BGC0000055

General information about the BGC

MIBiG accession	BGC0000055
Short description	erythromycin A biosynthetic gene cluster from Saccharopolyspora erythraea NRRL 2338
Status	Quality: questionable The quality level of this entry. Status: active The status of this entry. Completeness: complete Whether the entry covers everything needed for the pathway producing the compound(s)
Biosynthetic class(es)	PKS (Type I) saccharide (hybrid/tailoring)
Loci	AM420293.1 778214 - 832825 via Knock-out studies, Enzymatic assays, Heterologous expression, Gene expression correlated with compound production
Compounds	erythromycin A erythromycin B erythromycin C erythromycin D
Species	Saccharopolyspora erythraea NRRL 2338 [taxonomy]
References	[1] Transcriptional organization of the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea. Reeves AR et al., J Bacteriol (1999) PMID:10559177 [2] Type I polyketide biosynthesis in bacteria (Part A--erythromycin biosynthesis). Rawlings BJ, Nat Prod Rep (2001) PMID:11336289 [3] Analysis of an 8.1-kb DNA fragment contiguous with the erythromycin gene cluster of Saccharopolyspora erythraea in the eryCI-flanking region. Reeves AR et al., Antimicrob Agents Chemother (2002) PMID:12435693 [4] A specific role of the Saccharopolyspora erythraea thioesterase II gene in the function of modular polyketide synthases. Hu Z et al., Microbiology (Reading) (2003) PMID:12904561 [5] Reconstitution and characterization of a new desosaminyl transferase, EryCIII, from the erythromycin biosynthetic pathway. Lee HY et al., J Am Chem Soc (2004) PMID:15303858 [6] Improved bioconversion of 15-fluoro-6-deoxyerythronolide B to 15-fluoro-erythromycin A by overexpression of the eryK Gene in Saccharopolyspora erythraea. Desai RP et al., Biotechnol Prog (2004) PMID:15575696 [7] Identification of DEBS 1, DEBS 2 and DEBS 3, the multienzyme polypeptides of the erythromycin-producing polyketide synthase from Saccharopolyspora erythraea. Caffrey P et al., FEBS Lett (1992) PMID:1618327 [8] Effects of methylmalonyl-CoA mutase gene knockouts on erythromycin production in carbohydrate-based and oil-based fermentations of Saccharopolyspora erythraea. Reeves AR et al., J Ind Microbiol Biotechnol (2006) PMID:16491356 [9] Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Oliynyk M et al., Nat Biotechnol (2007) PMID:17369815 [10] Genetic modulation of the overexpression of tailoring genes eryK and eryG leading to the improvement of erythromycin A purity and production in Saccharopolyspora erythraea fermentation. Chen Y et al., Appl Environ Microbiol (2008) PMID:18223111 [11] Cloning and sequence analysis of genes involved in erythromycin biosynthesis in Saccharopolyspora erythraea: sequence similarities between EryG and a family of S-adenosylmethionine-dependent methyltransferases. Haydock SF et al., Mol Gen Genet (1991) PMID:1840640 [12] Knockout of the erythromycin biosynthetic cluster gene, eryBI, blocks isoflavone glucoside bioconversion during erythromycin fermentations in Aeromicrobium erythreum but not in Saccharopolyspora erythraea. Reeves AR et al., Appl Environ Microbiol (2008) PMID:18836015 [13] Knocking out of tailoring genes eryK and eryG in an industrial erythromycin-producing strain of Saccharopolyspora erythraea leading to overproduction of erythromycin B, C and D at different conversion ratios. Zhang Q et al., Lett Appl Microbiol (2011) PMID:21175699 [14] Organization of a cluster of erythromycin genes in Saccharopolyspora erythraea. Weber JM et al., J Bacteriol (1990) PMID:2185216 [15] An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Cortes J et al., Nature (1990) PMID:2234082 [16] Systems perspectives on erythromycin biosynthesis by comparative genomic and transcriptomic analyses of S. erythraea E3 and NRRL23338 strains. Li YY et al., BMC Genomics (2013) PMID:23902230 [17] Identification of a gene required for the terminal step in erythromycin A biosynthesis in Saccharopolyspora erythraea (Streptomyces erythreus). Weber JM et al., Gene (1989) PMID:2469627 [18] Architectures of whole-module and bimodular proteins from the 6-deoxyerythronolide B synthase. Edwards AL et al., J Mol Biol (2014) PMID:24704088 [19] Molecular characterization of a gene from Saccharopolyspora erythraea (Streptomyces erythraeus) which is involved in erythromycin biosynthesis. Dhillon N et al., Mol Microbiol (1989) PMID:2575703 [20] Cloning of genes governing the deoxysugar portion of the erythromycin biosynthesis pathway in Saccharopolyspora erythraea (Streptomyces erythreus). Vara J et al., J Bacteriol (1989) PMID:2681144 [21] Cloning and heterologous expression of the genes encoding nonspecific electron transport components for a cytochrome P450 system of Saccharopolyspora erythraea involved in erythromycin production. Zotchev SB et al., Gene (1995) PMID:7737500 [22] Structure of cytochrome P450eryF involved in erythromycin biosynthesis. Cupp-Vickery JR et al., Nat Struct Biol (1995) PMID:7749919 [23] Inhibition of erythromycin synthesis by disruption of malonyl-coenzyme A decarboxylase gene eryM in Saccharopolyspora erythraea. Hsieh YJ et al., J Bacteriol (1994) PMID:8300527 [24] Identification of a Saccharopolyspora erythraea gene required for the final hydroxylation step in erythromycin biosynthesis. Stassi D et al., J Bacteriol (1993) PMID:8416893 [25] Substrate specificity of 6-deoxyerythronolide B hydroxylase, a bacterial cytochrome P450 of erythromycin A biosynthesis. Andersen JF et al., Biochemistry (1993) PMID:8448148 [26] 6-Deoxyerythronolide B synthase 3 from Saccharopolyspora erythraea: over-expression in Escherichia coli, purification and characterisation. Roberts GA et al., Biochem Soc Trans (1993) PMID:8449313 [27] Sequencing and mutagenesis of genes from the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea that are involved in L-mycarose and D-desosamine production. Summers RG et al., Microbiology (Reading) (1997) PMID:9353926 [28] Analysis of seven genes from the eryAI-eryK region of the erythromycin biosynthetic gene cluster in Saccharopolyspora erythraea. Gaisser S et al., Mol Gen Genet (1997) PMID:9393448 [29] The loading domain of the erythromycin polyketide synthase is not essential for erythromycin biosynthesis in Saccharopolyspora erythraea. Pereda A et al., Microbiology (Reading) (1998) PMID:9493390 [30] Targeted gene inactivation for the elucidation of deoxysugar biosynthesis in the erythromycin producer Saccharopolyspora erythraea. Salah-Bey K et al., Mol Gen Genet (1998) PMID:9563840 [31] Analysis of eryBI, eryBIII and eryBVII from the erythromycin biosynthetic gene cluster in Saccharopolyspora erythraea. Gaisser S et al., Mol Gen Genet (1998) PMID:9613575

