Protein Prenylation: An (Almost) Comprehensive Overview on Discovery History, Enzymology, and Significance in Physiology and Disease

Benetka, Wolfgang; Koranda, Manfred; Eisenhaber, Frank

doi:10.1007/s00706-006-0534-9

Cited by 36 publications

(43 citation statements)

References 384 publications

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“…Furthermore, the ram1 mutant was shown to be biochemically defective for prenylation (233). These findings solidified what is now common knowledge, namely, that in all eukaryotes the CAAX motif directs a series of modifications: prenylation, endoproteolyis of the AAX, and carboxylmethylation of the farnesylated cysteine residue of the CAAX motif (23,99,113,274,281).…”

Section: Studies Of S Cerevisiae A-factor and Ras Connect Prenylatiosupporting

confidence: 77%

“…CAAX processing is a common posttranslational modification, as approximately 2% of proteins encoded in the genomes of yeast and other eukaryotes terminate with a CAAX motif, and many of these have been directly demonstrated to be prenylated (23,99,232,274,281). The C-terminal residue, X, of the CAAX motif dictates the type of prenyl group that is added to a protein: generally, if X is any amino acid except Phe or Leu, the 15-carbon isoprenoid moiety farnesyl is added by farnesyltransferase (FTase), while if X is Phe or Leu, the 20-carbon isoprenoid geranylgeranyl is added by protein geranylgeranyltransferase type I (GGTase I) (23,50,161). FTase and GGTase I are heterodimeric enzymes that share a ␤ subunit (Ram2) but contain distinct ␣ subunits, Ram1 and Cdc43, respectively (91,198).…”

Section: Studies Of S Cerevisiae A-factor and Ras Connect Prenylatiomentioning

confidence: 99%

“…The Ram1/Ram2 FTase covalently joins the 15-carbon-long isoprenoid moiety farnesyl to the cysteine sulfhydryl in CAAX proteins, via a thioether bond. Ram2 can alternatively heterodimerize with Cdc43 to form the GGTase I enzyme, which joins the 20-carbon isoprenoid geranylgeranyl to proteins in which the last residue of the CAAX motif is either Leu or Phe (23,50,91,198).…”

Section: C-terminal Caax Modification Of A-factor Is Mediated By Ram1mentioning

confidence: 99%

“…Soon after yeast RAM1 provided the initial link between a-factor and Ras, yeast FTase studies were eclipsed by dramatic advances from the Brown and Goldstein groups (57,212), who purified the mammalian FTase ␣ and ␤ subunits. Ultimately, the purification, biochemical characterization, crystallization, and structural analysis of the mammalian FTase advanced the field significantly and prompted the development of farnesyltransferase inhibitors (FTIs) that initially held great promise as potential chemotherapeutic agents for Ras-based cancers (21,23,29,99,156). FTIs have undergone clinical trials for cancer chemotherapy, but for Ras-based cancers they have been less effective than hoped, most likely due to the alternative geranylgeranylation of Ras by GGTase in FTI-treated tumor cells (156).…”

Section: C-terminal Caax Modification Of A-factor Is Mediated By Ram1mentioning

confidence: 99%

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Biogenesis of the Saccharomyces cerevisiae Pheromone a -Factor, from Yeast Mating to Human Disease

Michaelis¹,

Barrowman²

2012

Microbiol Mol Biol Rev

101

106

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SUMMARY The mating pheromone a -factor secreted by Saccharomyces cerevisiae is a farnesylated and carboxylmethylated peptide and is unusually hydrophobic compared to other extracellular signaling molecules. Mature a -factor is derived from a precursor with a C-terminal CAAX motif that directs a series of posttranslational reactions, including prenylation, endoproteolysis, and carboxylmethylation. Historically, a -factor has served as a valuable model for the discovery and functional analysis of CAAX-processing enzymes. In this review, we discuss the three modules comprising the a -factor biogenesis pathway: (i) the C-terminal CAAX-processing steps carried out by Ram1/Ram2, Ste24 or Rce1, and Ste14; (ii) two sequential N-terminal cleavage steps, mediated by Ste24 and Axl1; and (iii) export by a nonclassical mechanism, mediated by the ATP binding cassette (ABC) transporter Ste6. The small size and hydrophobicity of a -factor present both challenges and advantages for biochemical analysis, as discussed here. The enzymes involved in a -factor biogenesis are conserved from yeasts to mammals. Notably, studies of the zinc metalloprotease Ste24 in S. cerevisiae led to the discovery of its mammalian homolog ZMPSTE24, which cleaves the prenylated C-terminal tail of the nuclear scaffold protein lamin A. Mutations that alter ZMPSTE24 processing of lamin A in humans cause the premature-aging disease progeria and related progeroid disorders. Intriguingly, recent evidence suggests that the entire a -factor pathway, including all three biogenesis modules, may be used to produce a prenylated, secreted signaling molecule involved in germ cell migration in Drosophila . Thus, additional prenylated signaling molecules resembling a -factor, with as-yet-unknown roles in metazoan biology, may await discovery.

