E1ACR1 · NOTP_ASPSM
- ProteinLactamase-like protein notP
- GenenotP
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids321 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score3/5
Function
function
Lactamase-like protein; part of the gene cluster that mediates the biosynthesis of notoamide, a fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:20722388).
The first step of notoamide biosynthesis involves coupling of L-proline and L-tryptophan by the bimodular NRPS notE, to produce cyclo-L-tryptophan-L-proline called brevianamide F (PubMed:20722388).
The reverse prenyltransferase notF then acts as a deoxybrevianamide E synthase and converts brevianamide F to deoxybrevianamide E via reverse prenylation at C-2 of the indole ring leading to the bicyclo[2.2.2]diazaoctane core (PubMed:20722388).
Deoxybrevianamide E is further hydroxylated at C-6 of the indole ring, likely catalyzed by the cytochrome P450 monooxygenase notG, to yield 6-hydroxy-deoxybrevianamide E (Probable). 6-hydroxy-deoxybrevianamide E is a specific substrate of the prenyltransferase notC for normal prenylation at C-7 to produce 6-hydroxy-7-prenyl-deoxybrevianamide, also called notoamide S (PubMed:20722388).
As the proposed pivotal branching point in notoamide biosynthesis, notoamide S can be diverted to notoamide E through an oxidative pyran ring closure putatively catalyzed by either notH cytochrome P450 monooxygenase or the notD FAD-linked oxidoreductase (Probable). This step would be followed by an indole 2,3-epoxidation-initiated pinacol-like rearrangement catalyzed by the notB FAD-dependent monooxygenase leading to the formation of notoamide C and notoamide D (PubMed:22188465).
On the other hand notoamide S is converted to notoamide T by notH (or notD), a bifunctional oxidase that also functions as the intramolecular Diels-Alderase responsible for generation of +-notoamide T (Probable). To generate antipodal --notoaminide T, notH' (or notD') in Aspergillus versicolor is expected to catalyze a Diels-Alder reaction leading to the opposite stereochemistry (Probable). The remaining oxidoreductase notD (or notH) likely catalyzes the oxidative pyran ring formation to yield +-stephacidin A (Probable). The FAD-dependent monooxygenase notI is highly similar to notB and is predicted to catalyze a similar conversion from +-stephacidin A to --notoamide B via the 2,3-epoxidation of +-stephacidin A followed by a pinacol-type rearrangement (Probable). Finally, it remains unclear which enzyme could be responsible for the final hydroxylation steps leading to notoamide A and sclerotiamide (Probable). The function of notP in the notoamide biosynthesis has not been determined yet (Probable).
The first step of notoamide biosynthesis involves coupling of L-proline and L-tryptophan by the bimodular NRPS notE, to produce cyclo-L-tryptophan-L-proline called brevianamide F (PubMed:20722388).
The reverse prenyltransferase notF then acts as a deoxybrevianamide E synthase and converts brevianamide F to deoxybrevianamide E via reverse prenylation at C-2 of the indole ring leading to the bicyclo[2.2.2]diazaoctane core (PubMed:20722388).
Deoxybrevianamide E is further hydroxylated at C-6 of the indole ring, likely catalyzed by the cytochrome P450 monooxygenase notG, to yield 6-hydroxy-deoxybrevianamide E (Probable). 6-hydroxy-deoxybrevianamide E is a specific substrate of the prenyltransferase notC for normal prenylation at C-7 to produce 6-hydroxy-7-prenyl-deoxybrevianamide, also called notoamide S (PubMed:20722388).
As the proposed pivotal branching point in notoamide biosynthesis, notoamide S can be diverted to notoamide E through an oxidative pyran ring closure putatively catalyzed by either notH cytochrome P450 monooxygenase or the notD FAD-linked oxidoreductase (Probable). This step would be followed by an indole 2,3-epoxidation-initiated pinacol-like rearrangement catalyzed by the notB FAD-dependent monooxygenase leading to the formation of notoamide C and notoamide D (PubMed:22188465).
