Document Detail


Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line.
MedLine Citation:
PMID:  22586110     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Nonribosomal peptide synthetases (NRPSs) usually catalyze the biosynthesis of peptide natural products by sequential selection, activation, and condensation of amino acid precursors. It was reported that some fatty acids, α-ketoacids, and α-hydroxyacids originating from amino acid metabolism as well as polyketide-derived units can also be used by NRPS assembly lines as an alternative to amino acids. Ecteinascidin 743 (ET-743), naphthyridinomycin (NDM), and quinocarcin (QNC) are three important antitumor natural products belonging to the tetrahydroisoquinoline family. Although ET-743 has been approved as an anticancer drug, the origin of an identical two-carbon (C(2)) fragment among these three antibiotics has not been elucidated despite much effort in the biosynthetic research in the past 30 y. Here we report that two unexpected two-component transketolases (TKases), NapB/NapD in the NDM biosynthetic pathway and QncN/QncL in QNC biosynthesis, catalyze the transfer of a glycolaldehyde unit from ketose to the lipoyl group to yield the glycolicacyl lipoic acid intermediate and then transfer the C(2) unit to an acyl carrier protein (ACP) to form glycolicacyl-S-ACP as an extender unit for NRPS. Our results demonstrate a unique NRPS extender unit directly derived from ketose phosphates through (α,β-dihydroxyethyl)-thiamin diphosphate and a lipoyl group-tethered ester intermediate catalyzed by the TKase-ACP platform in the context of NDM and QNC biosynthesis, all of which also highlights the biosynthesis of ET-743. This hybrid system and precursor are distinct from the previously described universal modes involving the NRPS machinery. They exemplify an alternate strategy in hybrid NRPS biochemistry and enrich the diversity of precursors for NRPS combinatorial biosynthesis.
Authors:
Chao Peng; Jin-Yue Pu; Li-Qiang Song; Xiao-Hong Jian; Man-Cheng Tang; Gong-Li Tang
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-14
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-30     Completed Date:  2012-08-24     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8540-5     Citation Subset:  IM    
Affiliation:
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/JQ764999;  JQ765000
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MeSH Terms
Descriptor/Qualifier:
Acyl Carrier Protein / genetics,  metabolism
Amino Acid Sequence
Bacterial Proteins / genetics,  metabolism
Biosynthetic Pathways
Electrophoresis, Polyacrylamide Gel
Ketoses / chemistry,  metabolism*
Kinetics
Magnetic Resonance Spectroscopy
Models, Chemical
Molecular Sequence Data
Molecular Structure
Multigene Family
Mutation
Naphthyridines / chemistry,  metabolism
Peptide Synthases / genetics,  metabolism
Peptides / chemistry,  genetics,  metabolism*
Sequence Homology, Amino Acid
Streptomyces / chemistry,  genetics,  metabolism*
Substrate Specificity
Tetrahydroisoquinolines / chemistry,  metabolism
Transketolase / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Acyl Carrier Protein; 0/Bacterial Proteins; 0/Ketoses; 0/Naphthyridines; 0/Peptides; 0/Tetrahydroisoquinolines; 62046-87-1/naphthyridinomycin; EC 2.2.1.1/Transketolase; EC 6.3.2.-/Peptide Synthases; EC 6.3.2.-/non-ribosomal peptide synthase
Comments/Corrections

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