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Section: Studies Of S Cerevisiae A-factor and Ras Connect Prenylatiosupporting

confidence: 77%

Section: Studies Of S Cerevisiae A-factor and Ras Connect Prenylatiomentioning

confidence: 99%

Section: C-terminal Caax Modification Of A-factor Is Mediated By Ram1mentioning

confidence: 99%

Section: C-terminal Caax Modification Of A-factor Is Mediated By Ram1mentioning

confidence: 99%

See 2 more Smart Citations

Biogenesis of the Saccharomyces cerevisiae Pheromone a -Factor, from Yeast Mating to Human Disease

Michaelis¹,

Barrowman²

2012

Microbiol Mol Biol Rev

101

106

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show abstract

“…Isoprenyl diphosphate synthases catalyze the chain elongation of an allylic isoprenyl diphosphate substrate by reaction with isopentenyl diphosphate [4]. Protein PTases transfer a geranyl-geranyl or farnesyl group to the Cys residue on a CaaX motif at the C-terminus of several proteins to facilitate membrane anchoring in eukaryotes and possibly archaea [5]. Small-molecule aromatic PTases constituting the third category can be subdivided into membrane-associated and functionally soluble PTases.…”

mentioning

confidence: 99%

The ABBA family of aromatic prenyltransferases: broadening natural product diversity

Tello

Kuzuyama²,

Heide³

et al. 2008

Cell. Mol. Life Sci.

131

155

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Aromatic prenyltransferases (PTases) catalyze the transfer of a C5 (dimethylallyl), C10 (geranyl) or C15 (farnesyl) prenyl group derived from the corresponding isoprenyl diphosphate metabolites onto a variety of electron-rich aromatic acceptors. Prenyl groups appear in a wide variety of bioactive natural products of microbial and plant origin, including amino acids, stilbenes, alkaloids, polyketides and phenylpropanoids such as flavonoids, creating natural product hybrids with altered or enhanced bioactivities. Prenylation of flavonoids enhances some of the desirable pharmacological properties of these plant compounds [1], as demonstrated for apigenin and liquiritigenin [2]. Prenylation appears in many cases to provide a higher level of bioactivity compared to the non-prenylated precursor, often by increasing affinity for biological membranes and interactions with cellular targets [3]. With the recent identification of these enzymes there is increased interest in the role of these regiospecific catalysts in expanding the diversity and bioactivities of several important classes of natural products in vivo and in vitro.One way in which PTases can be categorized depends on whether they catalyze the synthesis of isoprenyl diphosphates, the prenylation of a protein or the prenylation of an aromatic substrate. Isoprenyl diphosphate synthases catalyze the chain elongation of an allylic isoprenyl diphosphate substrate by reaction with isopentenyl diphosphate [4]. Protein PTases transfer a geranyl-geranyl or farnesyl group to the Cys residue on a CaaX motif at the C-terminus of several proteins to facilitate membrane anchoring in eukaryotes and possibly archaea [5]. Small-molecule aromatic PTases constituting the third category can be subdivided into membrane-associated and functionally soluble PTases. Membrane-associated PTases contain a characteristic (N/D)DXXD Mg 2+ -diphosphate binding motif which is also found in the isoprenyl diphosphate synthases and are involved e.g. in the biosynthesis of ubiquinones and © Birkhäuser Verlag, Basel, 2008 Richard@salk.edu. [6], in the biosynthesis of membrane lipids in archaea [7] and in the formation of plant secondary metabolites [8].The functionally soluble PTases do not possess an obvious Mg 2+ -diphosphate binding motif. Moreover, most of the currently known soluble aromatic PTases segregate into two subgroups based on their primary sequence similarity and on the small-molecule substrates they accept for prenylation. The first subgroup commonly prenylates indole-containing ring systems. Examples of these PTases include the fungal enzymes FgaPT1 and FgaPT2 involved in the biosynthesis of fumigaclavin C [9], as well as the newly discovered N-reverse PTase CdpNPT [10] and the 7-dimethylallyl-tryptophan synthase Afu3 g12930 [11]. LtxC, which is involved in the biosynthesis of lyngbyatoxins obtained from the cyanobacteria Lyngbya majuscula [12], also prenylates an indole-containing ring system but shares no sequence similaritywith the fungal enzymes named above.The second subg...

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Prenylation of viral proteins by enzymes of the host: Virus‐driven rationale for therapy with statins and FT/GGT1 inhibitors

et al. 2017

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Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high‐confidence prenylation predictions by PrePS with a cut‐off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 (CMV) and few other proteins encoded by Herpesviridae, Nef (HIV‐1), E1A (human adenovirus 1), NS5A (HCV), PB2 (influenza), HN (human parainfluenza virus 3), L83L (African swine fever), MC155R (molluscum contagiosum virus), other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1‐based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Also see the video abstract here: https://youtu.be/0qVW3ym1R1g

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Protein Prenylation: An (Almost) Comprehensive Overview on Discovery History, Enzymology, and Significance in Physiology and Disease

Cited by 36 publications

References 384 publications

Biogenesis of the Saccharomyces cerevisiae Pheromone a -Factor, from Yeast Mating to Human Disease

Biogenesis of the Saccharomyces cerevisiae Pheromone a -Factor, from Yeast Mating to Human Disease

The ABBA family of aromatic prenyltransferases: broadening natural product diversity

Prenylation of viral proteins by enzymes of the host: Virus‐driven rationale for therapy with statins and FT/GGT1 inhibitors

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