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Information on EC 2.3.1.180 - beta-ketoacyl-[acyl-carrier-protein] synthase III and Organism(s) Mycobacterium tuberculosis and UniProt Accession P9WNG3
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EC Tree
2.3.1.180 beta-ketoacyl-[acyl-carrier-protein] synthase IIIIUBMB Comments
The enzyme is responsible for initiating straight-chain fatty acid biosynthesis by the dissociated (or type II) fatty-acid biosynthesis system that occurs in plants and bacteria. In contrast to EC 2.3.1.41, beta-ketoacyl-[acyl-carrier-protein] synthase I, and EC 2.3.1.179, beta-ketoacyl-[acyl-carrier-protein] synthase II, this enzyme specifically uses short-chain acyl-CoA thioesters (preferably acetyl-CoA) rather than acyl-[acp] as its substrate . The enzyme can also catalyse the reaction of EC 2.3.1.38, [acyl-carrier-protein] S-acetyltransferase, but to a much lesser extent . The enzymes from some organisms (e.g. the Gram-positive bacterium Streptococcus pneumoniae) can accept branched-chain acyl-CoAs in addition to acetyl-CoA (cf. EC 2.3.1.300, branched-chain beta-ketoacyl-[acyl-carrier-protein] synthase).
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Word Map
- 2.3.1.180
- malonyl-acp
- thiolactomycin
-
transacylase
-
mycolic
- drug development
- acyl-acps
-
claisen
- glaucescens
- isobutyryl-coa
-
transacylation
- cuphea
- pharmacology
-
malonyl-coa:acp
-
bcfas
- synthesis
- biofuel production
- medicine
The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
kas iii, mtfabh, kasiii, beta-ketoacyl-acyl carrier protein synthase iii, pqsbc, beta-ketoacyl-acyl carrier protein (acp) synthase iii, beta-ketoacyl-acp synthase iii, ecfabh, acetoacetyl-acp synthase, 3-ketoacyl-acp synthase iii, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
beta-ketoacyl-acyl carrier protein synthase III
-
3-oxoacyl:ACP synthase III
-
-
-
-
acetyl-CoA:malonyl-[acyl-carrier-protein] C-acyltransferase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
active site structure and catalytic reaction mechanism, T97, R46, W42, C122, R161, H258, and N289 are important for activity, structure-function relationship
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
catalytic reaction mechanism for decarboxylation and condensation
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
data support a new model for catalysis, in which FabH exists in an open form that permits binding of the long chain acyl-coenzyme A substrate binding and release of the corresponding 3-ketoacyl ACP product. Catalysis and intermediate steps in the process are proposed to occur in a closed form of the mtFabH. These conformational changes may be critical for binding and dissociation steps in other enzymes of the FAS pathways, including transfers between the type I and type II FASII components of Mycobacterium tuberculosis
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
the enzyme catalyzes the Claisen condensation reaction by a ping-pong mechanism
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
active site structure a catayltic triad of Cys-His-Asn residues
-
acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2
active site structure with a CoA/malonyl-ACP-binding channel leading from the enzyme surface to the buried active site Cys residue, a second channel leads from the active site to the surface with a threonine residue controlling the passage of longer acyl chains
-
SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:malonyl-[acyl-carrier protein] C-acyltransferase
The enzyme is responsible for initiating straight-chain fatty acid biosynthesis by the dissociated (or type II) fatty-acid biosynthesis system that occurs in plants and bacteria. In contrast to EC 2.3.1.41, beta-ketoacyl-[acyl-carrier-protein] synthase I, and EC 2.3.1.179, beta-ketoacyl-[acyl-carrier-protein] synthase II, this enzyme specifically uses short-chain acyl-CoA thioesters (preferably acetyl-CoA) rather than acyl-[acp] as its substrate [1]. The enzyme can also catalyse the reaction of EC 2.3.1.38, [acyl-carrier-protein] S-acetyltransferase, but to a much lesser extent [1]. The enzymes from some organisms (e.g. the Gram-positive bacterium Streptococcus pneumoniae) can accept branched-chain acyl-CoAs in addition to acetyl-CoA [5] (cf. EC 2.3.1.300, branched-chain beta-ketoacyl-[acyl-carrier-protein] synthase).
