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Enzyme Nomenclature
Information on EC 1.14.19.70 - mycocyclosin synthase and Organism(s) Mycobacterium tuberculosis and UniProt Accession P9WPP7
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1.14.19.70 mycocyclosin synthaseIUBMB Comments
A cytochrome P-450 (heme-thiolate) protein from the bacterium Mycobacterium tuberculosis catalysing an oxidative reaction that does not incorporate oxygen into the product.
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Word Map
- 1.14.19.70
- tuberculosis
- heme
- azole
-
antimycobacterial
- clotrimazole
- triazole
-
antituberculosis
-
fragment-based
- econazole
- fluconazole
- medicine
- isoniazid
- pharmacology
The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
2
+
2
+
=
+
2
+
2
+
2
reduced ferredoxin [iron-sulfur] cluster
+
2
+
=
+
2
oxidized ferredoxin [iron-sulfur] cluster
+
2
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CYP121
-
CYP121
-
-
-
-
rv2276
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
cyclo(L-tyrosyl-L-tyrosyl),reduced ferredoxin:oxygen oxidoreductase (diarylbridge-forming)
A cytochrome P-450 (heme-thiolate) protein from the bacterium Mycobacterium tuberculosis catalysing an oxidative reaction that does not incorporate oxygen into the product.
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
(3S,6S)-3,6-bis(4-hydroxybenzyl)piperazin-2-one + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
?
98% of the compound remains after 1 h incubation with CYP121
-
-
?
cyclo(L-tyrosyl-L-phenylalanyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
?
the rate of transformation of cyclo(L-tyrosyl-L-phenylalanyl) is very slow, with about 98% of compound remaining after 1 h of incubation with CYP121
-
-
?
cyclo(L-tyrosyl-L-tryptophanyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
?
about 50% of the initial compound remains after a 1 h incubation with CYP121
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
cyclo(L-tyrosyl-L-tyrosyl) + [reduced NADPH-hemoprotein reductase] + O2
mycocyclosin + [oxidized NADPH-hemoprotein reductase] + 2 H2O
cyclo-(L-tyrosyl-DOPA) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
?
transformation of cyclo-(L-tyrosyl-DOPA) by CYP121 is very slow, 91% of the compound remains after 1 h of incubation with CYP121
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
-
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
-
-
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
-
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
100% transformation
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + [reduced NADPH-hemoprotein reductase] + O2
mycocyclosin + [oxidized NADPH-hemoprotein reductase] + 2 H2O
the enzyme is involved in the biosynthesis of mycocyclosin. It is crucial for the viability of this pathogen
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + [reduced NADPH-hemoprotein reductase] + O2
mycocyclosin + [oxidized NADPH-hemoprotein reductase] + 2 H2O
classical and quantum based computer simulation methods are used to study in detail the reaction mechanism. Substrate binding promotes formation of the initial oxy complex. Compound I is responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a proton-coupled electron transfer reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + [reduced NADPH-hemoprotein reductase] + O2
mycocyclosin + [oxidized NADPH-hemoprotein reductase] + 2 H2O
study of substrate binding kinetics
-
-
?
additional information
?
-
no activity with cyclo(L-tyrosyl-L-alanyl)
-
-
?
additional information
?
-
-
no activity with cyclo(L-tyrosyl-L-alanyl)
-
-
?
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
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
cyclo(L-tyrosyl-L-tyrosyl) + [reduced NADPH-hemoprotein reductase] + O2
mycocyclosin + [oxidized NADPH-hemoprotein reductase] + 2 H2O
the enzyme is involved in the biosynthesis of mycocyclosin. It is crucial for the viability of this pathogen
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
-
-
-
?
cyclo(L-tyrosyl-L-tyrosyl) + 2 reduced ferredoxin [iron-sulfur] cluster + 2 H+ + O2
mycocyclosin + 2 oxidized ferredoxin [iron-sulfur] cluster + H2O
-
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
cytochrome P450
CYP121 is a highly specific cytochrome P450
-
cytochrome P450
a cytochrome P450 enzyme. Structural, spectroscopic, and kinetic experiments are applied to investigate the equilibria among various heme states as a function of pH and temperature
-
cytochrome P450
a plausible free radicalbased mechanisms for the CC bond coupling reaction is proposed
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
not inhibited by cyclo(L-Tyr-L-Leu) and cyclo(L-Tyr-L-Met)
-
additional information
-
not inhibited by cyclo(L-Tyr-L-Leu) and cyclo(L-Tyr-L-Met)
-
additional information
biophysical screening procedure employing a focused library of privileged scaffolds, which ultimately lead to the discovery of novel CYP121 inhibitors
-
additional information
-
biophysical screening procedure employing a focused library of privileged scaffolds, which ultimately lead to the discovery of novel CYP121 inhibitors
-
additional information
the cyclo-dipeptide substrates of the essential Mycobacterium tuberculosis enzyme CYP121 are deconstructed into their component fragments and screened against the enzyme
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
the enzyme is involved in the biosynthesis of mycocyclosin. It is crucial for the viability of this pathogen
physiological function
the enzyme is essential for bacterial viability
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
44962
2 * 44962, calculated from amino acid sequence, CYP121 is a predominantly dimeric protein, with a minor monomeric form present
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
2 * 44962, calculated from amino acid sequence, CYP121 is a predominantly dimeric protein, with a minor monomeric form present
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
fluconazole-bound CYP121, sitting drop vapor diffusion method, using 20% (w/v) polyethylene glycol 3350 and 0.2 M NaSCN
in complex with cyclo(L-tyrosyl-L-tyrosyl), sitting drop vapor diffusion method
ligand-bound enzyme, sitting drop vapor diffusion method, using in 100 mM Na-MES bufferat pH 5.0-5.5 and 1.6-2.2 M (NH4)2SO4, at 6°C
native enzyme or in complex with iodopyrazole, PtCN, K2PtCl4, or Hg(NO3)2, vapor diffusion method, using 30% (w/v) polyethylene glycol 8000, 0.2 M ammonium sulfate, pH 6.5
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate precipitation, phenyl Sepharose column chromatography, Q-Sepharose column chromatography, and hydroxyapatite column chromatography
ammonium sulfate precipitation, phenyl Sepharose column chromatography, Q-Sepharose column chromatography, and hydroxyapatite resin column chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
expressed in Escherichia coli HMS174 (DE3) cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
pharmacology
CYP121 is a potential target for the treatment of Mycobacterium tuberculosis infections
medicine
CYP121 is a potential target for the treatment of Mycobacterium tuberculosis infections
medicine
the CYP121 gene is essential for survival of Mycobacterium tuberculosis in vitro and the enzyme is believed to be the molecular target responsible for the anti-tubercular efficacy of azole antifungal compounds pharmacology
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Duffell, K.M.; Hudson, S.A.; McLean, K.J.; Munro, A.W.; Abell, C.; Matak-Vinkovic, D.
