Information on EC 2.5.1.60 - protein geranylgeranyltransferase type II

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
2.5.1.60
-
RECOMMENDED NAME
GeneOntology No.
protein geranylgeranyltransferase type II
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
mechanism, recombinant enzyme/REP-1 complex catalyzes the geranylgeranylation of both adjacent cysteines in Rab1A, Rab3A and Rab5A
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
enzyme is unique in the protein prenyltransferase family, consisting protein farnesyltransferase, EC 2.5.1.58, protein geranylgeranyltransferase type I, EC 2.5.1.59 and Rab geranylgeranyltransferase; mechanism
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
mechanism
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
mechanism, phosphoisoprenoid acts both as a substrate and as a sensor governing the kinetics of protein protein interactions in the double prenylation reaction
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
enzyme is unique in the protein prenyltransferase family, consisting protein farnesyltransferase, EC 2.5.1.58, protein geranylgeranyltransferase type I, EC 2.5.1.59 and Rab geranylgeranyltransferase; mechanism, geranylgeranyl diphosphate first acts as an allosteric regulator of enzyme, second acts as the phosphoisoprenoid donor in the prenylation reaction and third senses the completion of catalysis and concomitantly triggers substrate release by increasing the dissociation rate of the product
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
enzyme is unique in the protein prenyltransferase family, consisting protein farnesyltransferase, EC 2.5.1.58, protein geranylgeranyltransferase type I, EC 2.5.1.59 and Rab geranylgeranyltransferase; mammalian enzyme have revealed two alternative pathways for the assembly of catalytic complex. The classical pathway: the Rab protein forms a stable complex with REP. Enzyme covalently attaches the geranylgeranyl groups to two C-terminal cysteines of the Rab protein. Upon prenylation, the Rab/REP complex remains tightly associated with the enzyme until binding of a new molecule of isoprenoid decreases its affinity for the prenylated complex. The prenylated complex dissociated from enzyme and delivers Rab protein to its target membrane. In the alternative pathway, enzyme and REP form a tight complex in the presence of the phosphoisoprenoid. This complex is catalytically competent and can recruit and prenylate Rab protein.
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
enzyme is unique in the protein prenyltransferase family, consisting protein farnesyltransferase, EC 2.5.1.58, protein geranylgeranyltransferase type I, EC 2.5.1.59 and Rab geranylgeranyltransferase; mammalian enzyme have revealed two alternative pathways for the assembly of catalytic complex. The classical pathway: the Rab protein forms a stable complex with REP. Enzyme covalently attaches the geranylgeranyl groups to two C-terminal cysteines of the Rab protein. Upon prenylation, the Rab/REP complex remains tightly associated with the enzyme until binding of a new molecule of isoprenoid decreases its affinity for the prenylated complex. The prenylated complex dissociated from enzyme and delivers Rab protein to its target membrane. In the alternative pathway, enzyme and REP form a tight complex in the presence of the phosphoisoprenoid. This complex is catalytically competent and can recruit and prenylate Rab protein.; the yeast enzyme follows only the classical pathway
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
mammalian enzyme have revealed two alternative pathways for the assembly of catalytic complex. The classical pathway: the Rab protein forms a stable complex with REP. Enzyme covalently attaches the geranylgeranyl groups to two C-terminal cysteines of the Rab protein. Upon prenylation, the Rab/REP complex remains tightly associated with the enzyme until binding of a new molecule of isoprenoid decreases its affinity for the prenylated complex. The prenylated complex dissociated from enzyme and delivers Rab protein to its target membrane. In the alternative pathway, enzyme and REP form a tight complex in the presence of the phosphoisoprenoid. This complex is catalytically competent and can recruit and prenylate Rab protein.; mechanism of enzyme/REP-complex formation
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
enzyme is unique in the protein prenyltransferase family, consisting protein farnesyltransferase, EC 2.5.1.58, protein geranylgeranyltransferase type I, EC 2.5.1.59 and Rab geranylgeranyltransferase
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
prenylation mechanism of Rab potein by the RabGGTase:GGpp complex, overview
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
enzyme is unique in the protein prenyltransferase family, consisting protein farnesyltransferase, EC 2.5.1.58, protein geranylgeranyltransferase type I, EC 2.5.1.59 and Rab geranylgeranyltransferase
Saccharomyces cerevisiae JRY1550
-
-
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
geranylgeranyl-diphosphate:protein-cysteine geranyltransferase
This enzyme, along with protein farnesyltransferase (EC 2.5.1.58) and protein geranylgeranyltransferase type I (EC 2.5.1.59), constitutes the protein prenyltransferase family of enzymes. Attaches geranylgeranyl groups to two C-terminal cysteines in Ras-related GTPases of a single family, the Rab family (Ypt/Sec4 in lower eukaryotes) that terminate in XXCC, XCXC and CCXX motifs. Reaction is entirely dependent on the Rab substrate being bound to Rab escort protein (REP). Post-translational modification with the geranylgeranyl moiety is essential for Rab GTPases to be able to control the processes of membrane docking and fusion [5].
