Entry
Name
Biosynthesis of enediyne antibiotics
Description
Enediyne natural products are potent antitumor antibiotics produced by a variety of Actinomycetes. Enediyne has a unique structure consisting of three building blocks: aromatic, sugar and enediyne core. The enediyne core contains two acetylenic groups conjugated to a double bond in a 9- or 10-membered ring, and it is synthesized by an iterative type I polyketide synthase and other tailoring proteins [MD:
M00824 M00825 ]. The 10-membered enediyne such as calicheamicin also contains an allylic trisulfide group, which acts as a trigger for diradical formation. This diagram shows the biosynthesis of C-1027, maduropeptin, neocarzinostatin, kedarcidin and calicheamicin. Some aromatic moieties are synthesized via iterative type I polyketide synthases, and others are derived from chorismate and aromatic amino acids such as tyrosine and azatyrosine [MD:
M00829 M00830 M00831 M00834 M00826 M00827 M00828 M00832 ]. Finally, the aromatic and sugar building blocks are attached to the enediyne core by acyltransferases, condensation enzymes and glucosyltransferases [MD:
M00833 ].
Class
Metabolism; Metabolism of terpenoids and polyketides
BRITE hierarchy
Pathway map
ko01059 Biosynthesis of enediyne antibiotics
Ortholog table
Module
M00824 9-membered enediyne core biosynthesis, malonyl-CoA => 3-hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-ACP => 9-membered enediyne core [PATH:ko01059 ]
M00825 10-membered enediyne core biosynthesis, malonyl-CoA => 3-hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-ACP => 10-membered enediyne core [PATH:ko01059 ]
M00826 C-1027 benzoxazolinate moiety biosynthesis, chorismate => benzoxazolinyl-CoA [PATH:ko01059 ]
M00827 C-1027 beta-amino acid moiety biosynthesis, tyrosine => 3-chloro-4,5-dihydroxy-beta-phenylalanyl-PCP [PATH:ko01059 ]
M00828 Maduropeptin beta-hydroxy acid moiety biosynthesis, tyrosine => 3-(4-hydroxyphenyl)-3-oxopropanoyl-PCP [PATH:ko01059 ]
M00829 3,6-Dimethylsalicylyl-CoA biosynthesis, malonyl-CoA => 6-methylsalicylate => 3,6-dimethylsalicylyl-CoA [PATH:ko01059 ]
M00830 Neocarzinostatin naphthoate moiety biosynthesis, malonyl-CoA => 2-hydroxy-5-methyl-1-naphthoate => 2-hydroxy-7-methoxy-5-methyl-1-naphthoyl-CoA [PATH:ko01059 ]
M00831 Kedarcidin 2-hydroxynaphthoate moiety biosynthesis, malonyl-CoA => 3,6,8-trihydroxy-2-naphthoate => 3-hydroxy-7,8-dimethoxy-6-isopropoxy-2-naphthoyl-CoA [PATH:ko01059 ]
M00832 Kedarcidin 2-aza-3-chloro-beta-tyrosine moiety biosynthesis, azatyrosine => 2-aza-3-chloro-beta-tyrosyl-PCP [PATH:ko01059 ]
M00833 Calicheamicin biosynthesis, calicheamicinone => calicheamicin [PATH:ko01059 ]
M00834 Calicheamicin orsellinate moiety biosynthesis, malonyl-CoA => orsellinate-ACP => 5-iodo-2,3-dimethoxyorsellinate-ACP [PATH:ko01059 ]
Orthology
K15314 enediyne polyketide synthase
K15315 enediyne core biosynthesis thioesterase
K21160 enediyne biosynthesis protein E2
K21161 enediyne biosynthesis protein E3
K21162 enediyne biosynthesis protein E4
K21163 enediyne biosynthesis protein E5
K21164 enediyne biosynthesis protein E7
K21165 enediyne biosynthesis protein E8
