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Literature summary for 2.5.1.58 extracted from

  • Shen, M.; Pan, P.; Li, Y.; Li, D.; Yu, H.; Hou, T.
    Farnesyltransferase and geranylgeranyltransferase I: structures, mechanism, inhibitors and molecular modeling (2015), Drug Discov. Today, 20, 267-276.
    View publication on PubMed
Search for more literature for 2.5.1.58

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
4-[2-[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]-2-(1H-imidazol-5-yl)ethyl]benzonitrile binds into the CAAX peptide site and competes with the CAAX substrate of FTase; binds into the CAAX peptide site and competes with the CAAX substrate of FTase Homo sapiens
BMS-214662 bind into the CAAX peptide site and compete with the CAAX substrate of FTase; bind into the CAAX peptide site and compete with the CAAX substrate of FTase Homo sapiens
lonafarnib active in Ras-dependent and -independent malignant tumors; active in Ras-dependent and -independent malignant tumors Homo sapiens
methyl (2S)-2-([(2S)-2-[(2-[[(2R)-2-amino-3-sulfanylpropyl]amino]-3-methylpentyl)oxy]-3-phenylpropanoyl]amino)-4-(methylsulfonyl)butanoate a selective peptidomimetic enzme inhibitor Homo sapiens
additional information inhibition mechanisms for FTase and GGTase-I, EC 2.5.1.59, are different. Two classes of FTase enzyme inhibitors, bisubstrate imidazole-containing derivatives linked by an acidic substituent and a peptidyl chain and peptidomimetic molecules, which can be divided into two groups, namely thiol and non-thiol compounds. Molecular modeling studies of FTase and protein-inhibitor interactions, overview; inhibition mechanisms for FTase and GGTase-I, EC 2.5.1.59, are different. Two classes of FTase enzyme inhibitors, bisubstrate imidazole-containing derivatives linked by an acidic substituent and a peptidyl chain and peptidomimetic molecules, which can be divided into two groups, namely thiol and non-thiol compounds. Molecular modeling studies of FTase and protein-inhibitor interactions, overview Homo sapiens
R115777
-
 Homo sapiens
tipifarnib
-
 Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens
Zn2+ required Homo sapiens
Zn2+ required, binding and coordination structure, coordinated by residues Aspbeta297, Cysbeta299 and Hisbeta362 in FTase , overview Rattus norvegicus
Zn2+ required, binding and coordination structure, overview Rattus norvegicus

