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Information on EC 2.5.1.60 - protein geranylgeranyltransferase type II
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2.5.1.60 protein geranylgeranyltransferase type IIIUBMB Comments
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 .
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Word Map
- 2.5.1.60
- gtpases
- endosomes
-
geranylgeranylation
-
prenylation
- vesicular
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escort
-
traffic
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endocytic
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cargo
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rab11b
- choroideremia
- rab3a
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gdp-bound
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rab11-fip2
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farnesyltransferase
- prenyltransferase
- ftase
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hermansky-pudlak
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rab11-positive
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pericentrosomal
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unprenylated
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rabgdis
- medicine
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rab11-dependent
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
rab11a, rabggtase, rab geranylgeranyl transferase, rab geranylgeranyltransferase, ggtase-ii, rab ggtase, rab gg transferase, rabggt, rabggtb, rgtb1, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
geranylgeranyltransferase type II
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GGTase-II
GGTaseII
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PGGT-II
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protein geranylgeranyltransferase type-II
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Rab geranylgeranyl transferase
Rab geranylgeranyltransferase
Rab geranylgeranyltransferase type II
Rab GG transferase
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Rab GGTase
RAB-GGT
RabGGT
RabGGTase
Rabggtb
REP/GGTase
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RGGT
RGT alphabeta
GGTase-II
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Rab geranylgeranyl transferase
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Rab geranylgeranyltransferase
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RabGGTase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
mechanism
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
mechanism, recombinant enzyme/REP-1 complex catalyzes the geranylgeranylation of both adjacent cysteines in Rab1A, Rab3A and Rab5A
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
mechanism of enzyme/REP-complex formation
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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.
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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.
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
mechanism, phosphoisoprenoid acts both as a substrate and as a sensor governing the kinetics of protein protein interactions in the double prenylation reaction
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
the yeast enzyme follows only the classical pathway
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
prenylation mechanism of Rab potein by the RabGGTase:GGpp complex, overview
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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
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geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl-protein + diphosphate
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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].
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CAS REGISTRY NUMBER
COMMENTARY
135371-29-8
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
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
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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, 25°C, 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 25°C
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?
(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
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geranylgeranyl diphosphate analogue and Rab7 as substrates in the presence of Rab escort protein, in vitro inhibition assays
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?
biotinylated geranyl diphosphate + EYFP-Rab7
S-biotin-geranyl-Rab7 + diphosphate
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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
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?
geranylgeranyl diphosphate + Arabidopsis thaliana RAB-ATa protein
S-geranylgeranyl-RAB GTPase + diphosphate
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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, 32°C, 40 min
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?
geranylgeranyl diphosphate + FBXL2
geranylgeranyl-FBXL2 + diphosphate
P53611; Q7Z6K3
FBXL2 is an ubiquitin-ligase
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?
geranylgeranyl diphosphate + Rab
S-geranylgeranyl-Rab + diphosphate
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His6- and gluthathione S-transferase-tagged Rab proteins such as canine Rab1a, human Rab27a, Rab5a, Rab18, Rab6a, Rab13, and mouse Rab23
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?
geranylgeranyl diphosphate + Rab-protein-cysteine
S-geranylgeranyl-Rab-protein + diphosphate
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?
geranylgeranyl diphosphate + Rab7 protein
S-geranylgeranyl-Rab7 protein + diphosphate
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the N-terminal Cys207 is preferred to Cys205, activity with Rab7 mutants, overview
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?
geranylgeranyl diphosphate + Rab8
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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
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?
[3,7,11-trimethyl-12-(7-nitrobenzo[1,2,5]oxadiazo-4-ylamino)dodeca-2,6,10-trien-1] diphosphate + Rab7 protein
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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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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Rab protein forms a stable complex with Rab escort protein, REP
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
GDP-bound form of Rab3 is preferred substrate of enzyme
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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substrate motif: carboxy-terminal motifs such as -CC, -CXC, -CCX, -CCXX, -CCXXX, or CXXX
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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substrate are Rab3 and Rab4
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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enzyme catalyses the transfer of two 20-carbon geranylgeranyl groups from geranylgeranyl diphosphate onto C-terminal cysteine residues of Rab-proteins
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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enzyme catalyses the transfer of two 20-carbon geranylgeranyl groups from geranylgeranyl diphosphate onto C-terminal cysteine residues of Rab-proteins
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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this posttranslational modification is essential for the biological activity of Rab proteins
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
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-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
-
-
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
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
-
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
-
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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
Rab protein forms a stable complex with Rab escort protein, REP
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
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Rab protein forms a stable complex with Rab escort protein, REP
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
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
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?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
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
-
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
-
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 + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
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
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-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
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
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-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
with recombinantly expressed His6-tagged Saccharomyces cerevisiae Rab GTPase Ypt1 and Nicotiana tabacum NtaRabA1a in vitro substrates, overview
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-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
-
-
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?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
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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
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?
