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Crystal structure of Adenine phosphoribosyltransferase from Francisella tularensis in complex with adenine
Structural highlights
FunctionAPT_FRATT Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.[HAMAP-Rule:MF_00004] Publication Abstract from PubMedFrancisella tularensis is classified as a category A bioterrorism agent, which also causes tularemia. Here, we present the crystal structure of apo and adenine bound form of the adenine phosphoribosyltransferase (APRT) from Francisella tularensis.. APRT is an enzyme involved in the salvage of adenine (a 6-aminopurine) to adenosine monophosphate (AMP). The purine salvage pathway relies on two essential and distinct enzymes to convert 6-aminopurine and 6-oxopurines into corresponding nucleotides. The mechanism by which these enzymes differentiate different purines is not clearly understood. Analysis of structures of apo and adenine bound APRT from F. tularensis, together with all other available structures of APRTs, suggests that (1) the base-binding loop is stabilized by a cluster of aromatic and conformation restricting proline residues and (2) an N-H N hydrogen bond between the base-binding loop and N1 atom of adenine is the key interaction that differentiates adenine from 6-oxopurines. These observations were corroborated by bioinformatics analysis of ~4000 sequences of APRTs (with 80% identity cutoff) which confirms that the residues conferring rigidity to the base-binding loop are highly conserved. Furthermore, F23A mutation on the base-binding loop severely affects the efficiency of the enzyme. We extend our analysis to the structure and sequences of APRTs from Trypanosomatidae family with a destabilizing insertion on the base-binding loop and propose the mechanism by which these evolutionarily deviated enzymes achieve base specificity. Our results suggest that the base-binding loop not only confers appropriate affinity, but also provides defined specificity for adenine. This article is protected by copyright. All rights reserved. Crystal structures of APRT from Francisella tularensis: An N-H N hydrogen bond imparts adenine specificity in adenine phosporibosyltransferases.,Pavithra GC, Ramagopal UA FEBS J. 2018 Apr 25. doi: 10.1111/febs.14481. PMID:29694705[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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