A new class of type I protein geranylgeranyltransferase (GGTase I) inhibitor

Sunami, Satoshi; Ohkubo, Mitsuru; Sagara, Takeshi; Ono, Jun; Asahi, Shuichi; Koito, Seita; Morishima, Hajime

doi:10.1016/s0960-894x(01)00813-7

Cited by 8 publications

(8 citation statements)

References 22 publications

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“…Prenylation is catalyzed with the Zn 2+ metalloenzymes, farnesyl transferase (FTPase), and geranylgeranyltransferase (GGTase) . Proteins that are prenylated include small GTP-binding proteins, of which Rho1 is an essential regulatory subunit of 1,3-β-glucan synthase. , Since GGTase I from the pathogenic fungus Candida albicans shares only 30% amino acid sequence homology with the human GGTase, inhibitors of GGTase I are expected to be selective antifungal agents . In the course of our continuing search for drug leads from Japanese marine invertebrates, we found Candida GGTase I inhibitory activity 6 in the organic extract of the marine sponge Stylissa aff.…”

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confidence: 99%

Massadine, a Novel Geranylgeranyltransferase Type I Inhibitor from the Marine Sponge Stylissa aff. massa

et al. 2003

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Massadine, a Novel Geranylgeranyltransferase Type I Inhibitor from the Marine Sponge Stylissa aff. massa

et al. 2003

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“…Hundreds of compounds have been discovered or developed as inhibitors of either FTase or GGTase-I (or both); many of these have clinical potential as anticancer (121)(122)(123)(124)(125), antiparasitic (29,(126)(127)(128), antifungal (129)(130)(131), and antiviral (132-134) therapeutic agents. Some of these have been characterized by X-ray crystallographic studies, revealing a molecular basis for their inhibitory activities.…”

Section: Inhibition Of Caax Prenyltransferase Activitymentioning

confidence: 99%

Thematic review series: Lipid Posttranslational Modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I

Lane

Beese

2006

Journal of Lipid Research

233

197

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More than 100 proteins necessary for eukaryotic cell growth, differentiation, and morphology require posttranslational modification by the covalent attachment of an isoprenoid lipid (prenylation). Prenylated proteins include members of the Ras, Rab, and Rho families, lamins, CENPE and CENPF, and the g subunit of many small heterotrimeric G proteins. This modification is catalyzed by the protein prenyltransferases: protein farnesyltransferase (FTase), protein geranylgeranyltransferase type I (GGTase-I), and GGTase-II (or RabGGTase). In this review, we examine the structural biology of FTase and GGTase-I (the CaaX prenyltransferases) to establish a framework for understanding the molecular basis of substrate specificity and mechanism. These enzymes have been identified in a number of species, including mammals, fungi, plants, and protists. Prenyltransferase structures include complexes that represent the major steps along the reaction path, as well as a number of complexes with clinically relevant inhibitors. Such complexes may assist in the design of inhibitors that could lead to treatments for cancer, viral infection, and a number of deadly parasitic diseases.-Lane, K. T., and L. S. Beese. More than 100 proteins necessary for eukaryotic cell growth, differentiation, and morphology require posttranslational modification by the covalent attachment of an isoprenoid lipid (prenylation) (1). This modification is catalyzed by three protein prenyltransferases: protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase-I), collectively termed the CaaX prenyltransferases, as well as protein GGTase-II (or RabGGTase) [reviewed in this series in (2)], whose substrates are limited to members of the Rab subfamily of G proteins. FTase and GGTase-I transfer a 15 or 20 carbon isoprenoid [donated by farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP)], respectively, to the cysteine of a C-terminal CaaX motif, defined by a cysteine (C) residue, followed by two small, generally aliphatic (a) residues, and the X residue, which contributes significantly to specificity (Fig. 1) (3-9). Kinetic assays and analysis of lipidated CaaX proteins purified from the cell demonstrate the general preference of FTase for methionine, serine, glutamine, or alanine and the preference of GGTase-I for leucine or phenylalanine in the X position. Here, we review the structural biology of FTase and GGTase-I; the biochemical properties of these enzymes have been reviewed extensively elsewhere (1, 10-15).After covalent attachment of the isoprenoid in the cytoplasm, most CaaX proteins undergo two further prenylation-dependent processing steps at the endoplasmic reticulum (1): proteolytic removal of the aaX tripeptide by the CaaX protease Ras and a-factor-converting enzyme (Rce1), and carboxymethylation of the prenylcysteine residue by the enzyme Isoprenylcysteine carboxyl methyltransferase (Icmt). The fully processed proteins exhibit high affinity for cellular membranes and present a unique structure at thei...

