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IUBMB CommentsThe enzyme, characterized from mycobacteria, provides a link between the type I and type II fatty acid synthase systems (FAS-I and FAS-II, respectively) found in these organisms. The enzyme acts on medium- and long-chain acyl-CoAs (C12-C16) produced by the FAS-I system, condensing them with malonyl-[acyl-carrier protein] (malonyl-AcpM) and forming starter molecules for the FAS-II system, which elongates them into meromycolic acids. The enzyme has no activity with short-chain acyl-CoAs (e.g. acetyl-CoA), which are used by EC 2.3.1.180, beta-ketoacyl-[acyl-carrier-protein] synthase III, or branched-chain acyl-CoAs, which are used by EC 2.3.1.300, branched-chain beta-ketoacyl-[acyl-carrier-protein] synthase.
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arachoyl-CoA + malonyl-[ACP]
3-oxodocosanoyl-[ACP] + CoA + CO2
decanoyl-CoA + malonyl-[ACP]
3-oxododecanoyl-[ACP] + CoA + CO2
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
dodecanoyl-CoA + malonyl-[ACP]
3-oxotetradecanoyl-[ACP] + CoA + CO2
dodecanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxotetradecanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
hexanoyl-CoA + malonyl-[ACP]
3-oxooctanoyl-[ACP] + CoA + CO2
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
myristoyl-CoA + a malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
octanoyl-CoA + malonyl-[AcpM]
3-oxodecanoyl-[ACP] + CoA + CO2
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
palmitoyl-CoA + malonyl-[ACP]
3-oxostearoyl-[ACP] + CoA + CO2
-
-
-
?
palmitoyl-CoA + malonyl-[acyl-carrier protein]
3-oxostearoyl-[acyl-carrier protein] + CoA + CO2
stearoyl-CoA + malonyl-[ACP]
3-oxoicosanoyl-[ACP] + CoA + CO2
-
-
-
?
tetradecanoyl-CoA + malonyl-[ACP]
3-oxopalmitoyl-[ACP] + CoA + CO2
-
-
-
?
additional information
?
-
arachoyl-CoA + malonyl-[ACP]
3-oxodocosanoyl-[ACP] + CoA + CO2
-
-
-
?
arachoyl-CoA + malonyl-[ACP]
3-oxodocosanoyl-[ACP] + CoA + CO2
-
-
-
?
decanoyl-CoA + malonyl-[ACP]
3-oxododecanoyl-[ACP] + CoA + CO2
-
-
-
?
decanoyl-CoA + malonyl-[ACP]
3-oxododecanoyl-[ACP] + CoA + CO2
-
-
-
?
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
dodecanoyl-CoA + malonyl-[ACP]
3-oxotetradecanoyl-[ACP] + CoA + CO2
-
-
-
?
dodecanoyl-CoA + malonyl-[ACP]
3-oxotetradecanoyl-[ACP] + CoA + CO2
-
-
-
?
hexanoyl-CoA + malonyl-[ACP]
3-oxooctanoyl-[ACP] + CoA + CO2
ACP i.e. Escherichia coli acyl-carrier protein
-
-
?
hexanoyl-CoA + malonyl-[ACP]
3-oxooctanoyl-[ACP] + CoA + CO2
ACP i.e. Escherichia coli acyl-carrier protein
-
-
?
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + a malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + a malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
octanoyl-CoA + malonyl-[AcpM]
3-oxodecanoyl-[ACP] + CoA + CO2
AcpM i.e. natural partner Mycobacterium tuberculosis acyl-carrier protein
-
-
?
octanoyl-CoA + malonyl-[AcpM]
3-oxodecanoyl-[ACP] + CoA + CO2
AcpM i.e. natural partner Mycobacterium tuberculosis acyl-carrier protein
-
-
?
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
palmitoyl-CoA + malonyl-[acyl-carrier protein]
3-oxostearoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
palmitoyl-CoA + malonyl-[acyl-carrier protein]
3-oxostearoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
additional information
?
-
FabH clearly prefers long-chain acyl-CoA substrates rather than acyl-ACP primers and does not utilize acetyl-CoA as a primer. No substrates: acetyl-CoA, butyryl-CoA, or isovaleryl-CoA
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-
-
additional information
?
-
enzyme catalyzes a Claisen-type condensation between long chain acyl-CoA substrates such as myristoyl-CoA (C14) and malonyl-ACP. No substrates: acetyl-CoA, butanoyl-CoA
-
-
-
additional information
?
-
FabH clearly prefers long-chain acyl-CoA substrates rather than acyl-ACP primers and does not utilize acetyl-CoA as a primer. No substrates: acetyl-CoA, butyryl-CoA, or isovaleryl-CoA
-
-
-
additional information
?
