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Information on EC 2.3.1.97 - glycylpeptide N-tetradecanoyltransferase and Organism(s) Leishmania major and UniProt Accession Q4Q5S8

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IUBMB Comments
The enzyme catalyses the transfer of myristic acid from myristoyl-CoA to the amino group of the N-terminal glycine residue in a variety of eukaryotic proteins. It uses an ordered Bi Bi reaction in which myristoyl-CoA binds to the enzyme prior to the binding of the peptide substrate, and CoA release precedes the release of the myristoylated peptide. The enzyme from yeast is profoundly affected by amino acids further from the N-terminus, and is particularly stimulated by a serine residue at position 5.
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Leishmania major
UNIPROT: Q4Q5S8
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The taxonomic range for the selected organisms is: Leishmania major
The enzyme appears in selected viruses and cellular organisms
Synonyms
n-myristoyltransferase, nmt-1, myristoyl-coa:protein n-myristoyltransferase, n-myristoyl transferase, nmt1p, n-myristoyltransferase 1, myristoyltransferase, canmt, myristoyl-coa protein n-myristoyltransferase, tbnmt, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
myristoyl-CoA-protein N-myristoyltransferase
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myristoyl-CoA:protein N-myristoyltransferase
myristoyl-coenzyme A:protein N-myristoyl transferase
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myristoylating enzymes
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myristoyltransferase, protein N-
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N-myristoyltransferase
peptide N-myristoyltransferase
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protein N-myristoyltransferase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
tetradecanoyl-CoA + an N-terminal-glycyl-[protein] = CoA + an N-terminal-N-tetradecanoylglycyl-[protein]
show the reaction diagram
myristoylation by NMT proceeds via an ordered bi-bi reaction mechanism in which binding of myristoyl-CoA generates a second binding pocket for the docking of the substrate protein. The myristate group from myristoyl-CoA is then transferred to the N-terminal glycine of the bound protein in a nucleophilic addition-elimination reaction. This is followed by stepwise release, first of the free CoA and then the N-myristoylated protein
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acyl group transfer
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amide bond formation
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SYSTEMATIC NAME
IUBMB Comments
tetradecanoyl-CoA:N-terminal-glycine-[protein] N-tetradecanoyltransferase
The enzyme catalyses the transfer of myristic acid from myristoyl-CoA to the amino group of the N-terminal glycine residue in a variety of eukaryotic proteins. It uses an ordered Bi Bi reaction in which myristoyl-CoA binds to the enzyme prior to the binding of the peptide substrate, and CoA release precedes the release of the myristoylated peptide. The enzyme from yeast is profoundly affected by amino acids further from the N-terminus, and is particularly stimulated by a serine residue at position 5.
CAS REGISTRY NUMBER
COMMENTARY hide
110071-61-9
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
myristoyl-CoA + glycylpeptide
N-myristoylglycylpeptide + CoA
show the reaction diagram
the enzyme is essential for viability in Leishmania, constitutively expressed in all parasite stages
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?
myristoyl-CoA + GQLFTSLN
N-myristoylglycyl-GQLFTSLN + CoA
show the reaction diagram
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?
tetradecanoyl-CoA + GLYASKLA
CoA + N-tetradecanoyl-GLYASKLA
show the reaction diagram
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i.e. myristoyl-CoA
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?
tetradecanoyl-CoA + glycylpeptide
CoA + N-tetradecanoyl-glycylpeptide
show the reaction diagram
i.e. myristoyl-CoA, the enzyme attaches the fatty acid to a glycine at the N-terminus of a number of eukaryotic cellular and viral proteins
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?