On the other hand notoamide S is converted to notoamide T by notH (or notD), a bifunctional oxidase that also functions as the intramolecular Diels-Alderase responsible for generation of +-notoamide T (Probable). To generate antipodal --notoaminide T, notH' (or notD') in Aspergillus versicolor is expected to catalyze a Diels-Alder reaction leading to the opposite stereochemistry (Probable). The remaining oxidoreductase notD (or notH) likely catalyzes the oxidative pyran ring formation to yield +-stephacidin A (Probable). The FAD-dependent monooxygenase notI is highly similar to notB and is predicted to catalyze a similar conversion from +-stephacidin A to --notoamide B via the 2,3-epoxidation of +-stephacidin A followed by a pinacol-type rearrangement (Probable). Finally, it remains unclear which enzyme could be responsible for the final hydroxylation steps leading to notoamide A and sclerotiamide (Probable). The function of notP in the notoamide biosynthesis has not been determined yet (Probable).
Cofactor
Note: Binds 2 Zn2+ ions per subunit.
Biotechnology
Notoamides have been shown to exhibit antitumoral activities (PubMed:17304611).
Notoamides A-C show moderate cytotoxicity against HeLa and L1210 cells with IC50 values in the range of 22-52 mg/ml, but the IC50 value of notoamide D is greater than 100 mg/ml (PubMed:17304611).
Moreover, notoamide C induces G2/M-cell cycle arrest at a concentration of 6.3 mg/ml (PubMed:17304611).
Notoamides A-C show moderate cytotoxicity against HeLa and L1210 cells with IC50 values in the range of 22-52 mg/ml, but the IC50 value of notoamide D is greater than 100 mg/ml (PubMed:17304611).
Moreover, notoamide C induces G2/M-cell cycle arrest at a concentration of 6.3 mg/ml (PubMed:17304611).
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 108 | Zn2+ 1 (UniProtKB | ChEBI); catalytic | ||||
Sequence: H | ||||||
Binding site | 110 | Zn2+ 1 (UniProtKB | ChEBI); catalytic | ||||
Sequence: H | ||||||
Active site | 112 | Proton donor/acceptor | ||||
Sequence: D | ||||||
Binding site | 112 | Zn2+ 2 (UniProtKB | ChEBI); catalytic | ||||
Sequence: D | ||||||
Binding site | 113 | Zn2+ 2 (UniProtKB | ChEBI); catalytic | ||||
Sequence: H |
GO annotations
Aspect | Term | |
---|---|---|
Molecular Function | hydrolase activity | |
Molecular Function | metal ion binding | |
Biological Process | secondary metabolite biosynthetic process |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameLactamase-like protein notP
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Aspergillus
Accessions
- Primary accessionE1ACR1
Phenotypes & Variants
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000448825 | 1-321 | Lactamase-like protein notP | |||
Sequence: MAPGEGGYRQINKALNICAFEDYLEGQQKALPSLPDVEQISPRVLRVLGQNPASHCKFTLQGTNTFVVGTGPERLIVDTGQGIPEWADLIHETLARRGITLSHVLLTHWHGDHTGGVPDLIRMYPHLSSAIYKHEPSKTQQPITDGQIFRVEGATVRAVHTPGHSSDHMCFVLEEEHGMFTGDNILGHGTSAVEHLSTWMHTLYKMQAQDCTTGYPAHGIVISNLRTKIKGELAQKLQRERQVLKALVQAKQAERARMERAKGSVTVKELVATMYGNGVGAGIRELALEPFMDEVLRKLAEDGAVAFEVRGRVKKWFAPDA |
Structure
Sequence
- Sequence statusComplete
- Length321
- Mass (Da)35,451
- Last updated2010-11-02 v1
- Checksum7E4861981F501196