-
enzyme catalyzes a Claisen-type condensation between long chain acyl-CoA substrates such as myristoyl-CoA (C14) and malonyl-ACP. No substrates: acetyl-CoA, butanoyl-CoA
-
-
-
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decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
palmitoyl-CoA + malonyl-[acyl-carrier protein]
3-oxostearoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
additional information
?
-
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
decanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxolauroyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
lauroyl-CoA + malonyl-[acyl-carrier protein]
3-oxomyristoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
myristoyl-CoA + malonyl-[acyl-carrier protein]
3-oxopalmitoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
octanoyl-CoA + malonyl-[acyl-carrier protein]
3-oxodecanoyl-[acyl-carrier protein] + CoA + CO2
-
-
-
?
additional information
?
-
FabH clearly prefers long-chain acyl-CoA substrates rather than acyl-ACP primers and does not utilize acetyl-CoA as a primer. No substrates: acetyl-CoA, butyryl-CoA, or isovaleryl-CoA
-
-
-
additional information
?
-
FabH clearly prefers long-chain acyl-CoA substrates rather than acyl-ACP primers and does not utilize acetyl-CoA as a primer. No substrates: acetyl-CoA, butyryl-CoA, or isovaleryl-CoA
-
-
-
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1-(1-bromoheptyl)-4-(4-[[(2,4-difluorophenyl)methyl]amino]phenyl)-1H-pyrrole-2-carboxylic acid
compound exhibits strong inhibition on the growth of Mycobacterium tuberculosis H37Rv at 2 and at 4 weeks
1-(1-bromohexyl)-4-(4-[[(3,5-difluorophenyl)methyl]amino]phenyl)-1H-pyrrole-2-carboxylic acid
compound exhibits strong inhibition on the growth of Mycobacterium tuberculosis H37Rv at 2 and at 4 weeks
1-(1-bromooctyl)-4-(4-[[(2,5-difluorophenyl)methyl]amino]phenyl)-1H-pyrrole-2-carboxylic acid
compound exhibits strong inhibition on the growth of Mycobacterium tuberculosis H37Rv at 2 and at 4 weeks
1-(3-carboxypropyl)-4-[4-[(3,5-difluorophenyl)methoxy]phenyl]-1H-pyrrole-2-carboxylic acid
compound possesses good in vitro antimycobacterial activity, MIC value 12.5 microg/ml
1-([[(2-hydroxyethyl)disulfanyl]carbonyl]oxy)octane
-
1-[(3-chlorophenyl)methyl]-4-(4-[[(2,4-difluorophenyl)methyl]amino]phenyl)-1H-pyrrole-2-carboxylic acid
compound exhibits strong inhibition on the growth of Mycobacterium tuberculosis H37Rv at 2 and at 4 weeks
1-[(4-chlorophenyl)methyl]-4-(4-[[(2,4-difluorophenyl)methyl]amino]phenyl)-1H-pyrrole-2-carboxylic acid
compound exhibits strong inhibition on the growth of Mycobacterium tuberculosis H37Rv at 2 and at 4 weeks
11-[[(decyldisulfanyl)carbonyl]oxy]undecanoic acid
-
11-[[(decyloxy)carbonyl]disulfanyl]undecanoic acid
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2-(4-chlorobenzene-1-sulfonyl)naphthalene-1,4-diol
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2-(4-methylbenzene-1-sulfonyl)anthracene-1,4-diol
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2-(4-methylbenzene-1-sulfonyl)naphthalene-1,4-diol
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2-(4-methylbenzene-1-sulfonyl)naphthalene-1,4-dione
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2-(4-propylbenzene-1-sulfonyl)naphthalene-1,4-diol
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2-(benzenesulfonyl)naphthalene-1,4-diol
-
2-(methanesulfonyl)naphthalene-1,4-diol
-
2-(naphthalene-2-sulfonyl)naphthalene-1,4-diol
-
3-(1,4-dihydroxynaphthalene-2-sulfonyl)propanoic acid
-
[4-(1,4-dihydroxynaphthalene-2-sulfonyl)phenyl]carbamic acid
-
additional information
2-tosylnaphthalene-1,4-diol analogues are reversible inhibitors (30 nM-5 microM) of the Mycobacterium tuberculosis and Plasmodium falciparum FabH enzymes. The sulfonyl group and naphthalene-1,4 diol are required for activity against all enzymes but the toluene portion can be significantly altered. Inhibitors are also effective against Escherichia coli FabH, EC 2.3.1.180
-
additional information
not inhibitory: cerulenin
-
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0.0038
1-([[(2-hydroxyethyl)disulfanyl]carbonyl]oxy)octane
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0027
11-[[(decyldisulfanyl)carbonyl]oxy]undecanoic acid
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0024
11-[[(decyloxy)carbonyl]disulfanyl]undecanoic acid
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000036
2-(4-chlorobenzene-1-sulfonyl)naphthalene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000085
2-(4-methylbenzene-1-sulfonyl)anthracene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.00000061
2-(4-methylbenzene-1-sulfonyl)naphthalene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000002
2-(4-methylbenzene-1-sulfonyl)naphthalene-1,4-dione
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000031
2-(4-propylbenzene-1-sulfonyl)naphthalene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000028
2-(benzenesulfonyl)naphthalene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000035