Nanoelectrospray ionization mass spectrometric study of Mycobacterium tuberculosis CYP121-ligand interactions
Anal. Chem.
85
5707-5714
2013
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Hudson, S.; McLean, K.; Surade, S.; Yang, Y.; Leys, D.; Ciulli, A.; Munro, A.; Abell, C.
Application of fragment screening and merging to the discovery of inhibitors of the Mycobacterium tuberculosis cytochrome P450 CYP121
Angew. Chem. Int. Ed. Engl.
51
9311-9316
2012
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
McLean, K.J.; Dunford, A.J.; Sabri, M.; Neeli, R.; Girvan, H.M.; Balding, P.R.; Leys, D.; Seward, H.E.; Marshall, K.R.; Munro, A.W.
CYP121, CYP51 and associated redox systems in Mycobacterium tuberculosis: towards deconvoluting enzymology of P450 systems in a human pathogen
Biochem. Soc. Trans.
34
1178-1182
2006
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Sundaramurthi, J.C.; Kumar, S.; Silambuchelvi, K.; Hanna, L.E.
Molecular docking of azole drugs and their analogs on CYP121 of Mycobacterium tuberculosis
Bioinformation
7
130-133
2011
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Leys, D.; Mowat, C.G.; McLean, K.J.; Richmond, A.; Chapman, S.K.; Walkinshaw, M.D.; Munro, A.W.
Atomic structure of Mycobacterium tuberculosis CYP121 to 1.06 A reveals novel features of cytochrome P450
J. Biol. Chem.
278
5141-5147
2003
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Seward, H.E.; Roujeinikova, A.; McLean, K.J.; Munro, A.W.; Leys, D.
Crystal structure of the Mycobacterium tuberculosis P450 CYP121-fluconazole complex reveals new azole drug-P450 binding mode
J. Biol. Chem.
281
39437-39443
2006
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Fonvielle, M.; Le Du, M.H.; Lequin, O.; Lecoq, A.; Jacquet, M.; Thai, R.; Dubois, S.; Grach, G.; Gondry, M.; Belin, P.
Substrate and reaction specificity of Mycobacterium tuberculosis cytochrome P450 CYP121: insights from biochemical studies and crystal structures
J. Biol. Chem.
288
17347-17359
2013
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
McLean, K.J.; Cheesman, M.R.; Rivers, S.L.; Richmond, A.; Leys, D.; Chapman, S.K.; Reid, G.A.; Price, N.C.; Kelly, S.M.; Clarkson, J.; Smith, W.E.; Munro, A.W.
Expression, purification and spectroscopic characterization of the cytochrome P450 CYP121 from Mycobacterium tuberculosis
J. Inorg. Biochem.
91
527-541
2002
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Belin, P.; Le Du, M.H.; Fielding, A.; Lequin, O.; Jacquet, M.; Charbonnier, J.B.; Lecoq, A.; Thai, R.; Courcon, M.; Masson, C.; Dugave, C.; Genet, R.; Pernodet, J.L.; Gondry, M.
Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in Mycobacterium tuberculosis
Proc. Natl. Acad. Sci. USA
106
7426-7431
2009
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Kavanagh, M.E.; Gray, J.L.; Gilbert, S.H.; Coyne, A.G.; McLean, K.J.; Davis, H.J.; Munro, A.W.; Abell, C.
Substrate fragmentation for the design of M. tuberculosis CYP121 inhibitors
ChemMedChem
11
1924-1935
2016
Mycobacterium tuberculosis (P9WPP7)
Brengel, C.; Thomann, A.; Schifrin, A.; Allegretta, G.; Kamal, A.A.M.; Haupenthal, J.; Schnorr, I.; Cho, S.H.; Franzblau, S.G.; Empting, M.; Eberhard, J.; Hartmann, R.W.
Biophysical screening of a focused library for the discovery of CYP121 inhibitors as novel antimycobacterials
ChemMedChem
12
1616-1626
2017
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WPP7)
Fielding, A.J.; Dornevil, K.; Ma, L.; Davis, I.; Liu, A.
Probing ligand exchange in the P450 enzyme CYP121 from Mycobacterium tuberculosis Dynamic equilibrium of the distal heme ligand as a function of pH and temperature
J. Am. Chem. Soc.
139
17484-17499
2017
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis
Dornevil, K.; Davis, I.; Fielding, A.J.; Terrell, J.R.; Ma, L.; Liu, A.
Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis proceeds through a catalytic shunt pathway
J. Biol. Chem.
292
13645-13657
2017
Mycobacterium tuberculosis (P9WPP7), Mycobacterium tuberculosis
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