CAS REGISTRY NUMBER
COMMENTARY
9077-10-5
-
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
acetyl-CoA + a malonyl-[acyl-carrier protein]
an acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
3-oxobutanoyl-[acyl-carrier protein] + CoA + CO2
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-myristoyl-[acyl-carrier protein] + CoA + CO2
the primer substrate lauroyl-CoA is bound to subunit A, binding structure, lauroyl is bound in a channel
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
-
-
-
?
acyl-CoA + malonyl-[acyl-carrier protein]
acetoacyl-[acyl-carrier protein] + CoA + CO2
-
the condensation reaction is the first step in elongation in fatty acid synthesis by fatty acid synthase complex
-
-
?
arachidoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-docosanoyl-[acyl-carrier protein] + CoA + CO2
-
low activity
-
-
?
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-lauroyl-[acyl-carrier protein] + CoA + CO2
-
-
-
-
?
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-myristoyl-[acyl-carrier protein] + CoA + CO2
-
lauroyl-CoA is the preferred primer
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-palmitoyl-[acyl-carrier protein] + CoA + CO2
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-decanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
-
?
palmitoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-stearoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
-
?
stearoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-arachidoyl-[acyl-carrier protein] + CoA + CO2
-
low activity
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
3-oxobutanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
3-oxobutanoyl-[acyl-carrier protein] + CoA + CO2
FabH links FAS-I and FAS-II catalyzing the condensation of FAS-I-derived acyl-CoAs with malonyl-ACP
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
-
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
condensation of fatty acid synthase I-derived acyl-CoAs with malonyl-ACPs to initiates fatty acid synthase II-catalyzed fatty acid elongation, the enzyme links the two fatty acid synthase complexes
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
the enzyme initiates the fatty acid biosynthesis
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-palmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-palmitoyl-[acyl-carrier protein] + CoA + CO2
-
the enzyme plays a key role in initiation of the long-chain fatty acid route of meromycolic acid biosynthesis, a different enzyme with specificity for short-chain acyl-CoAs might also be responsible for meromycolic acid biosynthesis, biosynthetic pathway regulation mechanism
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-palmitoyl-[acyl-carrier protein] + CoA + CO2
-
the enzyme prefers long-chain acyl-CoA substrates for the Claisen condensation reaction
-
-
?
additional information
?
-
specificity of the enzyme for longer acyl-CoA chains, overview, the enzyme shows also acyl-CoA-[acyl-carrier-protein] transacylase activity
-
-
?
additional information
?
-
-
specificity of the enzyme for longer acyl-CoA chains, overview, the enzyme shows also acyl-CoA-[acyl-carrier-protein] transacylase activity
-
-
?
additional information
?
-
FabH is regulated by Ser/Thr protein kinase-dependent phosphorylation at Thr45, overview
-
-
?
additional information
?
-
-
FabH is regulated by Ser/Thr protein kinase-dependent phosphorylation at Thr45, overview
-
-
?
additional information
?
-
-
substrate specificity, no activity with isovaleryl-CoA, butyryl-CoA, and acetyl-CoA, the enzyme prefers long chain acyl-CoAs as primers rather than acyl-ACPs
-
-
?
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
acetyl-CoA + a malonyl-[acyl-carrier protein]
an acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
3-oxobutanoyl-[acyl-carrier protein] + CoA + CO2
FabH links FAS-I and FAS-II catalyzing the condensation of FAS-I-derived acyl-CoAs with malonyl-ACP
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
acyl-CoA + malonyl-[acyl-carrier protein]
acetoacyl-[acyl-carrier protein] + CoA + CO2
-
the condensation reaction is the first step in elongation in fatty acid synthesis by fatty acid synthase complex
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxo-palmitoyl-[acyl-carrier protein] + CoA + CO2
-
the enzyme plays a key role in initiation of the long-chain fatty acid route of meromycolic acid biosynthesis, a different enzyme with specificity for short-chain acyl-CoAs might also be responsible for meromycolic acid biosynthesis, biosynthetic pathway regulation mechanism
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
condensation of fatty acid synthase I-derived acyl-CoAs with malonyl-ACPs to initiates fatty acid synthase II-catalyzed fatty acid elongation, the enzyme links the two fatty acid synthase complexes
-
-
?
acetyl-CoA + malonyl-[acyl-carrier protein]
acetoacetyl-[acyl-carrier protein] + CoA + CO2
the enzyme initiates the fatty acid biosynthesis
-
-
?
additional information
?
