Crystal structures of adenine phosphoribosyltransferase from Leishmania donovani

Cynthia L. Phillips, Buddy Ullman, Richard G. Brennan, Christopher P. Hill

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The enzyme adenine phosphoribosyltransferase (APRT) functions to salvage adenine by converting it to adenosine-5-monophosphate (AMP). APRT deficiency in humans is a well characterized inborn error of metabolism, and APRT may contribute to the indispensable nutritional role of purine salvage in protozoan parasites, all of which lack de novo purine biosynthesis. We determined crystal structures for APRT from Leishmania donovani in complex with the substrate adenine, the product AMP, and sulfate and citrate ions that appear to mimic the binding of phosphate moieties. Overall, these structures are very similar to each other, although the adenine and AMP complexes show different patterns of hydrogen-bonding to the base, and the active site pocket opens slightly to accommodate the larger AMP ligand. Whereas AMP adopts a single conformation, adenine binds in two mutually exclusive orientations: one orientation providing adenine-specific hydrogen bonds and the other apparently positioning adenine for the enzymatic reaction. The core of APRT is similar to that of other phosphoribosyltransferases, although the adenine-binding domain is quite different. A C-terminal extension, unique to Leishmania APRTs, extends an extensive dimer interface by wrapping around the partner molecule. The active site involves residues from both subunits of the dimer, indicating that dimerization is essential for catalysis.

Original languageEnglish (US)
Pages (from-to)3533-3545
Number of pages13
JournalEMBO Journal
Volume18
Issue number13
DOIs
StatePublished - Jul 1 1999

Keywords

  • Adenine phosphoribosyltransferase
  • Crystal structure
  • Leishmania donovani
  • Purines

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Phillips, C. L., Ullman, B., Brennan, R. G., & Hill, C. P. (1999). Crystal structures of adenine phosphoribosyltransferase from Leishmania donovani. EMBO Journal, 18(13), 3533-3545. https://doi.org/10.1093/emboj/18.13.3533