additional information
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
myristoyl-CoA + glycylpeptide
N-myristoylglycylpeptide + CoA
show the reaction diagram
the enzyme is essential for viability in Leishmania, constitutively expressed in all parasite stages
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-(3,4-dihydroxyphenyl)ethyl 6-deoxy-alpha-L-gulopyranosyl-(1->3)-[alpha-L-ribopyranosyl-(1->6)]-4-O-[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]-beta-L-glucopyranoside
inhibitor identified by screening of chemical libraries using different docking programs, substance is predicted not to inhibit human isoforms
2-(3,4-dihydroxyphenyl)ethyl alpha-L-gulopyranosyl-(1->2)-6-deoxy-alpha-L-gulopyranosyl-(1->3)-4-O-[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]-beta-L-glucopyranoside
inhibitor identified by screening of chemical libraries using different docking programs, substance is predicted not to inhibit human isoforms
3-([3-methyl-2-[(2,3,4-trifluorophenoxy)methyl]-1-benzofuran-4-yl]oxy)-N-[(pyridin-3-yl)methyl]propan-1-amine
compound displays between the nitrogen from the C6 side chain of BF and both Leu421 carboxylic oxygens as well as with the Tyr92 aromatic hydroxy group. Pi-stacking interactions are observed between the aromatic ring from C2 side chain and Phe232 and between the benzofuran ring and Phe90
N-[(pyridin-3-yl)methyl]-3-([2-[(2,3,4-trifluorophenoxy)methyl]-1,3-benzothiazol-7-yl]oxy)propan-1-amine
the nitrogen from the C6 side chain forms hydrogen bonds with both carboxylate oxygens of Leu421. His219 interacts through hydrogen bonds with the oxygen from the C2 side chain as well as the nitrogen from benzothiazole ring with His219
N-[2-chloro-5-[(3S,4R)-1-[4-(4-chlorophenyl)-3-hydroxybutanoyl]-4-(hydroxymethyl)pyrrolidin-3-yl]phenyl]-2-(4-fluorophenyl)acetamide
inhibitor shows good selectiviy over the human enzyme
N-[5-[(4R)-1-[(3R)-3-amino-4-(4-chlorophenyl)butanoyl]-4-(hydroxymethyl)pyrrolidin-3-yl]-2-chlorophenyl]-2-(4-fluorophenyl)acetamide
inhibitor shows good selectiviy over the human enzyme
(1R,3S)-N-[2-[(cyclopentylcarbonyl)amino]-1,3-benzothiazol-6-yl]-3-[(naphthalen-2-ylmethyl)amino]cyclohexanecarboxamide
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(4S,5aS,12aS)-2-carbamoyl-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-6-methylidene-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracen-5-yl acetate
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1-hydroxy-2-[(1-methylethyl)amino]ethyl 2,6-dihydroxybenzoate
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2-(diethylamino)ethyl 2-[(cyclohexylcarbonyl)amino]-1,3-benzothiazole-6-carboxylate
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2-([[(1R,3S)-3-[[(5-chloro-7-methylnaphthalen-2-yl)methyl]amino]cyclohexyl]acetyl]amino)-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
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2-([[4-(aminomethyl)cyclohexyl]carbonyl]amino)-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
2-[([(1R,3S)-3-[(1-benzofuran-5-ylmethyl)amino]cyclohexyl]acetyl)amino]-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
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2-[([(1R,3S)-3-[(1-benzofuran-6-ylmethyl)amino]cyclohexyl]acetyl)amino]-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
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2-[([(1R,3S)-3-[(1-benzofuran-6-ylmethyl)amino]cyclohexyl]carbonyl)amino]-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
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2-[([(1R,3S)-3-[(1H-indol-5-ylmethyl)amino]cyclohexyl]acetyl)amino]-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
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2-[([(1R,3S)-3-[(1H-indol-6-ylmethyl)amino]cyclohexyl]acetyl)amino]-N,N-dimethyl-1,3-benzothiazole-6-carboxamide
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3,3'-[(3-carboxy-4-oxocyclohexa-2,5-dien-1-ylidene)methanediyl]bis(6-hydroxybenzoic acid)
3-([3-methyl-2-[(2,3,4-trifluorophenoxy)methyl]-1-benzofuran-4-yl]oxy)-N-(pyridin-3-ylmethyl)propan-1-amine
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4-(4,5-dihydroxy-9-methyl-3-oxo-1,3,3a,4,9,9a-hexahydronaphtho[2,3-c]furan-1-yl)-2,5,6-trihydroxycyclohexa-2,4-diene-1-carboxamide
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4-(4,5-dihydroxy-9-methyl-3-oxo-1,3,3a,4,9,9a-hexahydronaphtho[2,3-c]furan-1-yl)-2,5-dihydroxybenzamide
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cis-4-[(naphthalen-2-ylmethyl)amino]-N-(6-pyridin-2-yl-1,3-benzothiazol-2-yl)cyclohexanecarboxamide