2-(methanesulfonyl)naphthalene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000015
2-(naphthalene-2-sulfonyl)naphthalene-1,4-diol
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000035
3-(1,4-dihydroxynaphthalene-2-sulfonyl)propanoic acid
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0012
CoA decyldisulfide
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0301
CoA octyldisulfide
Mycobacterium tuberculosis
pH 7.4, 23°C
0.0000038
[4-(1,4-dihydroxynaphthalene-2-sulfonyl)phenyl]carbamic acid
Mycobacterium tuberculosis
pH 7.4, 23°C
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0.00006
substrates arachoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.0004
substrates hexanoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.0006
substrates stearoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.00174
substrates hexanoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.0022
substrates tetradecanoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.00549
substrates octanoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.006
substrates octanoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.00616
substrates decanoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.0063
substrates decanoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.00724
substrates dodecanoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.008
substrates dodecanoyl-CoA and malonyl-[ACP], pH 7, 37°C
0.009
substrates arachoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.00927
substrates palmitoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.00946
substrates tetradecanoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.0104
substrates stearoyl-CoA and malonyl-[AcpM], pH 7, 37°C
0.0134
substrate octanoyl-CoA, pH 7., 37°C
0.0269
substrate decanoyl-CoA, pH 7., 37°C
0.0569
substrate myristoyl-CoA, pH 7., 37°C
0.13
substrate lauroyl-CoA, pH 7., 37°C
0.0013
substrate palmitoyl-CoA, pH 7., 37°C
0.0013
substrates palmitoyl-CoA and malonyl-[ACP], pH 7, 37°C
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Sachdeva, S.; Musayev, F.; Alhamadsheh, M.; Neel Scarsdale, J.; Tonie Wright, H.; Reynolds, K.
Probing reactivity and substrate specificity of both subunits of the dimeric Mycobacterium tuberculosis FabH using alkyl-CoA disulfide inhibitors and acyl-CoA substrates
Bioorg. Chem.
36
85-90
2008
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis ATCC 25618 (P9WNG3)
brenda
Alhamadsheh, M.; Waters, N.; Sachdeva, S.; Lee, P.; Reynolds, K.
Synthesis and biological evaluation of novel sulfonyl-naphthalene-1,4-diols as FabH inhibitors
Bioorg. Med. Chem. Lett.
18
6402-6405
2008
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3)
brenda
Alhamadsheh, M.; Musayev, F.; Komissarov, A.; Sachdeva, S.; Wright, H.; Scarsdale, N.; Florova, G.; Reynolds, K.
Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes
Chem. Biol.
14
513-524
2007
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3)
brenda
Sachdeva, S.; Musayev, F.; Alhamadsheh, M.; Scarsdale, J.; Wright, H.; Reynolds, K.
Separate entrance and exit portals for ligand traffic in Mycobacterium tuberculosis FabH
Chem. Biol.
15
402-412
2008
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis ATCC 25618 (P9WNG3)
brenda
Zhang, X.; Yu, H.; Zhong, W.; Wang, L.; Li, S.
Structure-based design, synthesis of novel inhibitors of Mycobacterium tuberculosis FabH as potential anti-tuberculosis agents
Chin. Chem. Lett.
20
1019-1022
2009
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis ATCC 25618 (P9WNG3)
-
brenda
Choi, K.; Kremer, L.; Besra, G.; Rock, C.
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 (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3)
brenda
Scarsdale, J.; Kazanina, G.; He, X.; Reynolds, K.; Wright, H.
Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III
J. Biol. Chem.
276
20516-20522
2001
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3)
brenda
Brown, A.; Sridharan, S.; Kremer, L.; Lindenberg, S.; Dover, L.; Sacchettini, J.; Besra, G.
Probing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III mtFabH Factors influencing catalysis and substrate specificity
J. Biol. Chem.
280
32539-32547
2005
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3)
brenda
Veyron-Churlet, R.; Molle, V.; Taylor, R.; Brown, A.; Besra, G.; 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.
284
6414-6424
2009
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis H37Rv (P9WNG3)
brenda
Musayev, F.; Sachdeva, S.; Scarsdale, J.; Reynolds, K.; Wright, H.
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 ATCC 25618 (P9WNG3)
brenda
Sachdeva, S.; Reynolds, K.
Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase III (mtFabH) assay principles and method
Methods Mol. Med.
142
205-213
2008
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis ATCC 25618 (P9WNG3)
brenda
Liu, Y.; Zhong, W.; Li, R.; Li, S.
Synthesis of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents
Molecules
17
4770-4781
2012
Mycobacterium tuberculosis (P9WNG3), Mycobacterium tuberculosis ATCC 25618 (P9WNG3)
brenda