K21166 enediyne biosynthesis protein E9
K21167 enediyne biosynthesis protein E11
K21168 enediyne biosynthesis protein CalE1
K21169 enediyne biosynthesis protein CalE2
K21170 enediyne biosynthesis protein CalE3
K21171 enediyne biosynthesis protein CalE4
K21172 enediyne biosynthesis protein CalE5
K21174 enediyne biosynthesis protein CalE9
K21175 2-amino-4-deoxychorismate synthase, glutamine amidotransferase component [EC:2.6.1.86 ]
K21176 benzoxazolinate moiety biosynthesis protein SgcD5
K21177 cytochrome P450 hydroxylase [EC:1.14.-.-]
K21178 O-methyltransferase [EC:2.1.1.-]
K21182 (S)-beta-tyrosine adenylation enzyme [EC:6.2.1.-]
K16431 FAD-dependent halogenase [EC:1.14.19.-]
K21187 glycosyltransferase [EC:2.4.1.-]
K21188 PLP-dependent transaminase
K21189 O-methyltransferase [EC:2.1.1.-]
K21191 CoA ligase [EC:6.2.1.-]
K21192 methyltransferase [EC:2.1.1.-]
K21193 acetyltransferase/esterase
K21194 glycosyltransferase [EC:2.4.1.-]
K20421 2,7-dihydroxy-5-methyl-1-naphthoate 7-O-methyltransferase [EC:2.1.1.303 ]
K20423 2-hydroxy-7-methoxy-5-methyl-1-naphthoate---CoA ligase [EC:6.2.1.43 ]
K21211 NDP-hexose 4,6-dehydratase
K21212 NDP-hexose 2,3-dehydratase
K21214 NDP-hexose 4-ketoreductase
K21215 N-methyltransferase [EC:2.1.1.-]
K21216 glycosyltransferase [EC:2.4.1.-]
K21221 iterative type I polyketide synthase KedU38
K21222 cytochrome P450 monooxygenase [EC:1.14.-.-]
K21223 O-methyltransferase [EC:2.1.1.-]
K21224 radical SAM C-methyltransferase
K21226 acyl-CoA N-acyltransferase
K21227 MIO-dependent 2-aza-L-tyrosine aminomutase [EC:5.4.3.-]
K21228 (R)-2-aza-beta-tyrosine adenylation enzyme [EC:6.2.1.-]
K21229 glycosyltransferase [EC:2.4.1.-]
K21230 glycosyltransferase [EC:2.4.1.-]
K21254 orsellinic acid synthase [EC:2.3.1.-]
K21255 orsellinic acid C2-O-methyltransferase [EC:2.1.1.-]
K21256 flavin-dependent halogenase
K21257 orsellenic acid P450 oxidase [EC:1.14.-.-]
K21258 orsellinic acid C3-O-methyltransferase [EC:2.1.1.-]
K21259 calicheamicinone 4-hydroxyamino-4,6-dideoxy-alpha-D-glucosyltransferase [EC:2.4.1.-]
K21260 calicheamicin 4-deoxy-4-thio-alpha-D-digitoxosyltransferase [EC:2.4.1.-]
K21262 calicheamicin aminopentosyltransferase [EC:2.4.2.-]
K21263 calicheamicin 3'-O-methyl-rhamnosyltransferase [EC:2.4.1.-]
Compound
C11442 Aromatized C-1027 chromophore
C11447 dTDP-4-dimethylamino-4,6-dideoxy-5-C-methyl-D-allose
C11448 3,4-Dihydro-7-methoxy-2-methylene-3-oxo-2H-1,4-benzoxazine-5-carbonyl-CoA
C11449 (S)-3-Chloro-4,5-dihydroxy-beta-phenylalanyl-[pcp]
C11468 3,4-Dihydro-7-methoxy-2-methylene-3-oxo-2H-1,4-benzoxazine-5-carboxylic acid
C11469 Calicheamicin gamma(1)I
C12049 Neocarzinostatin chromophore
C18054 2-Amino-2-deoxyisochorismate
C19686 3-(1-Carboxyvinyloxy)anthranilate
C20810 (S)-3-Chloro-beta-tyrosyl-[pcp]
C20841 2-Hydroxy-7-methoxy-5-methyl-1-naphthoate
C20842 2-Hydroxy-7-methoxy-5-methyl-1-naphthoyl-CoA
C20856 2-Hydroxy-5-methyl-1-naphthoate
C20857 2,7-Dihydroxy-5-methyl-1-naphthoate
C21292 Maduropeptin chromophore
C21306 3,4-Dihydro-2-methylene-3-oxo-2H-1,4-benzoxazine-5-carboxylate
C21307 3,4-Dihydro-7-hydroxy-2-methylene-3-oxo-2H-1,4-benzoxazine-5-carboxylate
C21311 3-(4-Hydroxyphenyl)-3-oxopropanoyl-[pcp]
