Structural Comparison of MTA Phosphorylase and MTA/AdoHcy Nucleosidase Explains Substrate Preferences and Identifies Regions Exploitable for Inhibitor Design

Jeffrey E. Lee, Ethan C. Settembre, Kenneth A. Cornell, Michael Riscoe, Janice R. Sufrin, Steven E. Ealick, P. Lynne Howell

Research output: Contribution to journalArticle

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Abstract

The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5′ -Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/ AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5′-methylthiotubercidin have been solved to 2.0 and 2.1 Å resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5′-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5′-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases.

Original languageEnglish (US)
Pages (from-to)5159-5169
Number of pages11
JournalBiochemistry
Volume43
Issue number18
DOIs
StatePublished - May 11 2004

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adenosylhomocysteine nucleosidase
Pemetrexed
N-Glycosyl Hydrolases
Substrates
Phosphorylases
5'-methylthioadenosine phosphorylase
Binding Sites
Quorum Sensing
Methylation
Mammals
Ribose

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structural Comparison of MTA Phosphorylase and MTA/AdoHcy Nucleosidase Explains Substrate Preferences and Identifies Regions Exploitable for Inhibitor Design. / Lee, Jeffrey E.; Settembre, Ethan C.; Cornell, Kenneth A.; Riscoe, Michael; Sufrin, Janice R.; Ealick, Steven E.; Howell, P. Lynne.

In: Biochemistry, Vol. 43, No. 18, 11.05.2004, p. 5159-5169.

Research output: Contribution to journalArticle

Lee, Jeffrey E. ; Settembre, Ethan C. ; Cornell, Kenneth A. ; Riscoe, Michael ; Sufrin, Janice R. ; Ealick, Steven E. ; Howell, P. Lynne. / Structural Comparison of MTA Phosphorylase and MTA/AdoHcy Nucleosidase Explains Substrate Preferences and Identifies Regions Exploitable for Inhibitor Design. In: Biochemistry. 2004 ; Vol. 43, No. 18. pp. 5159-5169.
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