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Protein

Aklanonic acid methyl ester cyclase AcmA

Gene

acma

Organism
Streptomyces galilaeus
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Involved in the biosynthesis of aklavinone which is an important precursor common to the formation of the clinically significant anthracyclines such as carminomycin, daunorubicin (daunomycin), rhodomycin, aclacinomycin T (aklavin) and aclacinomycin A (aclarubicin). These compounds are aromatic polyketide antibiotics that exhibit high cytotoxicity and are widely applied in the chemotherapy of a variety of cancers. Catalyzes the cyclization of aklanonic acid methyl ester to yield aklaviketone. It is also able to use nogalonic acid methyl ester as substrate, but produces exclusively auraviketone with C9-R stereochemistry.2 Publications

Catalytic activityi

Aklaviketone = methyl aklanonate.

Kineticsi

kcat is 1 sec(-1) for cyclization with nogalonic acid methyl ester.

  1. KM=2 µM for nogalonic acid methyl ester1 Publication

    pH dependencei

    Optimum pH is 7.2.1 Publication

    Pathwayi: daunorubicin biosynthesis

    This protein is involved in the pathway daunorubicin biosynthesis, which is part of Antibiotic biosynthesis.
    View all proteins of this organism that are known to be involved in the pathway daunorubicin biosynthesis and in Antibiotic biosynthesis.

    Pathwayi: carminomycin biosynthesis

    This protein is involved in the pathway carminomycin biosynthesis, which is part of Antibiotic biosynthesis.
    View all proteins of this organism that are known to be involved in the pathway carminomycin biosynthesis and in Antibiotic biosynthesis.

    Pathwayi: rhodomycin biosynthesis

    This protein is involved in the pathway rhodomycin biosynthesis, which is part of Antibiotic biosynthesis.
    View all proteins of this organism that are known to be involved in the pathway rhodomycin biosynthesis and in Antibiotic biosynthesis.

    Pathwayi: aclacinomycin biosynthesis

    This protein is involved in the pathway aclacinomycin biosynthesis, which is part of Antibiotic biosynthesis.
    View all proteins of this organism that are known to be involved in the pathway aclacinomycin biosynthesis and in Antibiotic biosynthesis.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei51 – 511Substrate
    Binding sitei105 – 1051Substrate

    GO - Molecular functioni

    • intramolecular lyase activity Source: UniProtKB

    GO - Biological processi

    • antibiotic biosynthetic process Source: UniProtKB
    • daunorubicin biosynthetic process Source: UniProtKB
    • doxorubicin metabolic process Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Isomerase

    Keywords - Biological processi

    Antibiotic biosynthesis

    Enzyme and pathway databases

    BioCyciMetaCyc:MONOMER-18179.
    UniPathwayiUPA00054.
    UPA01040.
    UPA01042.
    UPA01043.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Aklanonic acid methyl ester cyclase AcmA (EC:5.5.1.23)
    Short name:
    AAME cyclase
    Alternative name(s):
    Methyl aklanonate cyclase
    Gene namesi
    Name:acma
    Synonyms:aknH
    OrganismiStreptomyces galilaeus
    Taxonomic identifieri33899 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaStreptomycetalesStreptomycetaceaeStreptomyces

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi15 – 151Y → F: Retains 45% of cyclase activity with a partial loss in stereoselectivity of the final product (20% of C9-S and 80% of C9-R isomers). Retains 20% of cyclase activity with a total loss in stereoselectivity of the final product (racemic mixture of both stereoisomers); when associated with L-51. 1 Publication
    Mutagenesisi51 – 511N → L: Retains 20% of cyclase activity with a total loss in stereoselectivity of the final product (racemic mixture of both stereoisomers); when associated with F-15. 1 Publication
    Mutagenesisi105 – 1051Q → A: Retains significant cyclase activity (100% of C9-R isomer). 1 Publication
    Mutagenesisi107 – 1071H → A: Retains significant cyclase activity (100% of C9-R isomer). 1 Publication
    Mutagenesisi121 – 1211D → A: Loss of cyclase activity. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 144144Aklanonic acid methyl ester cyclase AcmAPRO_0000425673Add
    BLAST

    Interactioni

    Subunit structurei

    Homotetramer.1 Publication

    Structurei

    Secondary structure

    1
    144
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi3 – 1715Combined sources
    Helixi23 – 253Combined sources
    Beta strandi27 – 326Combined sources
    Helixi34 – 363Combined sources
    Turni37 – 393Combined sources
    Helixi44 – 5916Combined sources
    Beta strandi64 – 7310Combined sources
    Beta strandi76 – 8611Combined sources
    Beta strandi100 – 11213Combined sources
    Beta strandi115 – 1239Combined sources
    Helixi125 – 1317Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2F98X-ray2.10A/B/C/D2-144[»]
    2F99X-ray1.90A/B/C/D2-144[»]
    ProteinModelPortaliO52646.
    SMRiO52646. Positions 2-143.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO52646.

