KEGG   PATHWAY: map01059
Entry
map01059                    Pathway                                

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
Pathway map
map01059  Biosynthesis of enediyne antibiotics
map01059

Module
M00824  9-membered enediyne core biosynthesis, malonyl-CoA => 3-hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-ACP => 9-membered enediyne core [PATH:map01059]
M00825  10-membered enediyne core biosynthesis, malonyl-CoA => 3-hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-ACP => 10-membered enediyne core [PATH:map01059]
M00826  C-1027 benzoxazolinate moiety biosynthesis, chorismate => benzoxazolinyl-CoA [PATH:map01059]
M00827  C-1027 beta-amino acid moiety biosynthesis, tyrosine => 3-chloro-4,5-dihydroxy-beta-phenylalanyl-PCP [PATH:map01059]
M00828  Maduropeptin beta-hydroxy acid moiety biosynthesis, tyrosine => 3-(4-hydroxyphenyl)-3-oxopropanoyl-PCP [PATH:map01059]
M00829  3,6-Dimethylsalicylyl-CoA biosynthesis, malonyl-CoA => 6-methylsalicylate => 3,6-dimethylsalicylyl-CoA [PATH:map01059]
M00830  Neocarzinostatin naphthoate moiety biosynthesis, malonyl-CoA => 2-hydroxy-5-methyl-1-naphthoate => 2-hydroxy-7-methoxy-5-methyl-1-naphthoyl-CoA [PATH:map01059]
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:map01059]
M00832  Kedarcidin 2-aza-3-chloro-beta-tyrosine moiety biosynthesis, azatyrosine => 2-aza-3-chloro-beta-tyrosyl-PCP [PATH:map01059]
M00833  Calicheamicin biosynthesis, calicheamicinone => calicheamicin [PATH:map01059]
M00834  Calicheamicin orsellinate moiety biosynthesis, malonyl-CoA => orsellinate-ACP => 5-iodo-2,3-dimethoxyorsellinate-ACP [PATH:map01059]
Reference
  Authors
Liang ZX
  Title
Complexity and simplicity in the biosynthesis of enediyne natural products.
  Journal
Nat Prod Rep 27:499-528 (2010)
DOI:10.1039/b908165h
Reference
  Authors
Van Lanen SG, Shen B
  Title
Biosynthesis of enediyne antitumor antibiotics.
  Journal
Curr Top Med Chem 8:448-59 (2008)
DOI:10.2174/156802608783955656
Reference
  Authors
Liu W, Christenson SD, Standage S, Shen B
  Title
Biosynthesis of the enediyne antitumor antibiotic C-1027.
  Journal
Science 297:1170-3 (2002)
DOI:10.1126/science.1072110
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
Science 297:1173-6 (2002)
DOI:10.1126/science.1072105
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
J Am Chem Soc 129:13082-94 (2007)
DOI:10.1021/ja073275o
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
Chem Biol 12:293-302 (2005)
DOI:10.1016/j.chembiol.2004.12.013
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
Mol Biosyst 9:478-91 (2013)
DOI:10.1039/c3mb25523a
Reference
  Authors
Horsman GP, Van Lanen SG, Shen B
  Title
Iterative type I polyketide synthases for enediyne core biosynthesis.
  Journal
Methods Enzymol 459:97-112 (2009)
DOI:10.1016/S0076-6879(09)04605-9
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
Chem Commun (Camb) 7399-401 (2009)
DOI:10.1039/b916751j
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
Proc Natl Acad Sci U S A 105:1460-5 (2008)
DOI:10.1073/pnas.0711625105
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
J Am Chem Soc 131:12564-6 (2009)
DOI:10.1021/ja904391r
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
J Biol Chem 284:15739-49 (2009)
DOI:10.1074/jbc.M809669200
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
J Am Chem Soc 135:14339-48 (2013)
DOI:10.1021/ja406697t
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
Proc Natl Acad Sci U S A 107:11331-5 (2010)
DOI:10.1073/pnas.1003442107
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
IUBMB Life 66:587-95 (2014)
DOI:10.1002/iub.1316
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
J Am Chem Soc 131:16410-7 (2009)
DOI:10.1021/ja901242s
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
Biochemistry 52:5217-24 (2013)
DOI:10.1021/bi400572a
Reference
  Authors
Lin S, Horsman GP, Shen B
  Title
Characterization of the epoxide hydrolase NcsF2 from the neocarzinostatin biosynthetic gene cluster.
  Journal
Org Lett 12:3816-9 (2010)
DOI:10.1021/ol101473t
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
Proc Natl Acad Sci U S A 105:494-9 (2008)
DOI:10.1073/pnas.0708750105
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
Biochemistry 42:12708-18 (2003)
DOI:10.1021/bi035223r
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
J Biol Chem 281:29633-40 (2006)
DOI:10.1074/jbc.M605887200
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
J Am Chem Soc 127:11594-5 (2005)
DOI:10.1021/ja052871k
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
J Am Chem Soc 130:6616-23 (2008)
DOI:10.1021/ja710601d
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
FEMS Microbiol Lett 300:237-41 (2009)
DOI:10.1111/j.1574-6968.2009.01802.x
Reference
  Authors
Lohman JR, Shen B
  Title
4-methylideneimidazole-5-one-containing aminomutases in enediyne biosynthesis.
  Journal
Methods Enzymol 516:299-319 (2012)
DOI:10.1016/B978-0-12-394291-3.00007-1
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
J Am Chem Soc 132:12534-6 (2010)
DOI:10.1021/ja1050814
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
Proc Natl Acad Sci U S A 110:8069-74 (2013)
DOI:10.1073/pnas.1304733110
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
Proteins 74:50-60 (2009)
DOI:10.1002/prot.22131
Reference
  Authors
Singh S, Nandurkar NS, Thorson JS
  Title
Characterization of the calicheamicin orsellinate C2-O-methyltransferase CalO6.
  Journal
Chembiochem 15:1418-21 (2014)
DOI:10.1002/cbic.201402119
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
Acta Crystallogr D Biol Crystallogr 67:197-203 (2011)
DOI:10.1107/S090744491100360X
Related
pathway
map00400  Phenylalanine, tyrosine and tryptophan biosynthesis
map00523  Polyketide sugar unit biosynthesis
map00620  Pyruvate metabolism
KO pathway
ko01059   
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