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
geranylgeranyltransferase II
-
-
geranylgeranyltransferase type II
-
-
-
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GGT2
-
-
GGTase-II
-
-
-
-
GGTase-II
-
-
GGTaseII
-
-
-
-
PGGT-II
-
-
-
-
protein geranylgeranyltransferase type-II
-
-
-
-
Rab geranylgeranyl transferase
-
-
-
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Rab geranylgeranyl transferase
-
-
Rab geranylgeranyl transferase
-
-
Rab geranylgeranyl transferase
-
-
Rab geranylgeranyl transferase
-
-
Rab geranylgeranyl transferase
-
-
Rab geranylgeranyl transferase
-
-
Rab geranylgeranyltransferase
-
-
-
-
Rab geranylgeranyltransferase
-
-
Rab geranylgeranyltransferase
-
-
Rab geranylgeranyltransferase type II
-
-
Rab geranylgeranyltransferase type II
-
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Rab GG transferase
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Rab GGTase
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Rab GGTase
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RabGGTase
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-
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RabGGTase
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Rabggtb
-
beta subunit of Rab geranylgeranyl transferase
REP/GGTase
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-
-
-
CAS REGISTRY NUMBER
COMMENTARY
135371-29-8
-
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
overexpression of Rabs Rab5a, Rab7, and Rab27 is observed in various cancers, elevated levels of Rab25 in breast and ovarian cancer cells are reported to increase the aggressiveness of these cancers
malfunction
-
homozygous mutants of the major beta-subunit of Arabidopsis enzyme (RGTB1) result in unprenylated RAB GTPase accumulation in the cytoplasm, up-regulation of several GTPases, endocytosis and exocytosis are downregulated, defects in shoot growth and morphogenesis, changed shoot gravitropism and reaction to etiolation
physiological function
-
attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport
physiological function
-
membrane localization of RAB GTPase is mediated by C-terminal double geranylgeranylation by the enzyme in cooperation with the RAB escort protein (REP)
physiological function
-
cells from the gunmetal gm/gm mouse, which bear a homozygous mutation in protein geranylgeranyltransferase-II that results in about 80% reduced activity of this enzyme compared to wild-type or heterozygous mice, are more sensitive to the effects of active phosphonocarboxylates, including reducing macrophage cell viability, inhibiting osteoclast formation and inhibiting fluid-phase endocytosis
physiological function
-
siRNA-mediated knockdown of alpha- or beta-subunits of the enzyme and Rab escort protein-1 markedley attenuates glucose-stimulated insulin secretion in INS-1 832/13 cells
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(2E,6E,10Z)-3,7,11-trimethyl-12-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]dodeca-2,6,10-trien-1-yl diphosphate + Rab7 GTPase
(2E,6E,10Z)-3,7,11-trimethyl-12-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]dodeca-2,6,10-trien-1-yl-Rab7 GTPase + diphosphate
show the reaction diagram
-
in vitro prenylation assay with 4 microM Rab7 wild type or mutants, 6 mircoM Rab escort protein, 6 microM enzyme, 50 mM HEPES buffer, pH 7.2, containing 50 mM NaCl, 5 mM dithioerythritol, 2 mM MgCl2, and 10 mircoM GDP, 25C, 50 microM of the geranylgeranyl diphosphate analogue (3,7,11-trimethyl-12-(7-nitro-benzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,10-triem-1) diphosphate, end-point assay with 6 microM Rab7 wild type or mutants, 10 microM Rab escort protein, 6 microM enzyme in the same buffer mixture, and 40 microM (3,7,11-trimethyl-12-(7-nitro-benzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,10-triem-1) diphosphate, 1.5 hours at 25C
-
-
?
(3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate + Rab7
(3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1)-Rab7 + diphosphate
show the reaction diagram
-
geranylgeranyl diphosphate analogue and Rab7 as substrates in the presence of Rab escort protein, in vitro inhibition assays
-
-
?
biotinylated geranyl diphosphate + EYFP-Rab7
S-biotin-geranyl-Rab7 + diphosphate
show the reaction diagram
-
COS-7 cells are transfected with EYFP-Rab7 fusion protein and incubated with inhibitors, cells lysed after 24 h, clarified supernatant incubated in biotinylated geranyl diphosphate (geranylgeranyl diphosphate substrate analogue), recombinant RabGGTase and Rab escort protein, in vivo inhibitor studies
-
-
?
geranylgeranyl diphosphate + Arabidopsis thaliana RAB-ATa protein
S-geranylgeranyl-RAB GTPase + diphosphate
show the reaction diagram
-
homozygous insertion mutants (rgtb1-1 and rgtb1-2) of the major beta-subunit of Arabidopsis enzyme (RGTB1) lead to reduced enzyme activity (about 25%), 50 mM phosphate buffer, pH 7.6, 10 mM MgCl2, 5 mM DTT, 0.5 microM tritium-labelled all trans-geranylgeranyl pyrophosphate, 4 microg recombinant Arabidopsis thaliana RAB-A2a protein, 32C, 40 min
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
substrate are Rab3 and Rab4
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme attaches geranylgeranyl groups to two C-terminal cysteines in Ras-related GTPases of a single family, the Rab family, Ypt/Sec4 in lower eukaryotes, that terminate in XXCC, XCXC and CCXX motifs, reaction only if Rab is bound to a carrier protein termed Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme attaches geranylgeranyl groups to two C-terminal cysteines in Ras-related GTPases of a single family, the Rab family, Ypt/Sec4 in lower eukaryotes, that terminate in XXCC, XCXC and CCXX motifs, reaction only if Rab is bound to a carrier protein termed Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme attaches geranylgeranyl groups to two C-terminal cysteines in Ras-related GTPases of a single family, the Rab family, Ypt/Sec4 in lower eukaryotes, that terminate in XXCC, XCXC and CCXX motifs, reaction only if Rab is bound to a carrier protein termed Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme attaches geranylgeranyl groups to two C-terminal cysteines in Ras-related GTPases of a single family, the Rab family, Ypt/Sec4 in lower eukaryotes, that terminate in XXCC, XCXC and CCXX motifs, reaction only if Rab is bound to a carrier protein termed Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme catalyses the transfer of two 20-carbon geranylgeranyl groups from geranylgeranyl diphosphate onto C-terminal cysteine residues of Rab-proteins
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme catalyses the transfer of two 20-carbon geranylgeranyl groups from geranylgeranyl diphosphate onto C-terminal cysteine residues of Rab-proteins
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
Rab protein forms a stable complex with Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
Rab protein forms a stable complex with Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
Rab protein forms a stable complex with Rab escort protein, REP
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
substrate are three tomato cDNAs endcoding Rab-like proteins: LeRab1A, B and C with mutant and wild-type prenylation motif, LeRab1B is the best substrate for the plant enzyme, but LeRab1A is the best substrate for yeast enzyme
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
P53611
GDP-bound form of Rab3 is preferred substrate of enzyme
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
the Rab protein Rab8-GTPase, which end with a Cys-Val-Leu-Leu motif able to serve as a substrate for either geranylgeranyl transferase I and II, but modified predominantly by either geranylgeranyl transferase II in vivo
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
this posttranslational modification is essential for the biological activity of Rab proteins
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
the enzyme catalyzes posttranslational modification of proteins, the farnesyl moieties attached to the substrates are directly involved in protein-protein interactions as well as in protein-membrane interactions, substrate motif: carboxy-terminal motifs such as -CC, -CXC, -CCX, -CCXX, -CCXXX, or CXXX
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
Saccharomyces cerevisiae JRY1550
-
enzyme attaches geranylgeranyl groups to two C-terminal cysteines in Ras-related GTPases of a single family, the Rab family, Ypt/Sec4 in lower eukaryotes, that terminate in XXCC, XCXC and CCXX motifs, reaction only if Rab is bound to a carrier protein termed Rab escort protein, REP
-
?
