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Literature summary for 2.5.1.59 extracted from
- Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling (2015), Drug Discov. Today, 20, 267-276.
Application
| Application | Comment | Organism |
|---|---|---|
| pharmacology | the enzyme is a promising therapeutic target for the treatment of various Ras-induced cancers and several other kinds of diseases | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| (2R,3R,5S)-5-tert-butyl-2-(4-chlorophenyl)-1-[(2-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid | compete with the substrate protein rather than GGPP; compete with the substrate protein rather than GGPP | Homo sapiens |  |
| 2-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid | compete with the substrate protein rather than GGPP; compete with the substrate protein rather than GGPP | Homo sapiens | |
| 4-[2-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]-2-(1H-imidazol-5-yl)ethyl]benzonitrile | is bound to the peptide-binding site by competing with the CAAX substrate in the 4-[2-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]-2-(1H-imidazol-5-yl)ethyl]benzonitrile-FTase complex, cf. EC 2.5.1.58, but is bound in the lipid-binding pocket together with a portion of the peptide-binding site in the 4-[2-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]-2-(1H-imidazol-5-yl)ethyl]benzonitrile-GGTase-I complex; is bound to the peptide-binding site by competing with the CAAX substrate in the 4-[2-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]-2-(1H-imidazol-5-yl)ethyl]benzonitrileFTase complex, cf. EC 2.5.1.58, but is bound in the lipid-binding pocket together with a portion of the peptide-binding site in the L-4-[2-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]-2-(1H-imidazol-5-yl)ethyl]benzonitrile-GGTase-I complex | Homo sapiens | |
| methyl N-([2-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridin-3-yl]carbonyl)leucinate | with anti-tumor activity; with anti-tumor activity | Homo sapiens | |
| additional information | most GGT inhibitors are CAAX-competitive inhibitors, except for a few GGPP-competitive inhibitors. Inhibition mechanisms for FTase, EC 2.5.1.58, and GGTase-I are different. Molecular modeling studies of GGTase-I and protein-inhibitor interactions, overview; most GGT inhibitors are CAAX-competitive inhibitors, except for a few GGPP-competitive inhibitors. Inhibition mechanisms for FTase, EC 2.5.1.58, and GGTase-I are different. Molecular modeling studies of GGTase-I and protein-inhibitor interactions, overview | Homo sapiens | |
| additional information | most GGT inhibitors are CAAX-competitive inhibitors, except for a few GGPP-competitive inhibitors; most GGT inhibitors are CAAX-competitive inhibitors, except for a few GGPP-competitive inhibitors | Rattus norvegicus | |
| N-([(2S)-2-benzyl-4-[(4-methyl-1H-imidazol-5-yl)methyl]-3-oxopiperazin-1-yl]carbonyl)-L-leucine | - |
Homo sapiens | |
| N-([5-[(1H-imidazol-5-ylamino)methyl]-2'-methylbiphenyl-2-yl]carbonyl)-L-leucine | a non-thiol-containing peptidomi-metic, it can inhibit human tumor growth in mice and the combination therapy with cytotoxic agents is more beneficial than monotherapy. N-([5-[(1H-imidazol-5-ylamino)methyl]-2'-methylbiphenyl-2-yl]carbonyl)-L-leucine is able to induce breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice; a non-thiol-containing peptidomi-metic, it can inhibit human tumor growth in mice and the combination therapy with cytotoxic agents is more beneficial than monotherapy. N-([5-[(1H-imidazol-5-ylamino)methyl]-2'-methylbiphenyl-2-yl]carbonyl)-L-leucine is able to induce breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice | Homo sapiens | |
| N-[(5-[[(2R)-2-amino-3-sulfanylpropyl]amino]biphenyl-2-yl)carbonyl]-L-leucine | - |
Homo sapiens | |
| N-[[4-(imidazol-4-yl)methylamino]-2-(1-naphthyl)benzoyl]leucine | - |
Homo sapiens | |
| Na-(4-[[1-(3,4-dichlorophenyl)-4-[2-(methylsulfanyl)ethyl]-3-(pyridin-3-yl)-1H-pyrazol-5-yl]oxy]butanoyl)-L-phenylalaninamide | - |
Homo sapiens | |
| Na-([(5R)-5-tert-butyl-2-(4-chlorophenyl)-1-[(2-methylphenyl)sulfonyl]-2,5-dihydro-1H-pyrrol-3-yl]carbonyl)-L-phenylalaninamide | with anti-tumor activity; with anti-tumor activity | Homo sapiens | |
| tetrapeptide CVIL | superposition of the crystal structures of the CVIL-GGTase-I complex; superposition of the crystal structures of the CVIL-GGTase-I complex | Homo sapiens | |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| additional information | Mg2+ is not required | Rattus norvegicus | |
| additional information | Mg2+ is not required | Homo sapiens | |
| Zn2+ | required for the enzymatic activities of GGTase-I, bound at the beta-subunit | Homo sapiens | |
| Zn2+ | required for the enzymatic activities of GGTase-I, bound at the beta-subunit, coordinated by residues Aspbeta269, Cysbeta271 and Hisbeta321 in GGTase-I | Rattus norvegicus | |
Molecular Weight [Da]
| Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|