-
FabH is regulated by Ser/Thr protein kinase-dependent phosphorylation at Thr45, overview
-
-
?
additional information
?
-
-
FabH is regulated by Ser/Thr protein kinase-dependent phosphorylation at Thr45, overview
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-amino-5-(3-chlorophenyl)thiazole-4-carboxylic acid
MIC value is 0.125 mM
2-amino-5-methylthiazole-4-carboxylic acid
MIC value is 0.00035 mM
4'-[(3-hydroxy-2,4-dimethyl-5-oxo-2,5-dihydrothiophen-2-yl)methyl]biphenyl-4-carboxylic acid
-
methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl) thiazole-4-carboxylate
-
methyl 2-(2-bromoacetamido)-5-phenylthiazole-4-carboxylate
-
methyl 2-amino-5-benzylthiazole-4-carboxylate
MIC value is 240 nM
methyl 2-amino-5-methylthiazole-4-carboxylate
MIC value is 0.093 mM
methyl 5-benzyl-2-(2-bromoacetamido)thiazole-4-carboxylate
-
(2R)-5-hydroxy-2,4-dimethyl-2-[(1E)-2-methylbuta-1,3-dien-1-yl]thiophen-3(2H)-one
-
-
(5R)-4-hydroxy-5-[[4'-(hydroxymethyl)biphenyl-4-yl]methyl]-3,5-dimethylthiophen-2(5H)-one
-
-
(5R)-5-[3-(4-acetyl-3-hydroxyphenyl)prop-2-yn-1-yl]-4-hydroxy-3,5-dimethylthiophen-2(5H)-one
-
-
(5R)-5-[3-(4-acetylphenyl)prop-2-yn-1-yl]-4-hydroxy-3,5-dimethylthiophen-2(5H)-one
-
-
10,10-dimethyl-7-(2-nitrophenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(3-chlorophenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(3-nitrophenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(4-chlorophenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(4-hydroxy-3-methoxyphenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(4-hydroxyphenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(4-nitrophenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(naphthalen-2-yl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
10,10-dimethyl-7-(thiophen-2-yl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
-
-
ampicillin
-
inhibition of the recombinant enzyme in transformed Mycobacterium bovis strain BCG in vivo
Ethionamide
-
inhibition of the recombinant enzyme in transformed Mycobacterium bovis strain BCG in vivo
isoniazid
-
inhibition of the recombinant enzyme in transformed Mycobacterium bovis strain BCG in vivo
isoxyl
-
inhibition of the recombinant enzyme in transformed Mycobacterium bovis strain BCG in vivo
rifampicin
-
inhibition of the recombinant enzyme in transformed Mycobacterium bovis strain BCG in vivo
thiolactomycin
-
inhibition of the purified enzyme in vitro, and of the recombinant enzyme in transformed Mycobacterium bovis strain BCG in vivo
additional information
no enzyme inhibition by several derivatives of cyclic sulfones, overview
-
additional information
-
no enzyme inhibition by several derivatives of cyclic sulfones, overview
-
additional information
modeling studies of binding of 2-aminothiazole-4-carboxylate analogues to FabH, overview
-
additional information
-
modeling studies of binding of 2-aminothiazole-4-carboxylate analogues to FabH, overview
-
additional information
inhibitors of bacterial FASII can act as potential antibacterial agents, structure-activity relationships of the inhibitors that mainly target beta-ketoacyl-ACP synthase, beta-ketoacyl-ACP reductase, beta-hydroxyacyl-ACP dehydratase, and enoyl-ACP reductase, overview. No inhibition of the enzyme FabH from Mycobacterium tuberculosis by methyl 2-amino-5-benzylthiazole-4-carboxylate
-
additional information
-
the mitochondrial enzyme is not affected by cerulenin
-
additional information
-
no significant inhibitory activity at 0.3 mM: methyl-CoA disulfide, butyl-CoA disulfide, sec-butyl-CoA disulfide
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.003
4'-[(3-hydroxy-2,4-dimethyl-5-oxo-2,5-dihydrothiophen-2-yl)methyl]biphenyl-4-carboxylic acid
Mycobacterium tuberculosis
-
0.718
5-benzyl-2-(2-bromoacetamido)thiazole-4-carboxylic acid