Chemical products information

erythromycin A Evidence: NMR, Mass spectrometry, X-ray crystallography, Chemical derivatisation, Total synthesis

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C₃₇H₆₇N₁O₁₃

Chemical database entries
PubCHEM
ChEBI
ChEMBL
ChemSpider

erythromycin B Evidence: NMR, Mass spectrometry, Chemical derivatisation, Total synthesis

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C₃₇H₆₇N₁O₁₂

Chemical database entries
NPAtlas
PubCHEM
ChEBI
ChEMBL
ChemSpider

erythromycin C Evidence: NMR, Mass spectrometry

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C₃₆H₆₅N₁O₁₃

Chemical database entries
NPAtlas
PubCHEM
ChEBI
ChemSpider

erythromycin D Evidence: NMR, Mass spectrometry

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C₃₆H₆₅N₁O₁₂

Chemical database entries
PubCHEM
ChEBI
ChemSpider

List of genes involved in compound(s) production

Identifiers	Position	Product	Functions	Evidence	Extra
SACE_0712 CAM00053.1	778214 - 778594 (+)	putative erythromycin esterase			copy AA seq copy Nt seq
SACE_0713 CAM00054.1 eryK	778654 - 779847 (+)	cytochrome P450 Erythromycin B/D C-12 hydroxylase	Tailoring	Knock-out Activity assay	copy AA seq copy Nt seq
SACE_0714 CAM00055.1 eryBVII	779802 - 780404 (-)	dTDP-4-deoxyglucose 3,5-epimerase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0715 CAM00056.1 eryCV	780412 - 781881 (-)	EryCV NDP-4,6-dideoxyhexose 3,4-enoyl reductase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0716 CAM00057.1 eryCIV	781919 - 783124 (-)	eryCIV NDP-6-deoxyhexose 3,4-dehydratase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0717 CAM00058.1 eryBVI	783121 - 784584 (-)	NDP-4-keto-6-deoxy-glucose 2,3-dehydratase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0718 CAM00059.1 eryCVI	784738 - 785451 (-)	TDP-desosamine-N-dimethyltransferase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0719 CAM00060.1 eryBV	785504 - 786751 (-)	6-DEB TDP-mycarosyl glycosyltransferase	Tailoring	Knock-out	copy AA seq copy Nt seq
SACE_0720 CAM00061.1 eryBIV	786751 - 787719 (-)	dTDP-4-keto-6-deoxy-L-hexose 4-reductase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0721 CAM00062.1 eryAI	787944 - 798581 (+)	EryAI Erythromycin polyketide synthase modules 1 and 2	Scaffold biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0722 CAM00063.1	798638 - 799849 (-)	transposase			copy AA seq copy Nt seq
SACE_0723 CAM00064.1 eryAII	800023 - 810726 (+)	EryAII Erythromycin polyketide synthase modules 3 and 4	Scaffold biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0724 CAM00065.1 eryAIII	810727 - 820242 (+)	EryAIII Erythromycin polyketide synthase modules 5 and 6	Scaffold biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0725 CAM00066.1 eryCII	820239 - 821324 (+)	TDP-4-keto-6-deoxy-glucose 3,4-isomerase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0726 CAM00067.1 eryCIII	821335 - 822600 (+)	glycosyl transferase, NDP-D-desosamine : 3-L-mycarosyl erythronolide B	Tailoring	Knock-out	copy AA seq copy Nt seq
SACE_0727 CAM00068.1 eryBII	822597 - 823598 (+)	TDP-4-keto-6-deoxyhexose 2,3-reductase	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq
SACE_0728 CAM00069.1 eryG	823630 - 824550 (+)	erythromycin C methlytransferase	Tailoring	Knock-out	copy AA seq copy Nt seq
SACE_0729 CAM00070.1	824527 - 825270 (-)	thioesterase, erythromycin biosynthesis	Activation / processing	Other in vivo study	copy AA seq copy Nt seq
SACE_0730 CAM00071.1 eryF	825267 - 826481 (-)	6-deoxyerythronolide B hydroxylase (6-DEB hydroxylase)	Tailoring	Knock-out	copy AA seq copy Nt seq
SACE_0731 CAM00072.1 eryBIII	826478 - 827710 (-)	eryBIII NDP-4-keto-2,6-dideoxyhexose 3-C-methyltransferase	Precursor biosynthesis	Other in vivo study	copy AA seq copy Nt seq
SACE_0732 CAM00073.1 eryBI	827912 - 830338 (+)	beta-D-glucosidase			copy AA seq copy Nt seq
SACE_0733 CAM00074.1 ermE	830393 - 831538 (-)	N-6-aminoadenine-N-methyltransferase, erythromycinresistance	Resistance/immunity	Other in vivo study	copy AA seq copy Nt seq
SACE_0734 CAM00075.1 eryCI	831725 - 832825 (+)	Erythromycin biosynthesis transaminase EryCI	Precursor biosynthesis	Knock-out	copy AA seq copy Nt seq

Biosynthesis information

Biosynthetic modules

Name

0

Type

pks-modular-starter

Genes

eryAI

Substrates

Integrated Monomers

Domains

acyltransferase, carrier (ACP)

Name

1

Type

pks-modular

Genes

eryAI

Substrates

Integrated Monomers

Domains

acyltransferase, ketosynthase, acyltransferase, ketoreductase, carrier (ACP)

Name

2

Type

pks-modular

Genes

eryAI

Substrates

Integrated Monomers

Domains

acyltransferase, ketosynthase, acyltransferase, ketoreductase, carrier (ACP)

Name

3

Type

pks-modular

Genes

eryAII

Substrates

Integrated Monomers

Domains

acyltransferase, ketosynthase, acyltransferase, ketoreductase, carrier (ACP)

Name

4

Type

pks-modular

Genes

eryAII

Substrates

Integrated Monomers

Domains

acyltransferase, ketosynthase, acyltransferase, dehydratase, enoylreductase, ketoreductase, carrier (ACP)

Name

5

Type

pks-modular

Genes

eryAIII

Substrates

Integrated Monomers

Domains

acyltransferase, ketosynthase, acyltransferase, ketoreductase, carrier (ACP)

Name

6

Type

pks-modular

Genes

eryAIII

Substrates

Integrated Monomers

Domains

acyltransferase, ketosynthase, acyltransferase, ketoreductase, thioesterase, carrier (ACP)

Annotation changelog

Entry version: 4

Date

Changes

Submitters

Reviewers

2022-10-07

Update chemical activity to schema version 2.11

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Entry version: 3

Date

Changes

Submitters

Reviewers

2022-09-15

Removed ketoreductase stereochemistry annotation from modules without ketoreductases

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Entry version: 2

Date

Changes

Submitters

Reviewers

2019-10-16

Migrated from v1.4

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2019-10-16

Updated compound(s) information (NPAtlas curation)

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Entry version: 1

Date

Changes

Submitters

Reviewers

2015-06-12

Submitted

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Detailed domain annotation

Selected features only

Show module domains

Similar known gene clusters from MIBiG 4.0

Legend:

Biosynthetic modules

Entry version: 4

Entry version: 3

Entry version: 2

Entry version: 1