| 48000 | - |
- |
Rattus norvegicus |
| 48000 | - |
- |
Homo sapiens |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| geranylgeranyl diphosphate + K Ras-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-K Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + K Ras-cysteine | Homo sapiens | - |
S-geranylgeranyl-K Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + N-Ras-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-N-Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + N-Ras-cysteine | Homo sapiens | - |
S-geranylgeranyl-N-Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + protein-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-protein + diphosphate | - |
? | |
| geranylgeranyl diphosphate + protein-cysteine | Homo sapiens | - |
S-geranylgeranyl-protein + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rac-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-Rac + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rac-cysteine | Homo sapiens | - |
S-geranylgeranyl-Rac + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-Rap + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap-cysteine | Homo sapiens | - |
S-geranylgeranyl-Rap + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap1A-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-Rap1A + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap1A-cysteine | Homo sapiens | - |
S-geranylgeranyl-Rap1A + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rho-cysteine | Rattus norvegicus | - |
S-geranylgeranyl-Rho + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rho-cysteine | Homo sapiens | - |
S-geranylgeranyl-Rho + diphosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P49354 | subunit alpha | - |
| Homo sapiens | P53609 | subunit beta | - |
| Rattus norvegicus | P53610 | subunit beta | - |
| Rattus norvegicus | Q04631 | subunit alpha | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| geranylgeranyl diphosphate + K Ras-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-K Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + K Ras-cysteine | - |
Homo sapiens | S-geranylgeranyl-K Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + N-Ras-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-N-Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + N-Ras-cysteine | - |
Homo sapiens | S-geranylgeranyl-N-Ras + diphosphate | - |
? | |
| geranylgeranyl diphosphate + protein-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-protein + diphosphate | - |
? | |
| geranylgeranyl diphosphate + protein-cysteine | - |
Homo sapiens | S-geranylgeranyl-protein + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rac-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-Rac + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rac-cysteine | - |
Homo sapiens | S-geranylgeranyl-Rac + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-Rap + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap-cysteine | - |
Homo sapiens | S-geranylgeranyl-Rap + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap1A-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-Rap1A + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rap1A-cysteine | - |
Homo sapiens | S-geranylgeranyl-Rap1A + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rho-cysteine | - |
Rattus norvegicus | S-geranylgeranyl-Rho + diphosphate | - |
? | |
| geranylgeranyl diphosphate + Rho-cysteine | - |
Homo sapiens | S-geranylgeranyl-Rho + diphosphate | - |
? | |
| additional information | GGTase-I can transfer isoprenoids to intracellular proteins that contain CAAX motifs. The isoprenoid groups can be selectively recognized by GGTase-I. The 20-carbon isoprenoid geranylgeranyl from its donor geranylgeranyl diphosphate (GGPP) is specific to GGTase-I. No activity with H-Ras | Homo sapiens | ? | - |
? | |
| additional information | GGTase-I can transfer isoprenoids to intracellular proteins that contain CAAX motifs. The isoprenoid groups can be selectively recognized by GGTase-I. The 20-carbon isoprenoid geranylgeranyl from its donor geranylgeranyl diphosphate (GGPP) is specific to GGTase-I. Residues Lysalpha164, Hisbeta219, Argbeta263, Lysbeta266 and Tyrbeta272 in GGTase-I can form hydrogen bonds with GGPP. No activity with H-Ras | Rattus norvegicus | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| heterodimer | alphabeta, 1 * 48000, alpha-subunit | Rattus norvegicus |
| heterodimer | alphabeta, 1 * 48000, alpha-subunit | Homo sapiens |
| More | the alpha subunit is primarily composed of alpha helices that are arranged into different shapes. The alpha subunit is a crescent-shaped super helix. The N-terminal domain is disordered and proline-rich, and has no direct influence on the catalytic activity | Rattus norvegicus |
| More | the alpha subunit is primarily composed of alpha helices that are arranged into different shapes. The alpha subunit is a crescent-shaped super helix. The N-terminal domain is disordered and proline-rich, and has no direct influence on the catalytic activity | Homo sapiens |