Mycobacterium tuberculosis
-
0.00243
methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl) thiazole-4-carboxylate
Mycobacterium tuberculosis
-
0.0032
methyl 2-(2-bromoacetamido)-5-phenylthiazole-4-carboxylate
Mycobacterium tuberculosis
-
0.1598
methyl 5-benzyl-2-(2-bromoacetamido)thiazole-4-carboxylate
Mycobacterium tuberculosis
-
0.08
(5R)-4-hydroxy-3,5-dimethyl-5-tetradecylthiophen-2(5H)-one
Mycobacterium tuberculosis
-
-
0.017 - 0.019
(5R)-4-hydroxy-5-[[4'-(hydroxymethyl)biphenyl-4-yl]methyl]-3,5-dimethylthiophen-2(5H)-one
0.00702
(5R)-5-[3-(4-acetyl-3-hydroxyphenyl)prop-2-yn-1-yl]-4-hydroxy-3,5-dimethylthiophen-2(5H)-one
Mycobacterium tuberculosis
-
-
0.00404
(5R)-5-[3-(4-acetylphenyl)prop-2-yn-1-yl]-4-hydroxy-3,5-dimethylthiophen-2(5H)-one
Mycobacterium tuberculosis
-
-
0.017
(5R)-4-hydroxy-5-[[4'-(hydroxymethyl)biphenyl-4-yl]methyl]-3,5-dimethylthiophen-2(5H)-one
Mycobacterium tuberculosis
-
-
0.019
(5R)-4-hydroxy-5-[[4'-(hydroxymethyl)biphenyl-4-yl]methyl]-3,5-dimethylthiophen-2(5H)-one
Mycobacterium tuberculosis
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
substrate specificity of the purified His-tagged enzyme
additional information
-
assay for the Mycobacterium tuberculosis FabH (mtFabH) enzyme involved in a key initiation step in the synthesis of mycolic acids, which are an integral component of the cell wall. The assay eliminates the need for the cumbersome washing steps or specialty scintillation proximity assay beads and the preparation of acyl-carrier proteins required in other assay formats. This discontinuous assay involves the reduction of radiolabled long-chain beta-ketoacyl CoA product to its dihydroxy derivative, which partitions into a nonpolar phase for quantitation, while the reduced radiolabeled substrate derivative remains in the aqueous phase
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
FabH is prevalent and necessary in a large number of clinical pathogens, such as Gram-positive and -negative bacteria, anaerobic bacteria, mycobacteria, chlamydia, and protozoa
metabolism
FabH catalyzes the first condensation of acetyl-CoA with malonyl-ACP to form beta-ketobutyryl-ACP and CO2, initiating the cycle of fatty acid elongation, FASII pathway, detailed overview
physiological function
additional information
FabH has a catalytic triad of Cys112/His244/Asn274
physiological function
FabH links FAS-I and FAS-II catalyzing the condensation of FAS-I-derived acyl-CoAs with malonyl-ACP. FabH represents a potential regulatory key point of the mycolic acid pathway
physiological function
enzyme FabH also plays a key regulatory role through a long-chain acyl-ACP in the rate of new chain initiation of the entire synthetic pathway
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
FabH is efficiently phosphorylated in vitro exclusively on Thr45 by several mycobacterial Ser/Thr protein kinases, particularly by PknF and PknA, as well as in vivo in mycobacteria, mass spectrometric analysis, overview. Mapping of the Thr45 phosphorylation site on the FabH crystal structure
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging-drop vapor diffusion method, crystal structures of mtFabH and C112A mtFabH with 1
mapping of the Thr45 phosphorylation site on the mtFabH crystal structure, overview
purified recombinant enzyme in complex with lauroyl-CoA, X-ray diffraction structure determination and analysis at 1.85-2.3 A resolution, modeling
purified recombinant mutant enzymes R46A/R161A and W42A/R163A, 0.003 ml R46A/R161A solution containing 20 mg/ml protein, 20 mM Tris-HCl, pH 7.5, 0.5 M NaCl, 2 mM 2-mercaptoethanol, 10% glycerol, mixed with 0.001 ml of crystallization solution containing 0.1 M HEPES, pH 7.5, 10% v/v isopropyl alcohol, 20% w/v PEG 4000, for the W42A/R163A solution 0.002 ml of protein solution is mixed with 0.001 ml of crystallization solution containing 0.2 M ammonium sulfate, and 30% w/v PEG 8000, X-ray diffraction structure determination and analysis at 2.0-2.65 A resolution
