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Information on EC 5.1.1.17 - isopenicillin-N epimerase
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5.1.1.17 isopenicillin-N epimeraseIUBMB Comments
This enzyme contains pyridoxal phosphate. Epimerization at C-5 of the 5-amino-5-carboxypentanoyl group to form penicillin N is required to make a substrate for EC 1.14.20.1, deactoxycephalosporin-C synthase, to produce cephalosporins. Forms part of the penicillin biosynthesis pathway (for pathway, click here).
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Word Map
- 5.1.1.17
- cephalosporin
- acremonium
- chrysogenum
- beta-lactam
- clavuligerus
-
epimerization
-
deacetoxycephalosporin
- cefef
- pyridoxal
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pcbab
-
deacetylcephalosporin
-
cephamycins
-
expandase
- acyltransferase
-
pende
-
untransformed
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alpha-aminoadipic
- lactamdurans
- daocs
- biotechnology
- synthesis
- medicine
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
cefd2, isopenicillin n epimerase, isopenicillin n-coa epimerase, ipn epimerase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
cefD2
IPN epimerase
isopenicillin N epimerase
isopenicillin N-CoA epimerase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
isopenicillin N = penicillin N
forms part of the penicillin biosynthesis pathway
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-
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isopenicillin N = penicillin N
this enzyme contains pyridoxal phosphate, epimerization at C-5 of the 5-amino-5-carboxypentanoyl group to form penicillin N is required to make a substrate for EC 1.14.20.1, deactoxycephalosporin-C synthase, to produce cephalosporins, forms part of the penicillin biosynthesis pathway
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
epimerization
epimerization
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-
-
-
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
penicillin-N 5-amino-5-carboxypentanoyl-epimerase
This enzyme contains pyridoxal phosphate. Epimerization at C-5 of the 5-amino-5-carboxypentanoyl group to form penicillin N is required to make a substrate for EC 1.14.20.1, deactoxycephalosporin-C synthase, to produce cephalosporins. Forms part of the penicillin biosynthesis pathway (for pathway, click here).
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CAS REGISTRY NUMBER
COMMENTARY
88201-43-8
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
deacetoxycephalosporin C
?
-
less than 1% of activity with penicillin N
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-
?
isopenicillin N
penicillin N
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part of the cephalosporin pathway
-
?
isopenicillin N
penicillin N
Acremonium chrysogenum C10 / ATCC 48272
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part of the cephalosporin pathway
-
?
isopenicillin N
penicillin N
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enzyme epimerizes the side chain of alpha-aminoadipic acid in isopenicillin N from the L- to the D-configuration, this is an important step since the next enzyme in the pathway, DAOCS, is unable to use isopenicillin N as substrate, in spite of the apparent minor structural difference between the two molecules
-
-
r
isopenicillin N
penicillin N
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part of the cephalosporin pathway
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?
isopenicillin N
penicillin N
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part of the cephalosporin pathway
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r
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
isopenicillin N
penicillin N
-
part of the cephalosporin pathway
-
?
isopenicillin N
penicillin N
Acremonium chrysogenum C10 / ATCC 48272
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part of the cephalosporin pathway
-
?
isopenicillin N
penicillin N
-
enzyme epimerizes the side chain of alpha-aminoadipic acid in isopenicillin N from the L- to the D-configuration, this is an important step since the next enzyme in the pathway, DAOCS, is unable to use isopenicillin N as substrate, in spite of the apparent minor structural difference between the two molecules
-
-
r
isopenicillin N
penicillin N
-
part of the cephalosporin pathway
-
?
