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PDBsum entry 5ctc
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Transferase/transferase inhibitor
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PDB id
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5ctc
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Humanized yeast acc carboxyltransferase domain bound to tert-butyl 7- [(7-methyl-1h-indazol-5-yl)carbonyl]-2,7-diazaspiro[3.5]nonane-2- carboxylate
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Structure:
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Acetyl-coa carboxylase. Chain: a, b, c. Fragment: carboxyltransferase domain (unp residues 1476-2233). Synonym: acc, fatty acid synthetase 3, mRNA transport-defective protein 7. Engineered: yes. Mutation: yes
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Source:
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Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Gene: acc1, abp2, fas3, mtr7, ynr016c, n3175. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.70Å
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R-factor:
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0.176
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R-free:
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0.201
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Authors:
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F.F.Vajdos
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Key ref:
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D.W.Kung
et al.
(2015).
Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.
Bioorg Med Chem Lett,
25,
5352-5356.
PubMed id:
DOI:
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Date:
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23-Jul-15
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Release date:
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14-Oct-15
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PROCHECK
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Headers
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References
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Q00955
(ACAC_YEAST) -
Acetyl-CoA carboxylase from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
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Seq:
Struc:
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2233 a.a.
691 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 9 residue positions (black
crosses)
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Enzyme class 2:
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E.C.6.3.4.14
- biotin carboxylase.
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Reaction:
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N6-biotinyl-L-lysyl-[protein] + hydrogencarbonate + ATP = N6- carboxybiotinyl-L-lysyl-[protein] + ADP + phosphate + H+
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N(6)-biotinyl-L-lysyl-[protein]
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+
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hydrogencarbonate
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+
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ATP
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=
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N(6)- carboxybiotinyl-L-lysyl-[protein]
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+
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ADP
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+
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phosphate
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+
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H(+)
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Enzyme class 3:
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E.C.6.4.1.2
- acetyl-CoA carboxylase.
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Reaction:
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hydrogencarbonate + acetyl-CoA + ATP = malonyl-CoA + ADP + phosphate + H+
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hydrogencarbonate
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+
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acetyl-CoA
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+
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ATP
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=
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malonyl-CoA
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+
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ADP
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+
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phosphate
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+
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H(+)
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Cofactor:
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Biotin
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Biotin
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
25:5352-5356
(2015)
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PubMed id:
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Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.
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D.W.Kung,
D.A.Griffith,
W.P.Esler,
F.F.Vajdos,
A.M.Mathiowetz,
S.D.Doran,
P.A.Amor,
S.W.Bagley,
T.Banks,
S.Cabral,
K.Ford,
C.N.Garcia-Irizarry,
M.S.Landis,
K.Loomis,
K.McPherson,
M.Niosi,
K.L.Rockwell,
C.Rose,
A.C.Smith,
J.A.Southers,
S.Tapley,
M.Tu,
J.J.Valentine.
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ABSTRACT
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A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of
acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were
discovered by design of a library to mimic the structural rigidity and
hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone
inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat
hepatocytes, with an IC50 of 0.30μM.
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Links