crystallization of the mtFabH/decyl-CoA disulfide is achieved using the hanging-drop vapour-diffusion technique. The active site cysteine in both subunits of the wild type mtFabH dimer is able to react with either a dodecanoyl-CoA substrate or a decyl-CoA disulfide inhibitor
-
purified FabH, X-ray diffraction structure determination and analysis at 2.1 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C122A
site-directed mutagenesis, the mutant shows 0.25% of wild-type enzyme condensation activity, and 2.4% of wild-type malonyl-ACP decarboxylation activity
H258A
site-directed mutagenesis, the mutant shows 0.46% of wild-type enzyme condensation activity, and 0.68% of wild-type malonyl-ACP decarboxylation activity
N289A
site-directed mutagenesis, the mutant shows 0.51% of wild-type enzyme condensation activity, and 2.24% of wild-type malonyl-ACP decarboxylation activity
R161A
site-directed mutagenesis, the mutant shows 69.7% of wild-type enzyme condensation activity, and 8.7% of wild-type malonyl-ACP decarboxylation activity
R46A
site-directed mutagenesis, the mutant shows 7.3% of wild-type enzyme condensation activity, and 0.79% of wild-type malonyl-ACP decarboxylation activity
R46A/R161A
site-directed mutagenesis, the mutant shows 0.31% of wild-type enzyme condensation activity, and 5.1% of wild-type malonyl-ACP decarboxylation activity
T45A
the mutant exhibits slightly decreased transacylation, malonyl-AcpM decarboxylation, and condensing activities compared to the wild-type protein
T45D
the mutant exhibits markedly decreased transacylation, malonyl-AcpM decarboxylation, and condensing activities compared to the wild-type protein
T97F
site-directed mutagenesis, the mutant shows 0.47% of wild-type enzyme condensation activity, and 0.84% of wild-type malonyl-ACP decarboxylation activity
W42A
site-directed mutagenesis, the mutant shows 21.6% of wild-type enzyme condensation activity, and 30.1% of wild-type malonyl-ACP decarboxylation activity
W42A/R161A
site-directed mutagenesis, the mutant shows 0.24% of wild-type enzyme condensation activity, and 9.7% of wild-type malonyl-ACP decarboxylation activity
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from strain C41(DE3) by nickel affinity chromatography
recombinant His-tagged wild-type and mutant FabHs from Mycobacterium bovis strain BCG by nickel affinity chromatography
recombinant His-tagged enzyme from Mycobacterium bovis strain BCG
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene fabH, overexpression of His-tagged wild-type and mutant FabHs in Mycobacterium bovis strain BCG
overexpression of His-tagged wild-type and mutant enzymes in strain C41(DE3)
gene fabH, overexpression of His-tagged enzyme in Mycobacterium bovis strain BCG
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the enzyme is a target for inhibitor development
drug development
-
the enzyme represents a target for structure-based design of antimycobacterial agents
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Brown, A.K.; Sridharan, S.; Kremer, L.; Lindenberg, S.; Dover, L.G.; Sacchettini, J.C.; Besra, G.S.
Probing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-ACP synthase III mtFabH: Factors influencing catalysis and substrate specificity
J. Biol. Chem.
280
32539-32547
2005
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNG3)
Musayev, F.; Sachdeva, S.; Scarsdale, J.N.; Reynolds, K.A.; Wright, H.T.
Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A
J. Mol. Biol.
346
1313-1321
2005
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNG3)
Choi, K.H.; Kremer, L.; Besra, G.S.; Rock, C.O.