C21313 3,6-Dimethylsalicylyl-CoA
C21315 NDP-4-oxo-6-deoxy-D-mannose
C21316 NDP-2,6-dideoxy-D-glycero-hex-2-enos-4-ulose
C21317 NDP-2-amino-4-oxo-2,6-dideoxy-D-galactose
C21318 NDP-2-amino-2,6-dideoxy-D-galactose
C21319 NDP-2-methylamino-2,6-dideoxy-D-galactose
C21320 3,6,8-Trihydroxy-2-naphthoate
C21321 3,6,7,8-Tetrahydroxy-2-naphthoate
C21322 3-Hydroxy-6,7,8-trimethoxy-2-naphthoate
C21323 3-Hydroxy-7,8-dimethoxy-6-isopropoxy-2-naphthoate
C21324 3-Hydroxy-7,8-dimethoxy-6-isopropoxy-2-naphthoyl-CoA
C21326 (R)-2-Aza-beta-tyrosine
C21327 (R)-2-Aza-beta-tyrosyl-[pcp]
C21328 (R)-2-Aza-3-chloro-beta-tyrosyl-[pcp]
C21339 4-Deoxy-4-thio-alpha-D-digitoxosyl-calicheamicin T0
C21341 Calicheamicin alpha1(I)
C21342 Calicheamicin alpha3(I)
C21344 2-Methoxyorsellinate-[acp]
C21345 5-Iodo-2-methoxyorsellinate-[acp]
C21346 3-Hydroxy-5-iodo-2-methoxyorsellinate-[acp]
C21347 5-Iodo-2,3-dimethoxyorsellinate-[acp]
C21348 dTDP-4-hydroxyamino-4,6-dideoxy-alpha-D-glucose
C21349 dTDP-4-deoxy-4-thio-alpha-D-digitoxose
C21350 dTDP-3-O-methyl-beta-L-rhamnose
C21356 dTDP-4-ethylamino-3-O-methyl-2,4-dideoxy-L-threo-pentopyranose
C21357 3-Hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-[acp]
C21358 1,3,5,7,9,11,13-Pentadecaheptaene
C21361 3-(2-Chloro-3-hydroxy-4-methoxyphenyl)-3-hydroxypropanoyl-[pcp]
Reference
Authors
Liang ZX
Title
Complexity and simplicity in the biosynthesis of enediyne natural products.
Journal
Reference
Authors
Van Lanen SG, Shen B
Title
Biosynthesis of enediyne antitumor antibiotics.
Journal
Reference
Authors
Liu W, Christenson SD, Standage S, Shen B
Title
Biosynthesis of the enediyne antitumor antibiotic C-1027.
Journal
Reference
Authors
Ahlert J, Shepard E, Lomovskaya N, Zazopoulos E, Staffa A, Bachmann BO, Huang K, Fonstein L, Czisny A, Whitwam RE, Farnet CM, Thorson JS
Title
The calicheamicin gene cluster and its iterative type I enediyne PKS.
Journal
Reference
Authors
Van Lanen SG, Oh TJ, Liu W, Wendt-Pienkowski E, Shen B
Title
Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis.
Journal
Reference
Authors
Liu W, Nonaka K, Nie L, Zhang J, Christenson SD, Bae J, Van Lanen SG, Zazopoulos E, Farnet CM, Yang CF, Shen B
Title
The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases.
Journal
Reference
Authors
Lohman JR, Huang SX, Horsman GP, Dilfer PE, Huang T, Chen Y, Wendt-Pienkowski E, Shen B
Title
Cloning and sequencing of the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics.
Journal
Reference
Authors
Horsman GP, Van Lanen SG, Shen B
Title
Iterative type I polyketide synthases for enediyne core biosynthesis.
Journal
Reference
Authors
Sun H, Kong R, Zhu D, Lu M, Ji Q, Liew CW, Lescar J, Zhong G, Liang ZX
Title
Products of the iterative polyketide synthases in 9- and 10-membered enediyne biosynthesis.
Journal
Reference
Authors
Zhang J, Van Lanen SG, Ju J, Liu W, Dorrestein PC, Li W, Kelleher NL, Shen B
Title
A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis.
Journal
Reference
Authors
Belecki K, Crawford JM, Townsend CA
Title
Production of octaketide polyenes by the calicheamicin polyketide synthase CalE8: implications for the biosynthesis of enediyne core structures.
