KEGG PATHWAY: rn01059

PATHWAY: rn01059

Entry

rn01059                     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

rn01059

Biosynthesis of enediyne antibiotics

Module

M00824

9-membered enediyne core biosynthesis, malonyl-CoA => 3-hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-ACP => 9-membered enediyne core [PATH:rn01059]

M00825

10-membered enediyne core biosynthesis, malonyl-CoA => 3-hydroxyhexadeca-4,6,8,10,12,14-hexaenoyl-ACP => 10-membered enediyne core [PATH:rn01059]

M00826

C-1027 benzoxazolinate moiety biosynthesis, chorismate => benzoxazolinyl-CoA [PATH:rn01059]

M00827

C-1027 beta-amino acid moiety biosynthesis, tyrosine => 3-chloro-4,5-dihydroxy-beta-phenylalanyl-PCP [PATH:rn01059]

M00828

Maduropeptin beta-hydroxy acid moiety biosynthesis, tyrosine => 3-(4-hydroxyphenyl)-3-oxopropanoyl-PCP [PATH:rn01059]

M00829

3,6-Dimethylsalicylyl-CoA biosynthesis, malonyl-CoA => 6-methylsalicylate => 3,6-dimethylsalicylyl-CoA [PATH:rn01059]

M00830

Neocarzinostatin naphthoate moiety biosynthesis, malonyl-CoA => 2-hydroxy-5-methyl-1-naphthoate => 2-hydroxy-7-methoxy-5-methyl-1-naphthoyl-CoA [PATH:rn01059]

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:rn01059]

M00832

Kedarcidin 2-aza-3-chloro-beta-tyrosine moiety biosynthesis, azatyrosine => 2-aza-3-chloro-beta-tyrosyl-PCP [PATH:rn01059]

M00833

Calicheamicin biosynthesis, calicheamicinone => calicheamicin [PATH:rn01059]

M00834

Calicheamicin orsellinate moiety biosynthesis, malonyl-CoA => orsellinate-ACP => 5-iodo-2,3-dimethoxyorsellinate-ACP [PATH:rn01059]

Reaction

R07253

acyl-CoA:malonyl-CoA C-acyltransferase (decarboxylating, oxoacyl-reducing, thioester-hydrolysing and cyclizing)

R08956

(2S)-2-amino-4-deoxychorismate:L-glutamate aminotransferase

R09559

(2S)-2-amino-4-deoxychorismate:FMN oxidoreductase

R10731

(3S)-3-amino-3-(3-chloro-4-hydroxyphenyl)propanoyl-[peptidyl-carrier protein],FADH2:oxygen oxidoreductase (5-hydroxylating)

R10771

2-hydroxy-7-methoxy-5-methyl-1-naphthoate:CoA ligase

R10796

2-hydroxy-5-methyl-1-naphthoate,reduced ferredoxin:oxygen oxidoreductase (7-hydroxylating)

R10963

S-adenosyl-L-methionine:2,7-dihydroxy-5-methyl-1-naphthoate 7-O-methyltransferase

R11125

malonyl-CoA:acetyl-CoA malonyltransferase (2-hydroxy-5-methyl-1-naphthoic acid forming)

R11362

R11363

R11364

R11365

R11366

L-tyrosine 2,3-aminomutase

R11367

(S)-beta-tyrosine:[peptidyl-carrier protein] ligase (AMP-forming)

R11368

(S)-beta-tyrosyl-[pcp]:FADH2 oxidoreductase

R11369

R11370

6-methylsalicylate:CoA ligase (AMP-forming)

R11371

S-adenosyl-L-methionine:6-methylsalicylyl-CoA 3-C-methyltransferase

R11387

R11388

R11389

R11390

R11391

2-aza-L-tyrosine 2,3-aminomutase

R11392

(R)-2-aza-beta-tyrosine:[peptidyl-carrier protein] ligase (AMP-forming)

R11393

(R)-2-aza-beta-tyrosyl-[pcp]:FADH2 oxidoreductase

R11412

R11413

S-adenosyl-L-methionine:orsellinate-[acp] O-methyltransferase

R11414

R11415

R11416

S-adenosyl-L-methionine:3-hydroxy-5-iodo-2-methoxyorsellinate-[acp] O-methyltransferase

R11417

dTDP-4-hydroxyamino-4,6-dideoxy-alpha-D-glucose:calicheamicinone 4-hydroxyamino-4,6-dideoxy-alpha-D-glucosyltransferase

R11418

dTDP-4-deoxy-4-thio-alpha-D-digitoxose:calicheamicin-T0 4-deoxy-4-thio-alpha-D-digitoxosyltransferase

R11419

R11420

dTDP-4-ethylamino-3-O-methyl-2,4-dideoxy-L-threo-pentopyranose:calicheamicin-PsAg 4-ethylamino-3-O-methyl-2,4-dideoxy-L-threo-pentosyltransferase

R11421

dTDP-4-ethylamino-3-O-methyl-2,4-dideoxy-L-threo-pentopyranose:calicheamicin-alpha3(I) 4-ethylamino-3-O-methyl-2,4-dideoxy-L-threo-pentosyltransferase

R11422

dTDP-3'-O-methyl-beta-L-rhamnose:calicheamicin-alpha1(I) 3'-O-methyl-beta-L-rhamnosyltransferase

R11423

dTDP-3'-O-methyl-beta-L-rhamnose:calicheamicin-PsAg 3'-O-methyl-beta-L-rhamnosyltransferase

R11429

R11430

R11431

R11432

R11433

R11434

R11435

R11436

Compound

C00082

L-Tyrosine

C00083

Malonyl-CoA

C00251

Chorismate

C00636

D-Mannose 1-phosphate

C02657

6-Methylsalicylate

C11438

C-1027 Chromophore

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

C21301

Kedarcidin 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

C21308

(S)-beta-Tyrosine

C21309

(S)-beta-Tyrosyl-[pcp]

C21311

3-(4-Hydroxyphenyl)-3-oxopropanoyl-[pcp]

C21312

6-Methylsalicylyl-CoA

C21313

3,6-Dimethylsalicylyl-CoA

C21314

NDP-D-mannose

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

C21325

Azatyrosine

C21326

(R)-2-Aza-beta-tyrosine

C21327

(R)-2-Aza-beta-tyrosyl-[pcp]

C21328

(R)-2-Aza-3-chloro-beta-tyrosyl-[pcp]

C21337

Calicheamicinone

C21338

Calicheamicin T0

C21339

4-Deoxy-4-thio-alpha-D-digitoxosyl-calicheamicin T0

C21340

Calicheamicin PsAg

C21341

Calicheamicin alpha1(I)

C21342

Calicheamicin alpha3(I)

C21343

Orsellinate-[acp]

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]

C21363

dTDP-madurosamine

Reference

PMID:20336235

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

PMID:18397168

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

PMID:12183628

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

PMID:12183629

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

PMID:17918933

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

PMID:15797213

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

PMID:23360970

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

PMID:19362637

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

PMID:20024241

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

PMID:18223152

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

PMID:19689130

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

PMID:19357082

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

PMID:24041368

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

PMID:20534556

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

PMID:25278375

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

PMID:19856960

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

PMID:23844627

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

PMID:20704329

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

PMID:18182490

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

PMID:14580219

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

PMID:16887797

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

PMID:16104723

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

PMID:18426211

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

PMID:19817865

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

PMID:23034235

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

PMID:20718468