isopenicillin N
penicillin N
-
part of the cephalosporin pathway
-
r
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pyridoxal 5'-phosphate
-
1 mol of pyridoxal 5'-phosphate per mol enzyme, 1.5fold increase in activity in the presence of 0.01 mM pyridoxal 5'-phosphate
pyridoxal 5'-phosphate
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stabilizes enzyme during purification, may be tightly bound to the enzyme
pyridoxal 5'-phosphate
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putative cofactor, does not increase enzyme activity in assay system, stabilizes enzyme during purification
pyridoxal 5'-phosphate
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cofactor of isopenicillin N epimerase is essential for activity and is supposed to bind the conserved amino acid sequence SXHKXL
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
hydroxylamine
-
10 mM, 68% inhibition, readdition of pyridoxal 5-phosphate causes an increase in activity to 63% of the control
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
92.0 units, 1 unit is the activity forming 1 ng of cephalosporin/min in a coupled assay, activity in cell extract
additional information
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strain C10 (ATCC 48272): 93 ng of cephalosporin C formed per min and mg of protein, transformant strain TMCD2: no activity, transformant strain TMCD26: 223 ng of cephalosporin C formed per min and mg of protein, transformant strain TMCD32: no activity, transformant strain TMCD39: no activity, transformant strain TMCD53: 226 ng of cephalosporin C formed per min and mg of protein, transformant strain TMCD242: 234 ng of cephalosporin C formed per min and mg of protein, transformant strain TMCD474: 202 ng of cephalosporin C formed per min and mg of protein
additional information
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19.53 units, 1 unit is defined as the amount of enzyme which produces 0.001 mg of penicillin N in 1 h
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8.3
-
isopenicillin N epimerase, standard assay mixture contains 1.4 mM isopenicillin N or penicillin N, 0.2 mM dithiothreitol, 0.1 mM pyridoxal phosphate and 50 mM pyrophosphate
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.5 - 8
-
strong decrease in activity above pH 8.0 and below pH 6.5
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Acremonium chrysogenum C10 / ATCC 48272
and transformant strains TMCD2, TMCD26, TMCD32, TMCD39, TMCD53, TMCD242, TMCD474
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and transformant strains TMCD2, TMCD26, TMCD32, TMCD39, TMCD53, TMCD242, TMCD474
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also known as Amycolatopsis lactamdurans, cefD1 and cefD2 gene products are involved in epimerization of isopenicillin N into penicillin N
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enzyme activity is greatly reduced in ammonium-supplemented cultures
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brenda
amino acid analysis reveals homology to aminotransferases
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-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
Show AA Sequence and Transmembrane Helices (500 entries)
Please use the AA Sequence and Transmembrane Helices Search for a specific query.
Please use the AA Sequence and Transmembrane Helices Search for a specific query.
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
50000
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70°C, 0.05 mM pyridoxal 5'-phosphate, 17 d, no loss of activity
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate, DE-52, DEAE-Affi-gel blue, Sephadex G-200, calcium phosphate, Mono Q
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by anion exchange chromatography, purified IPN epimerase is able to act in both orientations, leading in vitro to an equimolecular mixture of isopenicillin N and penicillin N
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Penicillium chrysogenum
Penecillium chrysogenum strains are constructed expressing cefD1 (isopenecillin N-CoA synthetase), cefD2 (isopenecillin N-CoA epimerase), cefEF (deacetylcephalosporin-actyltransferase), and cefG (deacetylcephalosporin C synthetase) genes cloned from Acremonium chrysogenum. HPLC analysis of cell extracts show that transformant TA64, TA71, and TA98 accumulate intracellularly deacetylcephalosporin C and, in the last strain (TA98), also cephalosporin C.
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
4% (v/v) glycerol causes the upregulation of isopenicillin N-CoA epimerase in the exponential phase
4% (v/v) glycerol causes the upregulation of isopenicillin N-CoA epimerase in the exponential phase
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4% (v/v) glycerol causes the upregulation of isopenicillin N-CoA epimerase in the exponential phase
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
biotechnology
medicine
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the conversion of isopenicillin N into penicillin N is part of the cephalosporin biosynthesis pathway. Cephalosporin is one of the most potent beta-lactam antibiotics, widely used in the treatment of infectious diseases
synthesis
biotechnology
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The results indicate that Penecillium chrysogenum can be used as heterologous host for the production of deacetylcephalosporin C
synthesis
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epimerization is a rate-limiting step in cephalosporin biosynthesis in Acremonium chrysogenum. When epimerase activity is enhanced, there is a clear increase in cephalosporin production. Thus, this method provides a strategy that could easily be applied to improve industrial cephalosporin producing strains
synthesis
Acremonium chrysogenum C10 / ATCC 48272
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epimerization is a rate-limiting step in cephalosporin biosynthesis in Acremonium chrysogenum. When epimerase activity is enhanced, there is a clear increase in cephalosporin production. Thus, this method provides a strategy that could easily be applied to improve industrial cephalosporin producing strains
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Cantwell, C.; Beckmann, R.; Whiteman, P.; Queener, S.W.; Abraham, E.P.
Isolation of deacetoxycephalosporin-c from fermentation broths of Penicillium chrysogenum transformants - construction of a new fungal biosynthetic-pathway
Proc. R. Soc. Lond. B Biol. Sci.
248
283-289
1992
Streptomyces microflavus
brenda
Yeh, W.K.; Ghag, S.K.; Queener, S.W.