cis-N-(6-fluoro-1,3-benzothiazol-2-yl)-4-[(naphthalen-2-ylmethyl)amino]cyclohexanecarboxamide
cis-N-1,3-benzothiazol-2-yl-4-[(naphthalen-2-ylmethyl)amino]cyclohexanecarboxamide
CP-030890-27
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ethyl 3-methyl-4-[3-[(pyridin-3-ylmethyl)amino]propoxy]-1-benzofuran-2-carboxylate
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N-([4-[5-(2-methyl-1H-imidazol-1-yl)pentyl]phenyl]acetyl)-L-seryl-N-(2-cyclohexylethyl)-L-lysinamide
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N-[(1R)-1-[3-(3-aminopropyl)-4-(2-cyclohexylethoxy)benzyl]-2-hydroxyethyl]-2-[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetamide
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S-(2-oxo)pentadecyl-CoA
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additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.11
GQLFTSLN
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0.00137
myristoyl-CoA
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
23.6
myristoyl-CoA
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
Q4Q5S8_LEIMA
421
0
48514
TrEMBL
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
comparative binding site analysis and molecular docking studies of Leishmania major and Candida albicans NMT and molecular docking studies with benzoheterocyclic analogues
in complex with inhibitors N-[5-[(4R)-1-[(3R)-3-amino-4-(4-chlorophenyl)butanoyl]-4-(hydroxymethyl)pyrrolidin-3-yl]-2-chlorophenyl]-2-(4-fluorophenyl)acetamide and N-[2-chloro-5-[(3S,4R)-1-[4-(4-chlorophenyl)-3-hydroxybutanoyl]-4-(hydroxymethyl)pyrrolidin-3-yl]phenyl]-2-(4-fluorophenyl)acetamide. The para-fluorophenyl acetamide in ortho-position to the chlorine atom in compound N-[5-[(4R)-1-[(3R)-3-amino-4-(4-chlorophenyl)butanoyl]-4-(hydroxymethyl)pyrrolidin-3-yl]-2-chlorophenyl]-2-(4-fluorophenyl)acetamide significantly improves potency. This could potentially introduce hydrogen bonding between the acetamide carbonyl and Tyr345 and Asn376 and allow the compound to extend into a hydrophobic pocket
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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the enzyme is a drug target
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Price, H.P.; Menon, M.R.; Panethymitaki, C.; Goulding, D.; McKean, P.G.; Smith, D.F.
Myristoyl-CoA:protein N-myristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites
J. Biol. Chem.
278
7206-7214
2003
Trypanosoma brucei, Leishmania major (Q9GPZ4), Leishmania major
Manually annotated by BRENDA team
Panethymitaki, C.; Bowyer, P.W.; Price, H.P.; Leatherbarrow, R.J.; Brown, K.A.; Smith, D.F.
Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major
Biochem. J.
396
277-285
2006
Leishmania major (Q9GPZ4), Leishmania major, Trypanosoma brucei (Q388H8), Trypanosoma brucei
Manually annotated by BRENDA team
Bowyer, P.; Tate, E.; Leatherbarrow, R.; Holder, A.; Smith, D.; Brown, K.
N-myristoyltransferase: A prospective drug target for protozoan parasites
ChemMedChem
3
402-408
2008
Histoplasma capsulatum, Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans, Leishmania major, Plasmodium falciparum, Trypanosoma brucei
Manually annotated by BRENDA team
Sheng, C.; Ji, H.; Miao, Z.; Che, X.; Yao, J.; Wang, W.; Dong, G.; Guo, W.; Lue, J.; Zhang, W.
Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design
J. Comput. Aided Mol. Des.
23
375-389
2009
Trypanosoma brucei, Leishmania major (Q9GPZ4), Leishmania major, Plasmodium falciparum (Q9U419), Plasmodium falciparum
Manually annotated by BRENDA team
Hutton, J.A.; Goncalves, V.; Brannigan, J.A.; Paape, D.; Wright, M.H.; Waugh, T.M.; Roberts, S.M.; Bell, A.S.; Wilkinson, A.J.; Smith, D.F.; Leatherbarrow, R.J.; Tate, E.W.
Structure-based design of potent and selective Leishmania N-myristoyltransferase inhibitors
J. Med. Chem.
57
8664-8670
2014
Leishmania donovani (D0AB09), Leishmania donovani, Leishmania major (Q4Q5S8), Leishmania major
Manually annotated by BRENDA team
Junqueira, L.; Da Costa, M.; Rando, D.
N-myristoyltransferases as antileishmanial targets A piggyback approach with benzoheterocyclic analogues
Braz. J. Pharm. Sci.
55
e18087
2019
Candida albicans (P30418), Leishmania major (Q4Q5S8)
-
Manually annotated by BRENDA team
Garcia-Sosa, A.T.
Designing ligands for Leishmania, Plasmodium, and Aspergillus N-myristoyl transferase with specificity and anti-target-safe virtual libraries
Curr. Comput. Aided Drug Des.
14
131-141
2018
Leishmania major (Q4Q5S8)
Manually annotated by BRENDA team