Document Detail

Biosynthesis of isoprenoids: crystal structure of 4-diphosphocytidyl-2C-methyl-D-erythritol kinase.
MedLine Citation:
PMID:  12878729     Owner:  NLM     Status:  MEDLINE    
4-Diphosphocytidyl-2C-methyl-d-erythritol kinase, an essential enzyme in the nonmevalonate pathway of isopentenyl diphosphate and dimethylallyl diphosphate biosynthesis, catalyzes the single ATP-dependent phosphorylation stage affording 4-diphosphocytidyl-2C-methyl-d-erythritol-2-phosphate. The 2-A resolution crystal structure of the Escherichia coli enzyme in a ternary complex with substrate and a nonhydrolyzable ATP analogue reveals the molecular determinants of specificity and catalysis. The enzyme subunit displays the alpha/beta fold characteristic of the galactose kinase/homoserine kinase/mevalonate kinase/phosphomevalonate kinase superfamily, arranged into cofactor and substrate-binding domains with the catalytic center positioned in a deep cleft between domains. Comparisons with related members of this superfamily indicate that the core regions of each domain are conserved, whereas there are significant differences in the substrate-binding pockets. The nonmevalonate pathway is essential in many microbial pathogens and distinct from the mevalonate pathway used by mammals. The high degree of sequence conservation of the enzyme across bacterial species suggests similarities in structure, specificity, and mechanism. Our model therefore provides an accurate template to facilitate the structure-based design of broad-spectrum antimicrobial agents.
Linda Miallau; Magnus S Alphey; Lauris E Kemp; Gordon A Leonard; Sean M McSweeney; Stefan Hecht; Adelbert Bacher; Wolfgang Eisenreich; Felix Rohdich; William N Hunter
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-07-23
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  100     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-06     Completed Date:  2003-10-03     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9173-8     Citation Subset:  IM    
Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
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MeSH Terms
Adenosine Triphosphate / metabolism
Amino Acid Sequence
Crystallography, X-Ray
Escherichia coli / metabolism
Escherichia coli Proteins*
Models, Chemical
Models, Molecular
Molecular Sequence Data
Phosphotransferases (Alcohol Group Acceptor) / chemistry*
Protein Binding
Protein Conformation
Protein Structure, Quaternary
Protein Structure, Tertiary
Substrate Specificity
Reg. No./Substance:
0/Escherichia coli Proteins; 56-65-5/Adenosine Triphosphate; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC protein, E coli

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