Publication Date:
2013-05-17
Description:
The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx-SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jungwook -- Xiao, Hui -- Bonanno, Jeffrey B -- Kalyanaraman, Chakrapani -- Brown, Shoshana -- Tang, Xiangying -- Al-Obaidi, Nawar F -- Patskovsky, Yury -- Babbitt, Patricia C -- Jacobson, Matthew P -- Lee, Young-Sam -- Almo, Steven C -- GM093342/GM/NIGMS NIH HHS/ -- GM094662/GM/NIGMS NIH HHS/ -- P30-EB-009998/EB/NIBIB NIH HHS/ -- U54 GM093342/GM/NIGMS NIH HHS/ -- U54 GM094662/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jun 6;498(7452):123-6. doi: 10.1038/nature12180. Epub 2013 May 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA. jungwook.kim@einstein.yu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23676670" target="_blank"〉PubMed〈/a〉
Keywords:
Biocatalysis
;
Biosynthetic Pathways
;
Catalytic Domain
;
Crystallography, X-Ray
;
Cyclohexanecarboxylic Acids/metabolism
;
Cyclohexenes/metabolism
;
Escherichia coli/enzymology
;
Escherichia coli Proteins/chemistry/genetics/*metabolism
;
Ligands
;
Methyltransferases/deficiency/genetics/*metabolism
;
Models, Molecular
;
Molecular Weight
;
One-Carbon Group Transferases/chemistry/*metabolism
;
Protein Multimerization
;
Protein Structure, Secondary
;
RNA, Bacterial/chemistry/genetics/metabolism
;
RNA, Transfer/chemistry/*genetics/*metabolism
;
S-Adenosylmethionine/*analogs & derivatives/biosynthesis/*chemistry/*metabolism
;
Uridine/analogs & derivatives/chemistry/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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