geranylgeranyl diphosphate + Rab
S-geranylgeranyl-Rab + diphosphate
show the reaction diagram
-
His6- and gluthathione S-transferase-tagged Rab proteins such as canine Rab1a, human Rab27a, Rab5a, Rab18, Rab6a, Rab13, and mouse Rab23
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
intracellular vesicular trafficking is regulated by Rab proteins, small GTPases that require posttranslational geranylgeranylation for biological activity, which is catalyzed by the enzyme, a Rab geranylgeranyl transferase in complex with the Rab escort protein, REP, overview
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
intracellular vesicular trafficking is regulated by Rab proteins, small GTPases that require posttranslational geranylgeranylation for biological activity, which is catalyzed by the enzyme, a Rab geranylgeranyl transferase together with the Rab escort protein, REP, overview
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
Rab proteins are members of the Ras superfamily of GTPases and are key regulators of intracellular vesicular transport, they undergo a cycle of GTPase activity, and this activity is interconnected to a cycle of reversible attachment to membranes. This cycle is mediated by geranylgeranylation of usually two C-terminal cysteines, which in turn is effected by Rab geranylgeranyltransferase in concert with Rab escort protein REP, Rab prenylation, delivery to membranes and the GTPase cycle, overview, alternative and classical pathways, overview
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
with recombinantly expressed His6-tagged Saccharomyces cerevisiae Rab GTPase Ypt1 and Nicotiana tabacum NtaRabA1a in vitro substrates, overview
-
-
?
geranylgeranyl diphosphate + Rab-protein-cysteine
S-geranylgeranyl-Rab-protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + Rab1A
?
show the reaction diagram
-
substrate motif: -XXCC
-
-
?
geranylgeranyl diphosphate + Rab1B
?
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + Rab3A
?
show the reaction diagram
-
substrate motif: -XCXC
-
-
?
geranylgeranyl diphosphate + Rab5A
?
show the reaction diagram
-
substrate motif: -CCXX
-
-
?
geranylgeranyl diphosphate + Rab7 protein
S-geranylgeranyl-Rab7 protein + diphosphate
show the reaction diagram
-
the N-terminal Cys207 is preferred to Cys205, activity with Rab7 mutants, overview
-
-
?
geranylgeranyl diphosphate + Rab8
?
show the reaction diagram
-
the Rab protein Rab8-GTPase, which end with a Cys-Val-Leu-Leu motif able to serve as a substrate for either geranylgeranyl transferase I and II, but modified predominantly by either geranylgeranyl transferase II in vitro, but the mutation of Y78D prevents Rab8 from serving as a substrate
-
-
?
[3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)dodeca-2,6,10-trien-1] diphosphate + Rab7 protein
?
show the reaction diagram
-
i.e. NBD-FPP, a fluorescent analogue of geranylgeranyl diphosphate, which is a lipid donor for RabGGTase
product is mono-NBD-farnesylated Rab7:REP-1 complex
-
?
geranylgeranyl diphosphate + Ypt1p
?
show the reaction diagram
Saccharomyces cerevisiae, Saccharomyces cerevisiae JRY1550
-
yeast enzyme catalyses the prenylation of Ypt1p in the presence of an escort protein, Msi4p
-
-
?
additional information
?
-
-
farnesyl diphosphate and geranylgeranyl diphosphate bind to enzyme with very similar rate constant, but the binding mechanism of farnesyl diphosphate differs from that of geranylgeranyl diphosphate, shortening of the isoprenoid chain leads to a drastic decreases in affinity
-
-
-
additional information
?
-
-
the affinity of the mono-prenylated Rab7/REP-1 complex is very close to that observed for double prenylated Rab7/REP-1 complex binding to enzyme
-
-
-
additional information
?
-
-
yeast enzyme binding of farnesyl diphosphate is as weaker as of geranylgeranyl diphosphate, the length of isoprenoids has an influence on their affinity for enzyme, but unlike the mammalian enzyme, yeast enzyme binds prenylated and unprenylated Yptp/Mrs6p complex with similar affinities, phosphoisoprenoids do not influence the affinity of Mrs6p for yeast enzyme
-
-
-
additional information
?
