KEGG PATHWAY: rn00253

PATHWAY: rn00253

Entry

rn00253                     Pathway

Name

Tetracycline biosynthesis

Description

Tetracyclines are aromatic polyketide antibiotics produced by Streptomyces species via type II polyketide synthases (PKSs). Tetracyclines contain a linear tetracyclic skeleton, which is formed from a malonamate starter unit and malonyl-CoA extender units through a common polyketide pathway [MD:M00778]. This diagram shows biosynthesis of naturally occurring tetracyclines (tetracycline, oxytetracycline and chlortetracycline) via a common intermediate anhydrotetracycline [MD:M00780 M00823].

Class

Metabolism; Metabolism of terpenoids and polyketides

Pathway map

rn00253

Tetracycline biosynthesis

Module

M00778

Type II polyketide backbone biosynthesis, acyl-CoA + malonyl-CoA => polyketide [PATH:rn00253]

M00780

Tetracycline/oxytetracycline biosynthesis, pretetramide => tetracycline/oxytetracycline [PATH:rn00253]

M00823

Chlortetracycline biosynthesis, pretetramide => chlortetracycline [PATH:rn00253]

Drug

D00201

Tetracycline (JAN/USP/INN)

D07689

Chlortetracycline (INN)

Other DBs

GO:

0043644

Reaction

R04060

anhydrotetracycline,NADPH:oxygen oxidoreductase (6-hydroxylating)

R05459

tetracycline:coenzyme-F420 oxidoreductase

R05462

4-hydroxy-6-methylpretetramide,NADPH:oxygen oxidoreductase (12a-hydroxylating)

R05463

6-methylpretetramide,NADPH:oxygen oxidoreductase (4-hydroxylating)

R06642

R09187

R09188

R09189

S-adenosyl-L-methionine:pretetramid C-methyltransferase

R09190

6-methylpretetramide,NADPH:oxygen oxidoreductase (4,12a-hydroxylating)

R09191

S-adenosyl-L-methionine:4-amino-anhydrotetracycline N-methyltransferase

R09192

oxytetracycline:coenzyme-F420 oxidoreductase

R09196

R09197

R09198

5a,11a-dehydrotetracycline,NADPH:oxygen oxidoreductase (5-hydroxylating)

R11449

tetracycline,NADPH:oxygen oxidoreductase (11a-hydroxylating)

R11478

tetracycline:FADH2 oxidoreductase (7-halogenating)

R11515

malonyl-[acyl-carrier protein]:L-glutamine amido-ligase (AMP-forming)

R11516

malonyl-CoA:malonamoyl-[acyl-carrier protein] malonyltransferase

R11525

oxytetracycline,NADPH:oxygen oxidoreductase (11a-hydroxylating)

R11526

chlortetracycline,NADPH:oxygen oxidoreductase (11a-hydroxylating)

Compound

C00083

Malonyl-CoA

C01209

Malonyl-[acyl-carrier protein]

C02811

Anhydrotetracycline

C03206

5a,11a-Dehydrotetracycline

C06570

Tetracycline

C06571

Chlortetracycline

C06624

Oxytetracycline

C06627

4-Keto-anhydrotetracycline

C06628

4-Hydroxy-6-methylpretetramide

C06629

6-Methylpretetramide

C06654

4-Amino-anhydrotetracycline

C12441

18-Carbamoyl-3,5,7,9,11,13,15,17-octaoxooctadecanoyl-[acp]

C12442

C-9 Reduced nonaketamide

C18293

Nonaketamide monocyclic intermediate

C18294

Nonaketamide tricyclic intermediate

C18295

Pretetramid

C18296

5a,11a-Dehydrooxytetracycline

C21391

11a-Hydroxytetracycline

C21430

Malonamoyl-[acyl-carrier protein]

C21438

11a-Hydroxyoxytetracycline

C21439

11a-Hydroxy-7-chlortetracycline

Reference

PMID:16959966

Authors

Petkovic H, Cullum J, Hranueli D, Hunter IS, Peric-Concha N, Pigac J, Thamchaipenet A, Vujaklija D, Long PF

Title

Genetics of Streptomyces rimosus, the oxytetracycline producer.

Journal

Microbiol Mol Biol Rev 70:704-28 (2006)
DOI:10.1128/MMBR.00004-06

Reference

PMID:20522541

Authors

Pickens LB, Tang Y

Title

Oxytetracycline biosynthesis.

Journal

J Biol Chem 285:27509-15 (2010)
DOI:10.1074/jbc.R110.130419

Reference

PMID:16597959

Authors

Zhang W, Ames BD, Tsai SC, Tang Y

Title

Engineered biosynthesis of a novel amidated polyketide, using the malonamyl-specific initiation module from the oxytetracycline polyketide synthase.

Journal

Appl Environ Microbiol 72:2573-80 (2006)
DOI:10.1128/AEM.72.4.2573-2580.2006

Reference

Authors

Dewick PM.

Title

Medicinal Natural Products: A Biosynthetic Approach, Second Edition

Journal

John Wiley and Sons (2001)

Reference

PMID:1134373

Authors

Miller PA, Hash JH

Title

S-adenosylmethionine:dedimethylamino-4-aminoanhydrotetracycline N-methyltransferase.

Journal

Methods Enzymol 43:603-6 (1975)
DOI:10.1016/0076-6879(75)43122-6

Reference

PMID:1134374

Authors

Miller PA, Hash JH

Title

ADP; tetracyclin 5a(11a)dehydrogenase.

Journal

Methods Enzymol 43:606-7 (1975)
DOI:10.1016/0076-6879(75)43123-8

Reference

PMID:19472250

Authors

Wang P, Zhang W, Zhan J, Tang Y

Title

Identification of OxyE as an ancillary oxygenase during tetracycline biosynthesis.

Journal

Chembiochem 10:1544-50 (2009)
DOI:10.1002/cbic.200900122

Reference

PMID:18422316

Authors

Zhang W, Watanabe K, Cai X, Jung ME, Tang Y, Zhan J

Title

Identifying the minimal enzymes required for anhydrotetracycline biosynthesis.

Journal

J Am Chem Soc 130:6068-9 (2008)
DOI:10.1021/ja800951e

Reference

PMID:10551844

Authors

Petkovic H, Thamchaipenet A, Zhou LH, Hranueli D, Raspor P, Waterman PG, Hunter IS

Title

Disruption of an aromatase/cyclase from the oxytetracycline gene cluster of Streptomyces rimosus results in production of novel polyketides with shorter chain lengths.

Journal

J Biol Chem 274:32829-34 (1999)
DOI:10.1016/S0021-9258(17)46583-5

Reference

PMID:16148009

Authors

Peric-Concha N, Borovicka B, Long PF, Hranueli D, Waterman PG, Hunter IS

Title

Ablation of the otcC gene encoding a post-polyketide hydroxylase from the oxytetracyline biosynthetic pathway in Streptomyces rimosus results in novel polyketides with altered chain length.

Journal

J Biol Chem 280:37455-60 (2005)
DOI:10.1074/jbc.M503191200

Reference

PMID:17631493

Authors

Zhang W, Watanabe K, Wang CC, Tang Y

Title

Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway.

Journal

J Biol Chem 282:25717-25 (2007)
DOI:10.1074/jbc.M703437200

Reference

PMID:8163168