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the polyketide cyclase DnrD family.Curated

    Phylogenomic databases

    KOiK15943.

    Family and domain databases

    Gene3Di3.10.450.50. 1 hit.
    InterProiIPR009959. Cyclase_SnoaL-like_dom.
    IPR032710. NTF2-like_dom.
    [Graphical view]
    PfamiPF07366. SnoaL. 1 hit.
    [Graphical view]
    SUPFAMiSSF54427. SSF54427. 1 hit.

    Sequencei

    Sequence statusi: Complete.

    O52646-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSEQIAAVRR MVEAYNTGKT DDVADYIHPE YMNPGTLEFT SLRGPELFAI
    60 70 80 90 100
    NVAWVKKTFS EEARLEEVGI EERADWVRAR LVLYGRHVGE MVGMAPTGRL
    110 120 130 140
    FSGEQIHLLH FVDGKIHHHR DWPDYQGTYR QLGEPWPETE HRRP
    Length:144
    Mass (Da):16,731
    Last modified:June 1, 1998 - v1
    Checksum:i30083BDD35E808C0
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF043550 Genomic DNA. Translation: AAB99853.1.
    AF257324 Genomic DNA. Translation: AAF70112.1.
    AB008466 Genomic DNA. Translation: BAB72051.1.

    Genome annotation databases

    KEGGiag:AAF70112.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF043550 Genomic DNA. Translation: AAB99853.1.
    AF257324 Genomic DNA. Translation: AAF70112.1.
    AB008466 Genomic DNA. Translation: BAB72051.1.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2F98X-ray2.10A/B/C/D2-144[»]
    2F99X-ray1.90A/B/C/D2-144[»]
    ProteinModelPortaliO52646.
    SMRiO52646. Positions 2-143.
    ModBaseiSearch...
    MobiDBiSearch...

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    KEGGiag:AAF70112.

    Phylogenomic databases

    KOiK15943.

    Enzyme and pathway databases

    UniPathwayiUPA00054.
    UPA01040.
    UPA01042.
    UPA01043.
    BioCyciMetaCyc:MONOMER-18179.

    Miscellaneous databases

    EvolutionaryTraceiO52646.

    Family and domain databases

    Gene3Di3.10.450.50. 1 hit.
    InterProiIPR009959. Cyclase_SnoaL-like_dom.
    IPR032710. NTF2-like_dom.
    [Graphical view]
    PfamiPF07366. SnoaL. 1 hit.
    [Graphical view]
    SUPFAMiSSF54427. SSF54427. 1 hit.
    ProtoNetiSearch...

    Publicationsi

    1. "Elucidation of anthracyclinone biosynthesis by stepwise cloning of genes for anthracyclines from three different Streptomyces spp."
      Kantola J., Kunnari T., Hautala A., Hakala J., Ylihonko K., Mantsala P.
      Microbiology 146:155-163(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SUBSTRATE SPECIFICITY.
      Strain: ATCC 31615.
    2. "Cloning and characterization of Streptomyces galilaeus aclacinomycins polyketide synthase (PKS) cluster."
      Raty K., Kantola J., Hautala A., Hakala J., Ylihonko K., Mantsala P.
      Gene 293:115-122(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: ATCC31615.
    3. "Expression, purification, and characterization of AknX anthrone oxygenase, which is involved in aklavinone biosynthesis in Streptomyces galilaeus."
      Chung J., Fujii I., Tsukamoto N., Sankawa U., Ebizuka Y.
      J. Bacteriol. 184:6115-6122(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: 3AR-33.
    4. Niemi J.
      Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: ATCC31615.
    5. "Crystal structure of the polyketide cyclase AknH with bound substrate and product analogue: implications for catalytic mechanism and product stereoselectivity."
      Kallio P., Sultana A., Niemi J., Mantsala P., Schneider G.
      J. Mol. Biol. 357:210-220(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 2-144 IN COMPLEX WITH SUBSTRATE ANALOGS, FUNCTION, MUTAGENESIS OF TYR-15; ASN-51; GLN-105; HIS-107 AND ASP-121, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE SPECIFICITY, REACTION MECHANISM, SUBUNIT.

    Entry informationi

    Entry nameiDNRD_STRGJ
    AccessioniPrimary (citable) accession number: O52646
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: March 19, 2014
    Last sequence update: June 1, 1998
    Last modified: January 20, 2016
    This is version 61 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.