-
P53611
the C-terminal cysteines of Rab3a contribute to the interaction with enzyme
-
-
-
additional information
?
-
-
reduction in RabGGT function can be sufficient to induce cancer cell lines to undergo p53-independent apoptosis
-
-
-
additional information
?
-
-
RabGGTase, which prenylates more than 60 members of the Rab GTPase family, can act on its protein substrates only when they are complexed to an additional factor termed REP, Rab escort protein
-
-
-
additional information
?
-
-
structural and mechanistic basis for recycling of Rab proteins between membrane compartments, overview
-
-
-
additional information
?
-
-
the enzyme is complexed with the Rab escort protein, REP, recombinant Arabidopsis thaliana REP interacts with yeast 6His-Ypt1, tobacco 6His-RabA1a, and Arabidopsis RabA2a in vitro preferring the GDP-bound form of the latter, overview, enzyme activity with different REPs, wild-type and mutant REPs, and involved REP residues, overview
-
-
-
additional information
?
-
-
the enzyme is complexed with the Rab escort protein, REP, which is essential for enzyme activity, binary complex structure, overview
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
geranylgeranyl diphosphate + Arabidopsis thaliana RAB-ATa protein
S-geranylgeranyl-RAB GTPase + diphosphate
show the reaction diagram
-
homozygous insertion mutants (rgtb1-1 and rgtb1-2) of the major beta-subunit of Arabidopsis enzyme (RGTB1) lead to reduced enzyme activity (about 25%), 50 mM phosphate buffer, pH 7.6, 10 mM MgCl2, 5 mM DTT, 0.5 microM tritium-labelled all trans-geranylgeranyl pyrophosphate, 4 microg recombinant Arabidopsis thaliana RAB-A2a protein, 32C, 40 min
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
-
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
the Rab protein Rab8-GTPase, which end with a Cys-Val-Leu-Leu motif able to serve as a substrate for either geranylgeranyl transferase I and II, but modified predominantly by either geranylgeranyl transferase II in vivo
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
this posttranslational modification is essential for the biological activity of Rab proteins
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
-
-
-
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
show the reaction diagram
-
the enzyme catalyzes posttranslational modification of proteins, the farnesyl moieties attached to the substrates are directly involved in protein-protein interactions as well as in protein-membrane interactions
-
-
?
geranylgeranyl diphosphate + Rab
S-geranylgeranyl-Rab + diphosphate
show the reaction diagram
-
His6- and gluthathione S-transferase-tagged Rab proteins such as canine Rab1a, human Rab27a, Rab5a, Rab18, Rab6a, Rab13, and mouse Rab23
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
intracellular vesicular trafficking is regulated by Rab proteins, small GTPases that require posttranslational geranylgeranylation for biological activity, which is catalyzed by the enzyme, a Rab geranylgeranyl transferase in complex with the Rab escort protein, REP, overview
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
intracellular vesicular trafficking is regulated by Rab proteins, small GTPases that require posttranslational geranylgeranylation for biological activity, which is catalyzed by the enzyme, a Rab geranylgeranyl transferase together with the Rab escort protein, REP, overview
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
show the reaction diagram
-
Rab proteins are members of the Ras superfamily of GTPases and are key regulators of intracellular vesicular transport, they undergo a cycle of GTPase activity, and this activity is interconnected to a cycle of reversible attachment to membranes. This cycle is mediated by geranylgeranylation of usually two C-terminal cysteines, which in turn is effected by Rab geranylgeranyltransferase in concert with Rab escort protein REP, Rab prenylation, delivery to membranes and the GTPase cycle, overview, alternative and classical pathways, overview
-
-
?
additional information
?
-
-
reduction in RabGGT function can be sufficient to induce cancer cell lines to undergo p53-independent apoptosis
-
-
-
additional information
?
-
-
RabGGTase, which prenylates more than 60 members of the Rab GTPase family, can act on its protein substrates only when they are complexed to an additional factor termed REP, Rab escort protein
-
-
-
additional information
?