| More | the beta subunit is primarily composed of alpha helices that are arranged into different shapes. The beta subunit is an alpha-alpha barrel. The beta subunit of GGTase-I consists of 13 alpha helices, with 12 alpha helices folded into an alpha-alpha barrel. This arrangement forms a funnel-shaped cavity in the center of the barrel, where the active sites of GGTase-I is located. This cavity is hydrophobic and contains a number of conserved aromatic residues. The N-terminal domain is disordered and proline-rich, and has no direct influence on the catalytic activity | Rattus norvegicus |
| More | the beta subunit is primarily composed of alpha helices that are arranged into different shapes. The beta subunit is an alpha-alpha barrel. The beta subunit of GGTase-I consists of 13 alpha helices, with 12 alpha helices folded into an alpha-alpha barrel. This arrangement forms a funnel-shaped cavity in the center of the barrel, where the active sites of GGTase-I is located. This cavity is hydrophobic and contains a number of conserved aromatic residues. The N-terminal domain is disordered and proline-rich, and has no direct influence on the catalytic activity | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| geranylgeranyltransferase type-I | - |
Rattus norvegicus |
| geranylgeranyltransferase type-I | - |
Homo sapiens |
| GGTase-I | - |
Rattus norvegicus |
| GGTase-I | - |
Homo sapiens |
Ki Value [mM]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.0000008 | - |
Na-(4-[[1-(3,4-dichlorophenyl)-4-[2-(methylsulfanyl)ethyl]-3-(pyridin-3-yl)-1H-pyrazol-5-yl]oxy]butanoyl)-L-phenylalaninamide | pH and temperature not specified in the publication | Homo sapiens | |
| 0.0000095 | - |
N-([(2S)-2-benzyl-4-[(4-methyl-1H-imidazol-5-yl)methyl]-3-oxopiperazin-1-yl]carbonyl)-L-leucine | pH and temperature not specified in the publication | Homo sapiens | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.000313 | - |
pH and temperature not specified in the publication | Homo sapiens | Na-(4-[[1-(3,4-dichlorophenyl)-4-[2-(methylsulfanyl)ethyl]-3-(pyridin-3-yl)-1H-pyrazol-5-yl]oxy]butanoyl)-L-phenylalaninamide | |
| 0.000466 | - |
pH and temperature not specified in the publication | Homo sapiens | N-([(2S)-2-benzyl-4-[(4-methyl-1H-imidazol-5-yl)methyl]-3-oxopiperazin-1-yl]carbonyl)-L-leucine | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | combined FTase/GGTase-I deficiency significantly reduces K-Ras-induced lung tumors and improves survival without obvious pulmonary toxicity | Rattus norvegicus |
| malfunction | combined FTase/GGTase-I deficiency significantly reduces K-Ras-induced lung tumors and improves survival without obvious pulmonary toxicity | Homo sapiens |
| additional information | FTase and GGTase-I recognize the same CAAX sequence motif in a protein substrate and catalyze the attachment of farnesyl and geranygeranyl groups to the protein, respectively. The X is the key residue that determines the farnesylation or geranylgeranylation of the CAAX-containing protein. When X is serine, methionine or glutamine the protein substrate is preferentially activated by FTase, but when X is leucine or phenylalanine the protein substrate is preferentially activated by GGTase-I | Rattus norvegicus |
| additional information | FTase and GGTase-I recognize the same CAAX sequence motif in a protein substrate and catalyze the attachment of farnesyl and geranygeranyl groups to the protein, respectively. The X is the key residue that determines the farnesylation or geranylgeranylation of the CAAX-containing protein. When X is serine, methionine or glutamine the protein substrate is preferentially activated by FTase, but when X is leucine or phenylalanine the protein substrate is preferentially activated by GGTase-I | Homo sapiens |
| physiological function | enzyme GGTase-I has a crucial role in the posttranslational modification of Ras proteins. The enzyme is involved in several diseases, e.g. glaucoma via Rho prenylation, and neurological diseases. GGTase-I catalyzes geranylgeranyl isoprenoid linked to the cysteine residue of the CAAX protein through a thioether linkage, which will enhance the hydrophobicity of the CAAX protein. Meanwhile, the formed CAAX-protein-isoprenoid complex is attached to the endoplasmic reticulum surface | Rattus norvegicus |
| physiological function | enzyme GGTase-I has a crucial role in the posttranslational modification of Ras proteins. The enzyme is involved in several diseases, e.g. glaucoma via Rho prenylation, and neurological diseases. GGTase-I catalyzes geranylgeranyl isoprenoid linked to the cysteine residue of the CAAX protein through a thioether linkage, which will enhance the hydrophobicity of the CAAX protein. Meanwhile, the formed CAAX-protein-isoprenoid complex is attached to the endoplasmic reticulum surface | Homo sapiens |
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