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“…In pathogenic microorganisms, such as C. albicans, disruption of protein prenylation of such essential cellular proteins has the potential for the development of new antifungal medications (5)(6)(7)(8)23). The Ram2 gene in C. albicans encodes the common ␣-subunit of FTase and GGTase-I; knock-out mutations of this gene are lethal (5).…”

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“…As in mammalian cells, knock-out of a single ␤-subunit is not lethal, because the remaining CaaX prenyltransferase can cross-prenylate non-cognate substrates (7). Even so, at least one series of selective CaGGTase-I inhibitors has shown significant antifungal activity, suggesting that impairment of one of the CaaX prenyltransferase may be sufficient for effective treatment (23). In C. albicans, Rho family substrates of the GGTase-I regulate cell wall biogenesis, while Ras family substrates of CaFTase have been strongly implicated in virulence by regulating the transition from yeast to hyphae (5).…”

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Structure of Protein Geranylgeranyltransferase-I from the Human Pathogen Candida albicans Complexed with a Lipid Substrate

Hast

Beese

2008

Journal of Biological Chemistry

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Protein geranylgeranyltransferase-I (GGTase-I) catalyzes the transfer of a 20-carbon isoprenoid lipid to the sulfur of a cysteine residue located near the C terminus of numerous cellular proteins, including members of the Rho superfamily of small GTPases and other essential signal transduction proteins. In humans, GGTase-I and the homologous protein farnesyltransferase (FTase) are targets of anticancer therapeutics because of the role small GTPases play in oncogenesis. Protein prenyltransferases are also essential for many fungal and protozoan pathogens that infect humans, and have therefore become important targets for treating infectious diseases. Candida albicans, a causative agent of systemic fungal infections in immunocompromised individuals, is one pathogen for which protein prenylation is essential for survival. Here we present the crystal structure of GGTase-I from C. albicans (CaGGTase-I) in complex with its cognate lipid substrate, geranylgeranylpyrophosphate. This structure provides a high-resolution picture of a non-mammalian protein prenyltransferase. There are significant variations between species in critical areas of the active site, including the isoprenoid-binding pocket, as well as the putative product exit groove. These differences indicate the regions where specific protein prenyltransferase inhibitors with antifungal activity can be designed.Candida albicans is an opportunistic pathogen associated with a variety of diseases, ranging from common vaginal yeast infections and oral thrush, to systemic fungal infections in immunocompromised individuals, such as AIDS patients and transplant recipients (1, 2). Estimates place the morbidity rate for systemic C. albicans infections that have reached the bloodstream at between 20 and 47% (1, 2). In addition, emerging resistance of C. albicans to existing antifungal therapies such as fluconazole has prompted a search for new drugs (3).The protein prenylation pathway may be a potential new target for antifungal treatment (4 -8). Prenylation is an essential post-translational lipid modification for more than 120 cellular proteins, including the signal transduction proteins in the Ras, Rho, and Rab families, PRL-family tyrosine phosphatases, centromeric proteins, and nuclear lamins (9, 10). Most eukaryotes possess three protein prenyltransferases: protein farnesyltransferase (FTase) adds a 15-carbon isoprenoid lipid. Protein geranylgeranyltransferase-I (GGTase-I) 2 a single 20-carbon isoprenoid lipid, and protein geranylgeranyltransferase-II (GGTase-II or Rab GGTase) successively adds two 20-carbon isoprenoid lipids. In each case, the lipid is transferred to the ␥ sulfur of the cysteine residue. All three protein prenyltransferases are obligate heterodimers and share a homologous architecture. Both FTase and GGTase-I prenylate a C-terminal CaaX tetrapeptide recognition sequence of their substrate proteins (C, cysteine; aa, two generally aliphatic residues; and X, a specificity determining residue). The X-residue usually determines the cognate substrate f...

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A new class of type I protein geranylgeranyltransferase (GGTase I) inhibitor

Cited by 8 publications

References 22 publications

Massadine, a Novel Geranylgeranyltransferase Type I Inhibitor from the Marine Sponge Stylissa aff. massa

Massadine, a Novel Geranylgeranyltransferase Type I Inhibitor from the Marine Sponge Stylissa aff. massa

Thematic review series: Lipid Posttranslational Modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I

Structure of Protein Geranylgeranyltransferase-I from the Human Pathogen Candida albicans Complexed with a Lipid Substrate

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