Journal
Reference
Authors
Kotaka M, Kong R, Qureshi I, Ho QS, Sun H, Liew CW, Goh LP, Cheung P, Mu Y, Lescar J, Liang ZX
Title
Structure and catalytic mechanism of the thioesterase CalE7 in enediyne biosynthesis.
Journal
Reference
Authors
Belecki K, Townsend CA
Title
Biochemical determination of enzyme-bound metabolites: preferential accumulation of a programmed octaketide on the enediyne polyketide synthase CalE8.
Journal
Reference
Authors
Horsman GP, Chen Y, Thorson JS, Shen B
Title
Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes.
Journal
Reference
Authors
Chen X, Ji R, Jiang X, Yang R, Liu F, Xin Y
Title
Iterative type I polyketide synthases involved in enediyne natural product biosynthesis.
Journal
Reference
Authors
Lin S, Horsman GP, Chen Y, Li W, Shen B
Title
Characterization of the SgcF epoxide hydrolase supporting an (R)-vicinal diol intermediate for enediyne antitumor antibiotic C-1027 biosynthesis.
Journal
Reference
Authors
Horsman GP, Lechner A, Ohnishi Y, Moore BS, Shen B
Title
Predictive model for epoxide hydrolase-generated stereochemistry in the biosynthesis of nine-membered enediyne antitumor antibiotics.
Journal
Reference
Authors
Lin S, Horsman GP, Shen B
Title
Characterization of the epoxide hydrolase NcsF2 from the neocarzinostatin biosynthetic gene cluster.
Journal
Reference
Authors
Van Lanen SG, Lin S, Shen B
Title
Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism.
Journal
Reference
Authors
Christenson SD, Wu W, Spies MA, Shen B, Toney MD
Title
Kinetic analysis of the 4-methylideneimidazole-5-one-containing tyrosine aminomutase in enediyne antitumor antibiotic C-1027 biosynthesis.
Journal
Reference
Authors
Van Lanen SG, Lin S, Dorrestein PC, Kelleher NL, Shen B
Title
Substrate specificity of the adenylation enzyme SgcC1 involved in the biosynthesis of the enediyne antitumor antibiotic C-1027.
Journal
Reference
Authors
Van Lanen SG, Dorrestein PC, Christenson SD, Liu W, Ju J, Kelleher NL, Shen B
Title
Biosynthesis of the beta-amino acid moiety of the enediyne antitumor antibiotic C-1027 featuring beta-amino acyl-S-carrier protein intermediates.
Journal
Reference
Authors
Lin S, Van Lanen SG, Shen B
Title
Characterization of the two-component, FAD-dependent monooxygenase SgcC that requires carrier protein-tethered substrates for the biosynthesis of the enediyne antitumor antibiotic C-1027.
Journal
Reference
Authors
Van Lanen SG, Lin S, Horsman GP, Shen B
Title
Characterization of SgcE6, the flavin reductase component supporting FAD-dependent halogenation and hydroxylation in the biosynthesis of the enediyne antitumor antibiotic C-1027.
Journal
Reference
Authors
Lohman JR, Shen B
Title
4-methylideneimidazole-5-one-containing aminomutases in enediyne biosynthesis.
Journal
Reference
Authors
Ling J, Horsman GP, Huang SX, Luo Y, Lin S, Shen B
Title
Enediyne antitumor antibiotic maduropeptin biosynthesis featuring a C-methyltransferase that acts on a CoA-tethered aromatic substrate.
Journal
Reference
Authors
Huang SX, Lohman JR, Huang T, Shen B
Title
A new member of the 4-methylideneimidazole-5-one-containing aminomutase family from the enediyne kedarcidin biosynthetic pathway.
Journal
Reference
Authors
McCoy JG, Johnson HD, Singh S, Bingman CA, Lei IK, Thorson JS, Phillips GN Jr
Title
Structural characterization of CalO2: a putative orsellinic acid P450 oxidase in the calicheamicin biosynthetic pathway.
Journal
Reference
Authors
Singh S, Nandurkar NS, Thorson JS
Title
Characterization of the calicheamicin orsellinate C2-O-methyltransferase CalO6.
Journal
Reference
Authors
Chang A, Singh S, Bingman CA, Thorson JS, Phillips GN Jr
Title
Structural characterization of CalO1: a putative orsellinic acid methyltransferase in the calicheamicin-biosynthetic pathway.
Journal
Related pathway
ko00400 Phenylalanine, tyrosine and tryptophan biosynthesis
ko00523 Polyketide sugar unit biosynthesis
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