-
-
structural and mechanistic basis for recycling of Rab proteins between membrane compartments, overview
-
-
-
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
additional information
-
the enzyme is absolutely dependent on the Rab escort protein, REP, cloning and expression of His-tagged REP in Escherichia coli, and purification, overview
-
additional information
-
RabGGTase can act on its protein substrates only when they are complexed to an additional factor termed REP, Rab escort protein
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Mg2+
-
requirement, KM 0.5 mM
Mg2+
-
not requirement
Mg2+
-
requirement, optimal concentration at 8 mM
Zn2+
-
the location of the zinc ion in the beta subunit, where it is coordinated by Asp238beta, Cys240beta and His290beta, the fourth ligand is residue His2alpha
Zn2+
-
requirement, optimal concentration at 0.008 mM, zinc content: 0.7-0.12 mol/mol enzyme
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(2-[(1-geranylgeranyl)-1H-1,2,3-triazol-4-yl]ethane-1,1-diyl)bis(phosphonate)
-
compound is able to induce cytotoxicity in human myeloma cells, IC50 value 1 mM
(2R,3R,4S,5R)-2-(3,4-dichlorophenyl)-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]-5-propylpyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-1-[(4-methylphenyl)sulfonyl]-4-(pentylsulfanyl)-5-propylpyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]-5-propylpyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-4-[(4-methoxyphenyl)sulfanyl]-1-[(4-methylphenyl)sulfonyl]-5-propylpyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-5-ethyl-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-5-hexyl-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-4-[(3-tert-butoxy-3-oxopropyl)sulfanyl]-2-(3-chlorophenyl)-5-(cyclopentylmethyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-4-[(3-tert-butoxy-3-oxopropyl)sulfanyl]-2-(4-chlorophenyl)-1-[(4-chlorophenyl)sulfonyl]-5-(cyclopentylmethyl)pyrrolidine-3-carboxylic acid
-
-
(2R,3R,4S,5R)-4-[(3-tert-butoxy-3-oxopropyl)sulfanyl]-2-(4-chlorophenyl)-5-(cyclopentylmethyl)-1-(phenylsulfonyl)pyrrolidine-3-carboxylic acid
-
-
(2S,5S)-5-tert-butyl-2-(4-chlorophenyl)-1-[(2-methylphenyl)sulfonyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid
-
slight inhibition of RabGGTase at concentrations above 0.01 mM
2-(2-pyridyl)-1-ethylidene-1,1-phosphonocarboxylic acid
-
i.e.2-PEPC, protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
-
2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid
-
causes rapid accumulation of unprenylated Rabs within the cytosol of osteoclasts and macrophages due to specific inhibition of Rab GGTase
2-(3-pyridinyl)-1-hydroxyethylidene-1,1-bisphosphonic acid
-
causes rapid accumulation of unprenylated Rabs within the cytosol of osteoclasts and macrophages due to specific inhibition of Rab GGTase
2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid
-
causes rapid accumulation of unprenylated Rabs within the cytosol of osteoclasts and macrophages due to specific inhibition of Rab GGTase
2-bromo-3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
2-chloro-3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
2-fluoro-3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
3-PEHPC, weak inhibitor, 100% activity remain with concentrations up to 1 microM inhibitor and substrate Rab1a, with 10 microM inhibitor about 60% activity remain, with 100 microM and more inhibitor the activity falls to 30% and below
2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid
-
(+)-3-IPEHPC, the (+)-enantiomer is selective towards the enzyme and more potent than the (-)-enantiomer, mixed type inhibitor with respect to geranylgeranyl diphosphate, uncompetitive inhibitor with respect to Rab substrate, 25fold more potent than 2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid, with 1 microM inhibitor activity falls to about 50%, with 10 microM inhibitor and more activity falls below 20%
3-(1-methylpyridin-1-ium-3-yl)-2-phosphonopropanoate
-
i.e.NE1048 , protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
-
3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
3-(3-pyridyl)-1-ethylidene-1,1-phosphonocarboxylic acid
-
i.e.3-PEPC, protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
-
3-(3-pyridyl)-2-hydroxy-2-phosphonocarboxylic acid
-
i.e.3-PEHPC, protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
-
3-pyridinyl ethylidene hydroxyl phosphonocarboxylate
-
previously known as NE10790
KCl
-
50% inhibition at 100 mM
N-([[2-(benzyloxy)benzyl]oxy]carbonyl)-D-histidyl-L-tyrosyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-([[2-(benzyloxy)benzyl]oxy]carbonyl)-L-histidyl-L-tyrosyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-butanoyl-L-histidyl-L-phenylalanyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-octanoyl-L-histidyl-L-phenylalanyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-pentadecanoyl-L-histidyl-L-phenylalanyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-undecanoyl-L-histidyl-L-histidyl-N-(4-aminobutyl)-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-undecanoyl-L-histidyl-L-histidyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide), not cytotoxic to COS-7 cells, fluorescence titration reveals competitive inhibition
N-undecanoyl-L-histidyl-L-phenylalanyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide), not cytotoxic to COS-7 cells, fluorescence titration reveals partial competitive inhibition which points to a different binding site
N-undecanoyl-L-histidyl-L-phenylalanyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-undecanoyl-L-tyrosyl-L-histidyl-N-(4-aminobutyl)-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-undecanoyl-L-tyrosyl-L-histidyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide), not cytotoxic to COS-7 cells, fluorescence titration reveals competitive inhibition
N-[(2,5-dimethyl-1,3-oxazol-4-yl)carbonyl]glycyl-L-phenylalanyl-1-trityl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2,5-dimethyl-1,3-oxazol-4-yl)carbonyl]glycyl-L-phenylalanyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]-1-trityl-L-histidylglycyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]-1-trityl-L-histidylglycyl-L-phenylalanine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]-L-histidylglycyl-1-trityl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus), not cytotoxic to COS-7 cells, fluorescence titration reveals competitive inhibition
