bibcode:1993Sci...259.1865M. doi:10.1126/science.8456312. ISSN   0036-8075. PMID   8456312.
  5. ↑ Bentinger, M.; Grünler, J.; Peterson, E.; Swiezewska, E.; Dallner, G. (1998). "Phosphorylation of farnesol in rat liver microsomes: properties of farnesol kinase and farnesyl phosphate kinase". Archives of Biochemistry and Biophysics. 353 (2): 191–198. doi:10.1006/abbi.1998.0611. PMID   9606952.
  6. ↑ Whyte, D.; Kirschmeier, P.; Hockenberry, T.; Nunez-Oliva, I.; James, L.; Catino, J.; Bishop, W.; Pai, J. (1997). "K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors". The Journal of Biological Chemistry. 272 (22): 14459–14464. doi: 10.1074/jbc.272.22.14459 . PMID   9162087.
  7. ↑ Inglese, J.; Glickman, J.F.; Lorenz, W.; Caron, M.G.; Lefkowitz, R.J. (1992). "Isoprenylation of a Protein Kinase: Farnesylation / α-Carboxyl Methylation Required for Full Enzymatic Activity of Rhodopsin Kinase". J. Biol. Chem. 267 (3): 1422–1425. doi: 10.1016/S0021-9258(18)45960-1 . PMID   1730692.
  8. ↑ Inglese, J.; Koch, W.J.; Caron, M.G.; Lefkowitz, R.J. (1992). "Isoprenylation in the Regulation of Signal Transduction by G Protein-Coupled Receptor Kinases". Nature. 359 (6391): 147–150. Bibcode:1992Natur.359..147I. doi:10.1038/359147a0. PMID   1522899. S2CID   4314755.
  9. ↑ Kleinman, Monica E. (11 June 2019). "Phase II trial of Lonafarnib (a farnesyltransferase inhibitor) for progeria".{{cite journal}}: Cite journal requires |journal= (help)
  10. ↑ Wall, MA; Coleman, DE; Lee, E; Iñiguez-Lluhi, JA; Posner, BA; Gilman, AG; Sprang, SR (15 December 1995). "The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2". Cell. 83 (6): 1047–58. doi: 10.1016/0092-8674(95)90220-1 . PMID   8521505.
  11. ↑ Clarke, CF; Allan, CM (2015). "Biochemistry: Unexpected role for vitamin B2". Nature. 522 (7557): 427–428. Bibcode:2015Natur.522..427C. doi: 10.1038/nature14536 . PMID   26083748.
  12. ↑ Spindler SR, Li R, Dhahbi JM, Yamakawa A, Mote P, Bodmer R, Ocorr K, Williams RT, Wang Y, Ablao KP (2012). "Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation". PLOS ONE. 7 (6): e39581. Bibcode:2012PLoSO...739581S. doi: 10.1371/journal.pone.0039581 . PMC   3380867 . PMID   22737247.
  13. ↑ Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, et al. (October 2012). "Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome". Proc. Natl. Acad. Sci. U.S.A. 109 (41): 16666–71. Bibcode:2012PNAS..10916666G. doi: 10.1073/pnas.1202529109 . PMC   3478615 . PMID   23012407.
  14. ↑ Young SG, Yang SH, Davies BS, Jung HJ, Fong LG (February 2013). "Targeting protein prenylation in progeria". Sci Transl Med. 5 (171): 171ps3. doi:10.1126/scitranslmed.3005229. PMC   3725554 . PMID   23390246.

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