Enzymes for epimerization of isopenicillin N, ring expansion of penicillin N, and 3'-hydroxylation of deacetoxycephalosporin C. Function, evolution, refolding, and enzyme engineering
Ann. N. Y. Acad. Sci.
672
396-408
1992
Streptomyces clavuligerus
-
brenda
Jensen, S.E.; Westlake, D.W.S.; Wolfe, S.
Partial purification and characterization of isopenicillin N epimerase activity from Streptomyces clavuligerus
Can. J. Microbiol.
29
1526-1531
1983
Streptomyces clavuligerus
brenda
Castro, J.M.; Liras, P.; Cortes, J.; Martin, J.F.
Regulation of a-aminoadipyl-cysteinyl-valine, isopenicillin N synthetase, isopenicillin N isomerase and deacetoxycephalosporin C synthetase by nitrogen sources in Streptomyces lactamdurans
Appl. Microbiol. Biotechnol.
22
32-40
1985
Amycolatopsis lactamdurans
-
brenda
Ramos, F.R.; Lopez-Nieto, M.J.; Martin, J.F.
Coordinate increase of isopenicillin N synthetase, isopenicillin N epimerase and deacetoxycephalosporin C synthetase in a high cephalosporin-producing mutant of Acremonium chrysogenum and simultaneous loss of the three enzymes in a non-producing mutant
FEMS Microbiol. Lett.
35
123-127
1986
Acremonium chrysogenum
-
brenda
Usui, S.; Yu, C.A.
Purification and properties of isopenicillin-N epimerase from Streptomyces clavuligerus
Biochim. Biophys. Acta
999
78-85
1989
Streptomyces clavuligerus
brenda
Laiz, L.; Liras, P.; Castro, J.M.; Martin, J.F.
Purification and characterization of the isopenicillin-N epimerase from Nocardia lactamdurans
J. Gen. Microbiol.
136
663-671
1990
Amycolatopsis lactamdurans
-
brenda
Mehta, P.K.; Christen, P.
Homology of 1-aminocyclopropane-1-carboxylate synthase, 8-amino-7-oxononanoate synthase, 2-amino-6-caprolactam racemase, 2,2-dialkylglycine decarboxylase, glutamate-1-semialdehyde 2,1-aminomutase and isopenicillin-N-epimerase with aminotransferases
Biochem. Biophys. Res. Commun.
198
138-143
1994
Streptomyces clavuligerus
brenda
Ullan, R.V.; Casqueiro, J.; Banuelos, O.; Fernandez, F.J.; Gutierrez, S.; Martin, J.F.
A novel epimerization system in fungal secondary metabolism involved in the conversion of isopenicillin N into penicillin N in Acremonium chrysogenum
J. Biol. Chem.
277
46216-46225
2002
Acremonium chrysogenum, Amycolatopsis lactamdurans
brenda
Martin, J.F.; Ullan, R.V.; Casqueiro, J.
Novel genes involved in cephalosporin biosynthesis: the three-component isopenicillin N epimerase system
Adv. Biochem. Eng. Biotechnol.
88
91-109
2004
Acremonium chrysogenum
brenda
Ullan, R.V.; Casqueiro, J.; Naranjo, L.; Vaca, I.; Martin, J.F.
Expression of cefD2 and the conversion of isopenicillin N into penicillin N by the two-component epimerase system are rate-limiting steps in cephalosporin biosynthesis
Mol. Genet. Genomics
272
562-570
2004
Acremonium chrysogenum, Acremonium chrysogenum C10 / ATCC 48272
brenda
Ullan, R.V.; Campoy, S.; Casqueiro, J.; Fernandez, F.J.; Martin, J.F.
Deacetylcephalosporin C production in Penicillium chrysogenum by expression of the isopenicillin N epimerization, ring expansion, and acetylation genes
Chem. Biol.
14
329-339
2007
Acremonium chrysogenum
brenda
Liras, P.; Demain, A.L.
Enzymology of beta-lactam compounds with cephem structure produced by actinomycete
Methods Enzymol.
458
401-429
2009
Actinomyces sp.
brenda
Shin, H.Y.; Lee, J.Y.; Park, C.; Kim, S.W.
Utilization of glycerol as cysteine and carbon sources for cephalosporin C production by Acremonium chrysogenum M35 in methionine-unsupplemented culture
J. Biotechnol.
151
363-368
2011
Acremonium chrysogenum, Acremonium chrysogenum M35
brenda
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