Structural snapshots of MTA/AdoHcy nucleosidase along the reaction coordinate provide insights into enzyme and nucleoside flexibility during catalysis

Jeffrey E. Lee, G. David Smith, Cathy Horvatin, David J T Huang, Kenneth A. Cornell, Michael Riscoe, P. Lynne Howell

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

MTA/AdoHcy nucleosidase (MTAN) irreversibly hydrolyzes the N9-C1′ bond in the nucleosides, 5′-methylthioadenosine (MTA) and S-adenosylhomocysteine (AdoHcy) to form adenine and the corresponding thioribose. MTAN plays a vital role in metabolic pathways involving methionine recycling, biological methylation, polyamine biosynthesis, and quorum sensing. Crystal structures of a wild-type (WT) MTAN complexed with glycerol, and mutant-enzyme and mutant-product complexes have been determined at 2.0 Å, 2.0 Å, and 2.1 Å resolution, respectively. The WT MTAN-glycerol structure provides a purine-free model and in combination with the previously solved thioribose-free MTAN-ADE structure, we now have separate apo structures for both MTAN binding subsites. The purine and thioribose-free states reveal an extensive enzyme-immobilized water network in their respective binding subsites. The Asp197Asn MTAN-MTA and Glu12Gln MTAN-MTR·ADE structures are the first enzyme-substrate and enzyme-product complexes reported for MTAN, respectively. These structures provide representative snapshots along the reaction coordinate and allow insight into the conformational changes of the enzyme and the nucleoside substrate. A "catalytic movie" detailing substrate binding, catalysis, and product release is presented.

Original languageEnglish (US)
Pages (from-to)559-574
Number of pages16
JournalJournal of Molecular Biology
Volume352
Issue number3
DOIs
StatePublished - Sep 23 2005
Externally publishedYes

Fingerprint

adenosylhomocysteine nucleosidase
Pemetrexed
N-Glycosyl Hydrolases
Catalysis
Nucleosides
Enzymes
Glycerol
S-Adenosylhomocysteine
Quorum Sensing
Immobilized Enzymes
5'-methylthioadenosine phosphorylase
Polyamines
Recycling
Adenine
Motion Pictures
Metabolic Networks and Pathways
Methionine
Methylation

Keywords

  • 5′-methylthioadenosine
  • 5′-methylthioadenosine/S- adenosylhomocysteine nucleosidase
  • Conformational flexibility
  • Reaction coordinate
  • S-adenosylhomocysteine

ASJC Scopus subject areas

  • Virology

Cite this

Structural snapshots of MTA/AdoHcy nucleosidase along the reaction coordinate provide insights into enzyme and nucleoside flexibility during catalysis. / Lee, Jeffrey E.; Smith, G. David; Horvatin, Cathy; Huang, David J T; Cornell, Kenneth A.; Riscoe, Michael; Howell, P. Lynne.

In: Journal of Molecular Biology, Vol. 352, No. 3, 23.09.2005, p. 559-574.

Research output: Contribution to journalArticle

Lee, Jeffrey E. ; Smith, G. David ; Horvatin, Cathy ; Huang, David J T ; Cornell, Kenneth A. ; Riscoe, Michael ; Howell, P. Lynne. / Structural snapshots of MTA/AdoHcy nucleosidase along the reaction coordinate provide insights into enzyme and nucleoside flexibility during catalysis. In: Journal of Molecular Biology. 2005 ; Vol. 352, No. 3. pp. 559-574.
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