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
(2E,6E)-farnesyl diphosphate + (protein)-L-cysteine Homo sapiens
-
 S-(2E,6E)-farnesyl protein + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [H Ras]-L-cysteine Rattus norvegicus
-
 S-(2E,6E)-farnesyl-[H Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [H Ras]-L-cysteine Homo sapiens
-
 S-(2E,6E)-farnesyl-[H Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [K Ras]-L-cysteine Rattus norvegicus
-
 S-(2E,6E)-farnesyl-[K Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [K Ras]-L-cysteine Homo sapiens
-
 S-(2E,6E)-farnesyl-[K Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [N Ras]-L-cysteine Rattus norvegicus
-
 S-(2E,6E)-farnesyl-[N Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [N Ras]-L-cysteine Homo sapiens
-
 S-(2E,6E)-farnesyl-[N Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [protein]-L-cysteine Rattus norvegicus
-
 S-(2E,6E)-farnesyl-[protein]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [protein]-L-cysteine Homo sapiens
-
 S-(2E,6E)-farnesyl-[protein]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [Rho]-L-cysteine Rattus norvegicus
-
 S-(2E,6E)-farnesyl-[Rho]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [Rho]-L-cysteine Homo sapiens
-
 S-(2E,6E)-farnesyl-[Rho]-L-cysteine + diphosphate
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens P49354 alpha-subunit
-
Homo sapiens P49356 beta-subunit
-
Rattus norvegicus Q02293 beta-subunit
-
Rattus norvegicus Q04631 alpha-subunit
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
(2E,6E)-farnesyl diphosphate + (protein)-L-cysteine
-
 Homo sapiens S-(2E,6E)-farnesyl protein + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + K Ras-cysteine
-
 Rattus norvegicus S-(2E,6E)-farnesyl-[K Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [H Ras]-L-cysteine
-
 Rattus norvegicus S-(2E,6E)-farnesyl-[H Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [H Ras]-L-cysteine
-
 Homo sapiens S-(2E,6E)-farnesyl-[H Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [K Ras]-L-cysteine
-
 Rattus norvegicus S-(2E,6E)-farnesyl-[K Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [K Ras]-L-cysteine
-
 Homo sapiens S-(2E,6E)-farnesyl-[K Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [N Ras]-L-cysteine
-
 Rattus norvegicus S-(2E,6E)-farnesyl-[N Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [N Ras]-L-cysteine
-
 Homo sapiens S-(2E,6E)-farnesyl-[N Ras]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [protein]-L-cysteine
-
 Rattus norvegicus S-(2E,6E)-farnesyl-[protein]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [protein]-L-cysteine
-
 Homo sapiens S-(2E,6E)-farnesyl-[protein]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [Rho]-L-cysteine
-
 Rattus norvegicus S-(2E,6E)-farnesyl-[Rho]-L-cysteine + diphosphate
-
 ?
(2E,6E)-farnesyl diphosphate + [Rho]-L-cysteine
-
 Homo sapiens S-(2E,6E)-farnesyl-[Rho]-L-cysteine + diphosphate
-
 ?
additional information FTase-I can transfer isoprenoids to intracellular proteins that contain CAAX motifs. The isoprenoid groups can be selectively recognized by GGTase-I. The 15-carbon isoprenoid geranylgeranyl from its donor farnesyldiphosphate (FPP) is specific to FTase-I. Residues Lysalpha164, Hisbeta248, Argbeta291 and Tyrbeta300 in FTase can form hydrogen bonds with farnesyl diphosphate. When FTase is inhibited by a FTI, N-Ras and K-Ras can be alternatively prenylated by GGTase-I, EC 2.5.1.59, but H-Ras cannot Rattus norvegicus ?
-
 ?
additional information FTase-I can transfer isoprenoids to intracellular proteins that contain CAAX motifs. The isoprenoid groups can be selectively recognized by GGTase-I. The 15-carbon isoprenoid geranylgeranyl from its donor farnesyldiphosphate (FPP) is specific to FTase-I. Residues Lysalpha164, Hisbeta248, Argbeta291 and Tyrbeta300 in FTase can form hydrogen bonds with farnesyl diphosphate. When FTase is inhibited by a FTI, N-Ras and K-Ras can be alternatively prenylated by GGTase-I, EC 2.5.1.59, but H-Ras cannot Homo sapiens ?
-
 ?

Synonyms

Synonyms Comment Organism
farnesyltransferase
-
 Rattus norvegicus
farnesyltransferase
-
 Homo sapiens
FTase
-
 Rattus norvegicus
FTase
-
 Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00024
-
 pH and temperature not specified in the publication Homo sapiens methyl (2S)-2-([(2S)-2-[(2-[[(2R)-2-amino-3-sulfanylpropyl]amino]-3-methylpentyl)oxy]-3-phenylpropanoyl]amino)-4-(methylsulfonyl)butanoate

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. Enzyme deficiency is involved in progeria, also known as Hutchinson-Gilford progeria syndrome, a fatal and rare genetic disease caused by the mutation of the LMNA gene 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 FTase catalyzes farnesyl 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 FTase catalyzes farnesyl 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. FTase is involvedin hematologic malignancies due via prenylation of Ras. The enzyme is also important in the pathological process of neurological diseases, such as neuroinflammatory disease and Parkinson's disease Homo sapiens