Linked Life Data

15518551

Source:http://linkedlifedata.com/resource/pubmed/id/15518551

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
44
pubmed:dateCreated
2004-11-2
pubmed:databankReference
pubmed:abstractText
Acetyl-CoA carboxylase (ACC) and propionyl-CoA carboxylase (PCC) catalyze the carboxylation of acetyl- and propionyl-CoA to generate malonyl- and methylmalonyl-CoA, respectively. Understanding the substrate specificity of ACC and PCC will (1) help in the development of novel structure-based inhibitors that are potential therapeutics against obesity, cancer, and infectious disease and (2) facilitate bioengineering to provide novel extender units for polyketide biosynthesis. ACC and PCC in Streptomyces coelicolor are multisubunit complexes. The core catalytic beta-subunits, PccB and AccB, are 360 kDa homohexamers, catalyzing the transcarboxylation between biotin and acyl-CoAs. Apo and substrate-bound crystal structures of PccB hexamers were determined to 2.0-2.8 A. The hexamer assembly forms a ring-shaped complex. The hydrophobic, highly conserved biotin-binding pocket was identified for the first time. Biotin and propionyl-CoA bind perpendicular to each other in the active site, where two oxyanion holes were identified. N1 of biotin is proposed to be the active site base. Structure-based mutagenesis at a single residue of PccB and AccB allowed interconversion of the substrate specificity of ACC and PCC. The di-domain, dimeric interaction is crucial for enzyme catalysis, stability, and substrate specificity; these features are also highly conserved among biotin-dependent carboxyltransferases. Our findings enable bioengineering of the acyl-CoA carboxylase (ACCase) substrate specificity to provide novel extender units for the combinatorial biosynthesis of polyketides.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
14027-36
pubmed:dateRevised
2011-3-1
pubmed:meshHeading
pubmed-meshheading:15518551-Acetyl Coenzyme A, pubmed-meshheading:15518551-Acyl Coenzyme A, pubmed-meshheading:15518551-Amino Acid Sequence, pubmed-meshheading:15518551-Binding Sites, pubmed-meshheading:15518551-Carbon-Carbon Ligases, pubmed-meshheading:15518551-Crystallization, pubmed-meshheading:15518551-Crystallography, X-Ray, pubmed-meshheading:15518551-Dimerization, pubmed-meshheading:15518551-Methylmalonyl-CoA Decarboxylase, pubmed-meshheading:15518551-Molecular Sequence Data, pubmed-meshheading:15518551-Protein Engineering, pubmed-meshheading:15518551-Protein Folding, pubmed-meshheading:15518551-Protein Subunits, pubmed-meshheading:15518551-Protein Transport, pubmed-meshheading:15518551-Static Electricity, pubmed-meshheading:15518551-Streptomyces coelicolor, pubmed-meshheading:15518551-Structure-Activity Relationship, pubmed-meshheading:15518551-Substrate Specificity, pubmed-meshheading:15518551-Surface Properties
pubmed:year
2004
pubmed:articleTitle
Crystal structure of the beta-subunit of acyl-CoA carboxylase: structure-based engineering of substrate specificity.
pubmed:affiliation
Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't