geranylgeranyl diphosphate + Ypt1p
?
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yeast enzyme catalyses the prenylation of Ypt1p in the presence of an escort protein, Msi4p
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?
geranylgeranyl diphosphate + Ypt1p
?
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yeast enzyme catalyses the prenylation of Ypt1p in the presence of an escort protein, Msi4p
-
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?
additional information
?
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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
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?
additional information
?
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Arabidopsis thaliana Rab geranylgeranyltransferases demonstrate redundancy and broad substrate specificity in vitro, comparisons of isozymes and subunits, respectively, overview. RGTB1 and RGTB2 are biochemically redundant Rab-GGT alpha-subunits in Arabidopsis, whereas RGTA1 is the active alpha subunit, while RGTA2 is not. Rab-GGT alpha-subunits in Arabidopsis partner with putative beta-subunits as functional Rab-GGTs. The two subunits in all of the four combinations physically interact with each other, interaction analysis
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?
additional information
?
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Arabidopsis thaliana Rab geranylgeranyltransferases demonstrate redundancy and broad substrate specificity in vitro, comparisons of isozymes and subunits, respectively, overview. RGTB1 and RGTB2 are biochemically redundant Rab-GGT alpha-subunits in Arabidopsis, whereas RGTA1 is the active alpha subunit, while RGTA2 is not. Rab-GGT alpha-subunits in Arabidopsis partner with putative beta-subunits as functional Rab-GGTs. The two subunits in all of the four combinations physically interact with each other, interaction analysis
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?
additional information
?
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Arabidopsis thaliana Rab geranylgeranyltransferases demonstrate redundancy and broad substrate specificity in vitro, comparisons of isozymes and subunits, respectively, overview. RGTB1 and RGTB2 are biochemically redundant Rab-GGT alpha-subunits in Arabidopsis, whereas RGTA1 is the active alpha subunit, while RGTA2 is not. Rab-GGT alpha-subunits in Arabidopsis partner with putative beta-subunits as functional Rab-GGTs. The two subunits in all of the four combinations physically interact with each other, interaction analysis
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?
additional information
?
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Arabidopsis thaliana Rab geranylgeranyltransferases demonstrate redundancy and broad substrate specificity in vitro, comparisons of isozymes and subunits, respectively, overview. RGTB1 and RGTB2 are biochemically redundant Rab-GGT alpha-subunits in Arabidopsis, whereas RGTA1 is the active alpha subunit, while RGTA2 is not. Rab-GGT alpha-subunits in Arabidopsis partner with putative beta-subunits as functional Rab-GGTs. The two subunits in all of the four combinations physically interact with each other, interaction analysis
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-
?
additional information
?
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Arabidopsis thaliana Rab geranylgeranyltransferases demonstrate redundancy and broad substrate specificity in vitro, comparisons of isozymes and subunits, respectively, overview. RGTB1 and RGTB2 are biochemically redundant Rab-GGT alpha-subunits in Arabidopsis, whereas RGTA1 is the active alpha subunit, while RGTA2 is not. Rab-GGT alpha-subunits in Arabidopsis partner with putative beta-subunits as functional Rab-GGTs. The two subunits in all of the four combinations physically interact with each other, interaction analysis
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?
additional information
?
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reduction in RabGGT function can be sufficient to induce cancer cell lines to undergo p53-independent apoptosis
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?
additional information
?
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the C-terminal cysteines of Rab3a contribute to the interaction with enzyme
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?
additional information
?
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reduction in RabGGT function can be sufficient to induce cancer cell lines to undergo p53-independent apoptosis
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-
?
additional information
?
