Document Detail


Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase.
MedLine Citation:
PMID:  17071746     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Polyketides are a class of natural products that exhibit a wide range of functional and structural diversity. They include antibiotics, immunosuppressants, antifungals, antihypercholesterolemics, and cytotoxins. Polyketide synthases (PKSs) use chemistry similar to fatty acid synthases (FASs), although building block variation and differing extents of reduction of the growing polyketide chain underlie their biosynthetic versatility. In contrast to the well studied sequential modular type I PKSs, less is known about how the iterative type I PKSs carry out and control chain initiation, elongation, folding, and cyclization during polyketide processing. Domain structure analysis of a group of related fungal, nonreducing PKSs has revealed well defined N-terminal domains longer than commonly seen for FASs and modular PKSs. Predicted structure of this domain disclosed a region similar to malonyl-CoA:acyl-carrier protein (ACP) transacylases (MATs). MATs play a key role transferring precursor CoA thioesters from solution onto FASs and PKSs for chain elongation. On the basis of site-directed mutagenesis, radiolabeling, and kinetics experiments carried out with individual domains of the norsolorinic acid PKS, we propose that the N-terminal domain is a starter unit:ACP transacylase (SAT domain) that selects a C(6) fatty acid from a dedicated yeast-like FAS and transfers this unit onto the PKS ACP, leading to the production of the aflatoxin precursor, norsolorinic acid. These findings could indicate a much broader role for SAT domains in starter unit selection among nonreducing iterative, fungal PKSs, and they provide a biochemical rationale for the classical acetyl "starter unit effect."
Authors:
Jason M Crawford; Blair C R Dancy; Eric A Hill; Daniel W Udwary; Craig A Townsend
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-10-27
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  103     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-08     Completed Date:  2006-12-20     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16728-33     Citation Subset:  IM    
Affiliation:
Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
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MeSH Terms
Descriptor/Qualifier:
Acyl-Carrier Protein S-Acetyltransferase / chemistry*,  genetics,  metabolism
Aflatoxins / biosynthesis,  chemistry
Amino Acid Sequence
Aspergillus / enzymology,  genetics
Base Sequence
Cloning, Molecular
DNA, Fungal / genetics
Genes, Fungal
Molecular Sequence Data
Molecular Structure
Mutagenesis, Site-Directed
Polyketide Synthases / chemistry*,  genetics,  metabolism
Protein Structure, Tertiary
Recombinant Proteins / chemistry,  genetics,  metabolism
Sequence Homology, Amino Acid
Grant Support
ID/Acronym/Agency:
ES 001670/ES/NIEHS NIH HHS; R37 AI014937-30/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Aflatoxins; 0/DNA, Fungal; 0/Recombinant Proteins; 79956-01-7/Polyketide Synthases; EC 2.3.1.38/Acyl-Carrier Protein S-Acetyltransferase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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