The Leishmania donovani UMP synthase is essential for promastigote viability and has an unusual tetrameric structure that exhibits substrate-controlled oligomerization

Jarrod B. French, Phillip A. Yates, D. Radika Soysa, Jan M. Boitz, Nicola S. Carter, Bailey Chang, Buddy Ullman, Steven E. Ealick

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

The final two steps of de novo uridine 5′-monophosphate (UMP) biosynthesis are catalyzed by orotate phosphoribosyl-transferase (OPRT) and orotidine 5′-monophosphate decarboxylase (OMPDC). In most prokaryotes and simple eukaryotes these two enzymes are encoded by separate genes, whereas in mammals they are expressed as a bifunctional gene product called UMP synthase (UMPS), with OPRT at the N terminus and OMPDC at the C terminus. Leishmania and some closely related organisms also express a bifunctional enzyme for these two steps, but the domain order is reversed relative to mammalian UMPS. In this work we demonstrate that L. donovani UMPS (LdUMPS) is an essential enzyme in promastigotes and that it is sequestered in the parasite glycosome. We also present the crystal structure of the LdUMPS in complex with its product, UMP. This structure reveals an unusual tetramer with two head to head and two tail to tail interactions, resulting in two dimeric OMPDC and two dimeric OPRT functional domains. In addition, we provide structural and biochemical evidence that oligomerization of LdUMPS is controlled by product binding at the OPRT active site. We propose a model for the assembly of the catalytically relevant LdUMPS tetramer and discuss the implications for the structure of mammalian UMPS.

Original languageEnglish (US)
Pages (from-to)20930-20941
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number23
DOIs
StatePublished - Jun 10 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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