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]-L-histidylglycyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]glycyl-L-phenylalanyl-1-(tert-butoxycarbonyl)-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]glycyl-L-phenylalanyl-1-benzyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]glycyl-L-phenylalanyl-1-trityl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]glycyl-L-phenylalanyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]histidylglycyl-L-phenylalanine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[(2E)-3-(biphenyl-4-yl)prop-2-enoyl]-D-histidyl-L-tyrosyl-L-tyrosine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-[(2E)-3-[2-[(1Z)-pent-1-en-1-yl]phenyl]prop-2-enoyl]-D-histidyl-L-tyrosyl-D-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-[(benzyloxy)carbonyl]-D-tyrosyl-L-phenylalanyl-L-tyrosine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), fluorescence titration reveals competitive inhibition
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-L-tyrosine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), fluorescence titration reveals competitive inhibition
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-D-tyrosinamide
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-L-tryptophanamide
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), not cytotoxic to COS-7 cells
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-L-tyrosinamide
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), not cytotoxic to COS-7 cells
N-[3-(4-pentylphenyl)propanoyl]-D-histidyl-N-methyl-L-phenylalanyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-[3-(4-pentylphenyl)propanoyl]-D-tyrosyl-L-tyrosyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini)
N-[4-(undecyloxy)benzoyl]-L-histidyl-L-histidyl-N-(4-aminobutyl)-L-histidinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-[4-(undecyloxy)benzoyl]-L-histidyl-L-histidyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-histidinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-[4-(undecyloxy)benzoyl]-L-histidyl-L-tyrosyl-N-[3-(1H-imidazol-1-yl)propyl]-L-phenylalaninamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-[4-(undecyloxy)benzoyl]-L-tyrosyl-L-tyrosyl-N-(4-aminobutyl)-L-tyrosinamide
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
N-[[2-(pyridin-3-yl)-1,3-thiazol-4-yl]carbonyl]glycyl-L-phenylalanyl-1-trityl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[[2-(pyridin-3-yl)-1,3-thiazol-4-yl]carbonyl]glycyl-L-phenylalanyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[[2-(thiophen-2-yl)-1,3-thiazol-4-yl]carbonyl]glycyl-L-phenylalanyl-1-trityl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
N-[[2-(thiophen-2-yl)-1,3-thiazol-4-yl]carbonyl]glycyl-L-phenylalanyl-L-histidine
-
class II inhibitors (combining a heterocyclic ring system at the N-terminus with a free carboxylate at the C-terminus)
NaCl
-
50% inhibition at 100 mM
NaOAc
-
50% inhibition at 100 mM
NE10790
-
a weak bisphosphonate inhibitor
risedronate
-
-
Zn2+
-
in the presence of saturating concentrations of MgCl2 100% inhibition at 0.2 mM
Zn2+
-
at concentrations above 0.01 mM
methyl N-undecanoyl-L-tyrosyl-L-histidyl-L-tyrosinate
-
class III inhibitors (comprising a lipophilic N-terminus and an amine or N-heterocycle containing a C-terminal amide)
additional information
-
perillyl alcohol inhibits insulin induced activation of enzyme, but not GGTI-298 and alpha-hxdroxyfarnesylphosphonic acid, PD 98056 inhibits the ability of insulin to increase the amount of geranylgeranylated Rab3 and Rab4 proteins
-
additional information
-
plant enzyme is inhibited by mutant Rab lacking a prenylation consence sequence
-
additional information
-
peptidic library based on the farnesyl transferase inhibitor pepticinnamin E, a natural tripeptide from Streptomyces OH-4652
-
additional information
-
protein geranylgeranyltransferase-II is the major pharmacological target of phosphonocarboxylate inhibitors. Analysis of several different phosphonocarboxylate drugs demonstrates a very good correlation between the ability of these drugs to inhibit the enzyme with their ability to reduce macrophage cell viability and induce apoptosis
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
Nonidet P-40
-
the plant enzyme activity is enhanced by detergent
Nonidet P-40
-
the plant enzyme activity is enhanced by detergent
Nonidet P-40
-
in assay requirement
Rab escort protein
-
RGGT increases the ability of Rab escort protein to extract endogenous prenylated Rabs from membranes in vitro by stabilizing a soluble Rab escort protein-RGGT-geranylgeranylated Rab complex
-
Insulin
-
promotes the phosphorylation of the alpha subunit of enzyme without an effect on beta subunit, and activation of enzyme, insulin increases the amount of geranylgeranylated Rab3 and Rab4 proteins
-
additional information
-
the enzyme is absolutely dependent on the Rab escort protein, REP, cloning and expression of His-tagged REP in Escherichia coli, and purification, overview, recombinant Arabidopsis thaliana REP-6His stimulates Rab geranylgeranylation activity in plant but not yeast cell extracts, overview
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.00002
-
geranylgeranyl diphosphate
-
pH 7.2, 37C
0.00002
-
Rab3A
-
pH 7.2, 37C
-
0.0011
-
Ypt1p
-
pH 7.3, 30C
-
0.0016
-
geranylgeranyl diphosphate
-
pH 7.3, 30C
additional information
-
additional information
-
yeast enzyme displays significantly lower affinity for its reaction product than its mammalian counterpart
-
additional information
-
additional information
P53611
comparison of KM of Rab3a proteins
-
additional information
-
additional information
-
-
-
additional information
-
additional information
-
kinetics
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.013
-
Rab protein
-
pH 7.2, 37C
-
additional information
-
additional information
-