Identification and substrate specificity of beta-ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis
J. Biol. Chem.
275
28201-28207
2000
Mycobacterium tuberculosis
Scarsdale, J.N.; Kazanina, G.; He, X.; Reynolds, K.A.; Wright, H.T.
Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III
J. Biol. Chem.
276
20516-20522
2001
Mycobacterium tuberculosis
Alhamadsheh, M.M.; Waters, N.C.; Huddler, D.P.; Kreishman-Deitrick, M.; Florova, G.; Reynolds, K.A.
Synthesis and biological evaluation of thiazolidine-2-one 1,1-dioxide as inhibitors of Escherichia coli beta-ketoacyl-ACP-synthase III (FabH)
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879-883
2007
Escherichia coli (P0A6R0), Escherichia coli, Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNG3), Plasmodium falciparum, Plasmodium falciparum D6
Sachdeva, S.; Musayev, F.; Alhamadsheh, M.M.; Neel Scarsdale, J.; Tonie Wright, H.; Reynolds, K.A.
Probing reactivity and substrate specificity of both subunits of the dimeric Mycobacterium tuberculosis FabH using alkyl-CoA disulfide inhibitors and acyl-CoA substrates
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2008
Mycobacterium tuberculosis
Alhamadsheh, M.M.; Musayev, F.; Komissarov, A.A.; Sachdeva, S.; Wright, H.T.; Scarsdale, N.; Florova, G.; Reynolds, K.A.
Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes
Chem. Biol.
14
513-524
2007
Escherichia coli, Mycobacterium tuberculosis
Sachdeva, S.; Musayev, F.N.; Alhamadsheh, M.M.; Scarsdale, J.N.; Wright, H.T.; Reynolds, K.A.
Separate entrance and exit portals for ligand traffic in Mycobacterium tuberculosis FabH
Chem. Biol.
15
402-412
2008
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNG3)
Sachdeva, S.; Reynolds, K.A.
Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase III (mtFabH) assay: principles and method
Methods Mol. Med.
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205-213
2008
Mycobacterium tuberculosis
Castillo, Y.P.; Perez, M.A.
Bacterial beta-ketoacyl-acyl carrier protein synthase III (FabH): an attractive target for the design of new broad-spectrum antimicrobial agents
Mini Rev. Med. Chem.
8
36-45
2008
Streptococcus pneumoniae, Escherichia coli, Enterococcus faecium, Haemophilus influenzae, Staphylococcus aureus, Mycobacterium tuberculosis, Neisseria meningitidis, Pseudomonas aeruginosa, Streptococcus pyogenes
Veyron-Churlet, R.; Molle, V.; Taylor, R.C.; Brown, A.K.; Besra, G.S.; Zanella-Cleon, I.; Fuetterer, K.; Kremer, L.
The Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue
J. Biol. Chem.
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6414-6424
2009
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNG3)
Al-Balas, Q.; Anthony, N.G.; Al-Jaidi, B.; Alnimr, A.; Abbott, G.; Brown, A.K.; Taylor, R.C.; Besra, G.S.; McHugh, T.D.; Gillespie, S.H.; Johnston, B.F.; Mackay, S.P.; Coxon, G.D.
Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH
PLoS ONE
4
e5617
2009
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WNG3)
Wang, Y.; Ma, S.
Recent advances in inhibitors of bacterial fatty acid synthesis type II (FASII) system enzymes as potential antibacterial agents
ChemMedChem
8
1589-1608
2013
Bacillus subtilis (O34746), Escherichia coli (P0A6R0), Haemophilus influenzae (P43711), Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3), Pseudomonas aeruginosa (A0A072ZQE7), Staphylococcus aureus (P99159), Staphylococcus aureus N315 (P99159), Streptococcus pneumoniae (P0A3C5)
Patil, K.; Wakkar, L.; Undare, S.; Kolekar, G.; Deshmukh, M.; Choudhari, P.; Anbhule, P.
Selective synthesis of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione using copper oxide nanoparticles for potential inhibitors of beta-ketoacyl-[acyl-carrier-protein] synthase III of Mycobacterium tuberculosis
Indian J. Chem.
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2016
Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv
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