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unlike the other prenyltransferases, farnesyl-transferase and geranylgeranyl-transferase I (GGTaseI), RabGGTase does not rely on a consensus sequence such as the CAAX box, but instead has delegated substrate recognition to a third protein, the Rab escort protein (REP)
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?
additional information
?
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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
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?
additional information
?
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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
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-
?
additional information
?
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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
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?
additional information
?
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-
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
?
-
-
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
?
-
-
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, which is essential for enzyme activity, binary complex structure, overview
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
geranylgeranyl diphosphate + Arabidopsis thaliana RAB-ATa protein
S-geranylgeranyl-RAB GTPase + diphosphate
-
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, 32°C, 40 min
-
-
?
geranylgeranyl diphosphate + Rab
S-geranylgeranyl-Rab + diphosphate
-
His6- and gluthathione S-transferase-tagged Rab proteins such as canine Rab1a, human Rab27a, Rab5a, Rab18, Rab6a, Rab13, and mouse Rab23
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
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
-
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
-
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 + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
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
-
this posttranslational modification is essential for the biological activity of Rab proteins
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
enzyme crucial for membrane association and function of Rab proteins in intracellular vesicular trafficking
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
-
-
-
?
geranylgeranyl diphosphate + protein-cysteine
S-geranylgeranyl-protein + diphosphate
-
reaction is critical for membrane localization of Rab proteins and for their interaction with soluble regulatory proteins
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
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
-
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
-
-
-
-
?
geranylgeranyl diphosphate + Rab protein
S-geranylgeranyl-Rab protein + diphosphate
-
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
?
-
-
reduction in RabGGT function can be sufficient to induce cancer cell lines to undergo p53-independent apoptosis
-
-
?
additional information
?
-
-
unlike the other prenyltransferases, farnesyl-transferase and geranylgeranyl-transferase I (GGTaseI), RabGGTase does not rely on a consensus sequence such as the CAAX box, but instead has delegated substrate recognition to a third protein, the Rab escort protein (REP)
-
-
?
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
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
RabGGTase can act on its protein substrates only when they are complexed to an additional factor termed REP, Rab escort protein
-
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
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Zn2+
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
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INHIBITOR
ORGANISM
UNIPROT
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-(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-fluoro-3-(1-methyl-1H-imidazol-5-yl)-2-phosphonopropanoic acid
compound inhibits isoform Rab11A, but not Rap1A/Rap1B prenylation in HeLa cells
2-fluoro-3-(1H-imidazol-4(5)-yl)-2-phosphonopropanoic acid
compound inhibits isoform Rab11A, but not Rap1A/Rap1B prenylation in HeLa cells
2-fluoro-3-(6-methylimidazo[1,2-a]pyridin-3-yl)-2-phosphonopropanoic acid
compound is an micromolar inhibitor of Rab11A prenylation, is inactive against Rap1A/Rap1B modification, and able to inhibit proliferation of HeLa cell line with IC50 value of 0.36 mM
2-fluoro-3-(6-phenylimidazo[1,2-a]pyridin-3-yl)-2-phosphonopropanoic acid
compound is an micromolar inhibitor of Rab11A prenylation, is inactive against Rap1A/Rap1B modification, and able to inhibit proliferation of HeLa cell line with IC50 value of 0.51 mM
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%
2-PEPC
-
i.e.3-PEPC, protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
3-(1-methylpyridin-1-ium-3-yl)-2-phosphonopropanoate
-
i.e.NE1048 , protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
3-(6-bromoimidazo[1,2-a]pyridin-3-yl)-2-fluoro-2-phosphonopropanoic acid
compound is an micromolar inhibitor of Rab11A prenylation, is inactive against Rap1A/Rap1B modification, and able to inhibit proliferation of HeLa cell line with IC50 value of 0.50 mM
3-(6-chloroimidazo[1,2-a]pyridin-3-yl)-2-fluoro-2-phosphonopropanoic acid
compound is an micromolar inhibitor of Rab11A prenylation, is inactive against Rap1A/Rap1B modification, and able to inhibit proliferation of HeLa cell line with IC50 value of 0.52 mM
3-PEHPC
-
i.e.3-PEHPC, protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
3-PEPC
-
i.e.2-PEPC, protein geranylgeranyltransferase-II is the major pharmacological target of the inhibitor
3-pyridinyl ethylidene hydroxyl phosphonocarboxylate
-
previously known as NE10790
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)
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