double prenylation the rate for the first prenyl transfer reaction is 0.00026/min, while the second prenyl transfer reaction is 4fold slower
-
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.005
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
mixed-type inhibition with geranylgeranyl diphosphate 1 as variable substrate, 50 mM sodium HEPES, pH 7.2, 5 mM MgCl2, 1 mM Nonidet P-40, 1 mM dithioerythritol, 4 microM Rab1a, 50 nM enzyme, 20 min, 37C
0.0011
-
N-undecanoyl-L-histidyl-L-histidyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
displacement titration
0.0054
-
N-undecanoyl-L-histidyl-L-phenylalanyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
displacement titration
0.0028
-
N-undecanoyl-L-tyrosyl-L-histidyl-N-methyl-N-[2-(pyridin-2-yl)ethyl]-L-tyrosinamide
-
displacement titration
0.0053
-
N-[(2-phenyl-1,3-oxazol-4-yl)carbonyl]-L-histidylglycyl-1-trityl-L-histidine
-
displacement titration
0.0045
-
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-L-tyrosine
-
9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme; displacement titration
0.0145
-
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-L-tyrosinamide
-
displacement titration
0.03356
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
uncompetitive reaction with Rab1a as variable substrate, 50 mM sodium HEPES, pH 7.2, 5 mM MgCl2, 1 mM Nonidet P-40, 1 mM dithioerythritol, 5 microM geranylgeranyl diphosphate 1, 50 nM enzyme, 20 min, 37C
additional information
-
additional information
-
inhibition kinetics
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.1
-
(2-[(1-geranylgeranyl)-1H-1,2,3-triazol-4-yl]ethane-1,1-diyl)bis(phosphonate)
-
temperature not specified in the publication, pH not specified in the publication
0.007
-
(2R,3R,4S,5R)-2-(3,4-dichlorophenyl)-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]-5-propylpyrrolidine-3-carboxylic acid
-
-
0.0036
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-1-[(4-methylphenyl)sulfonyl]-4-(pentylsulfanyl)-5-propylpyrrolidine-3-carboxylic acid
-
-
0.0021
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]-5-propylpyrrolidine-3-carboxylic acid
-
-
0.0045
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-4-[(4-methoxyphenyl)sulfanyl]-1-[(4-methylphenyl)sulfonyl]-5-propylpyrrolidine-3-carboxylic acid
-
-
0.0048
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-5-ethyl-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid
-
-
0.0022
-
(2R,3R,4S,5R)-2-(4-bromophenyl)-5-hexyl-4-(hexylsulfanyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid
-
-
0.0047
-
(2R,3R,4S,5R)-4-[(3-tert-butoxy-3-oxopropyl)sulfanyl]-2-(3-chlorophenyl)-5-(cyclopentylmethyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine-3-carboxylic acid
-
-
0.0031
-
(2R,3R,4S,5R)-4-[(3-tert-butoxy-3-oxopropyl)sulfanyl]-2-(4-chlorophenyl)-1-[(4-chlorophenyl)sulfonyl]-5-(cyclopentylmethyl)pyrrolidine-3-carboxylic acid
-
-
0.007
-
(2R,3R,4S,5R)-4-[(3-tert-butoxy-3-oxopropyl)sulfanyl]-2-(4-chlorophenyl)-5-(cyclopentylmethyl)-1-(phenylsulfonyl)pyrrolidine-3-carboxylic acid
-
-
0.0177
-
2-bromo-3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
0.0164
-
2-chloro-3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
0.0163
-
2-fluoro-3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
0.03185
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
50 mM sodium HEPES, pH 7.2, 5 mM MgCl2, 1 mM Nonidet P-40, 1 mM dithioerythritol, 6 microM tritium-labelled geranylgeranyl diphosphate, 4 microM Rab1a-CC (wild type), 2 microM Rab escort protein 1, 50 nM enzyme, 20 min, 37C
0.03268
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
50 mM sodium HEPES, pH 7.2, 5 mM MgCl2, 1 mM Nonidet P-40, 1 mM dithioerythritol, 6 microM tritium-labelled geranylgeranyl diphosphate, 4 microM Rab27a-CGC (wild type), 2 microM Rab escort protein 1, 50 nM enzyme, 20 min, 37C
0.04347
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
50 mM sodium HEPES, pH 7.2, 5 mM MgCl2, 1 mM Nonidet P-40, 1 mM dithioerythritol, 6 microM tritium-labelled geranylgeranyl diphosphate, 4 microM Rab5a-CCSN (wild type), 2 microM Rab escort protein 1, 50 nM enzyme, 20 min, 37C
0.86
-
2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid
-
50 mM sodium HEPES, pH 7.2, 5 mM MgCl2, 1 mM Nonidet P-40, 1 mM dithioerythritol, 6 microM tritium-labelled geranylgeranyl diphosphate, 4 microM Rab5a-CCVLL, 2 microM Rab escort protein 1, 50 nM enzyme, 20 min, 37C
0.0353
-
3-(3-pyridinyl)-2-phosphonopropionic acid
-
-
0.0156
-
N-([[2-(benzyloxy)benzyl]oxy]carbonyl)-D-histidyl-L-tyrosyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0193
-
N-([[2-(benzyloxy)benzyl]oxy]carbonyl)-L-histidyl-L-tyrosyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0227
-
N-[(2E)-3-(biphenyl-4-yl)prop-2-enoyl]-D-histidyl-L-tyrosyl-L-tyrosine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0152
-
N-[(2E)-3-[2-[(1Z)-pent-1-en-1-yl]phenyl]prop-2-enoyl]-D-histidyl-L-tyrosyl-D-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0041
-
N-[(benzyloxy)carbonyl]-D-tyrosyl-L-phenylalanyl-L-tyrosine
-
most potent of the class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0227
-
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-L-tyrosine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0136
-
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-D-tyrosinamide
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0052
-
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-L-tryptophanamide
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.009
-
N-[(benzyloxy)carbonyl]-L-histidyl-N-methyl-L-phenylalanyl-N-hydroxy-L-tyrosinamide
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.019
-
N-[3-(4-pentylphenyl)propanoyl]-D-histidyl-N-methyl-L-phenylalanyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.011
-
N-[3-(4-pentylphenyl)propanoyl]-D-tyrosyl-L-tyrosyl-L-phenylalanine
-
class I inhibitors (compounds possessing a free carboxylic or hydroxamic acid at the C-terminus and lipophilic N-termini), 9 microM (3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)-dodeca-2,6,19-trien-1) diphosphate, 3 microM Rab7, 3 microM Rab escort protein, 400 nM enzyme
0.0241
-
3-pyridinyl ethylidene hydroxyl phosphonocarboxylate
-
-
additional information
-
additional information
-
the inhibitory action of 2-hydroxy-2-phosphono-3-pyridin-3-yl-propionic acid with substrates Rab1a-CSC and Rab1a-CCS are not determined, and is not significant (IC50 > 2 mM) with the substrates Rab1a-CS, Rab1aSC, Rab27a-CVLS, Rab5a-CCQNI, Rab5a-CVLL, Rab13-CSLG (wild type), Rab18-CSVL (wild type), and Rab23-CSVP (wild type), and IC50 > 1.592 mM with Rab6a-CSC
-
additional information
-
additional information
-
chemicals that cause an activity decrease of more than 70% at 100 microM are selected for inhibition studies
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
development of a continuous fluorometric assay using a protein fluorescence amplifier, overview
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.2
-
-
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
adenocarcinoma of colon, significant overexpression of RabGGT-beta compared to normal tissue
Manually annotated by BRENDA team
-
both beta subunit levels are similar in male gametophytes, subunit A1 is expressed in all tissues, subunit A2 is expressed significantly only in pollen
Manually annotated by BRENDA team
-
expression of both alpha- and beta-subunit of enzyme as well as Rab escort protein-1
Manually annotated by BRENDA team
-
large cell lung carcinomas, significant overexpression of RabGGT-beta compared to normal tissue
Manually annotated by BRENDA team
-
significant overexpression of RabGGT-beta and Rab-GGT-alpha compared to normal tissue
Manually annotated by BRENDA team
-
significant overexpression of RabGGT-beta and RabGGT-alpha compared to normal tissue
Manually annotated by BRENDA team
-
expression of both alpha- and beta-subunit of enzyme as well as Rab escort protein-1
Manually annotated by BRENDA team
-
subunit B1 is about 10times more abundant in sporophytes than subunit B2, subunit A1 is expressed in all tissues
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
subcellular localization study, overview
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
38000
-
-
theoretical molecular weight of c-Myc-protein-labelled Rabggtb
100000
-
-
-
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
heterodimer
-
alpha,beta, 1 * 60000 + 1 * 38000
heterodimer
-
alpha,beta, 1 * 60000 + 1 * 38000
heterodimer
-
-
heterodimer
-
alpha,beta
heterodimer
-
alpha,beta, but structural differences between enzyme of higher and lower eukaryotes
heterodimer
-
x-ray crystallography
heterodimer
-
2 * ?, computational model based on crystals of subcomplexes
additional information
-
yeast enzyme does not possess the immunoglobulin-like domain and a leucine-rich repeat domain found in mammalian enzyme
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
enzyme-inhibitor complex with an engeneered enyzme lacking the LRR- and Ig-domains, complexes are prepared by soaking of co-crystallization, diffraction data collection at -173C
-
at 2.0 Angstrom resolution, the beta subunit forms an alpha-alpha barrel that contains most of the residues in the active site, the alpha subunit consists of a helical domain, an immunoglobulin-like domain and a leucine-rich repeat domain, the N-terminal alpha subunit binds to the active site in the beta subunit
-
at 2.7 Angstom, crystal structure of REP-1 in complex with farnesyl-loaded enzyme, contact between the two proteins is formed through domain II of REP-1 and the alpha subunit of the enzyme
-
in complex with geranylgeranyl diphosphate, hanging drop vapour diffusion method, with 14% (w/v) PEG 3350, 0.2M CaAc2, 0.1 M HEPES pH 7.2
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
fresh plant material is frozen in liquid nitrogen, ground on ice with acid-washed sand in 100 mM Tris buffer, pH 7.8, containing 5 mM EGTA, 5 mM EDTA, 10 mM beta-mercaptoethanol, and 10% glycerol, lysate is centrifuged, dialyzed against 50 mM Tris buffer, pH 7.8, containing 10% glycerol, and 1 mM DTT
-
nickel-Sepharose affinity chromatography
-
component B
-
recombinant enzyme
-
recombinant enzyme
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cloning of the beta subunit of enzyme by means of the yeast two-hybrid system
P53611
expressed in Sf9 cells
-
expression in Sf9 cells with recombinant baculovirus
-
development of a two plasmid expression system in Escherichia coli that achieves large quantities of enzyme
-
expressed in Escherichia coli
-
expression in SF21 cells
-
recombinant enzyme produced in baculovirus and Escherichia coli system
-
recombinant enzyme produced in insect cells
-
expression in Escherichia coli
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
recombinant Arabidopsis thaliana REP interacts with yeast 6His-Ypt1, tobacco 6His-RabA1a, and Arabidopsis RabA2a in vitro preferring the GDP-bound form of the latter
additional information
-
homozygous insertion mutants (rgtb1-1 and rgtb1-2) of the major beta-subunit of Arabidopsis enzyme (RGTB1) lead to reduced enzyme activity (about 25%) and result in unprenylated RAB GTPase accumulation in the cytoplasm, up-regulation (50% and more) of about one third of RAB-GTPase paralogs in dark-grown plants compared to light-grown plants, down-regulation of about one tenth, endocytosis and exocytosis are downregulated in homozygotes defective in shoot growth and morphogenesis, root gravitropism is normal but compromised in shoots, etiolation is defective, mutants show constitutive photomorphogenic phenotypes, smaller rosette diameter, loss of apical dominance
additional information
-
mutant Rab7 substrates with truncated C-terminal show that a lack of more than 3 residues leads to dramatic reduction in Rab prenylation efficiency of the enzyme, residual prenylation activity with 4-5 lacking residues, further reduction abolishes the ability of Rab7 to be an enzyme substrate
additional information
-
enyzme lacking the LRR- and Ig-domains for crystallization complexes
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
RabGGT is a therapeutically relevant target for modulation of apoptosis
medicine
-
siRNA-mediated knockdown of alpha- or beta-subunits of the enzyme and Rab escort protein-1 markedley attenuates glucose-stimulated insulin secretion in INS-1 832/13 cells