5u99

Transition state analysis of adenosine triphosphate phosphoribosyltransferase

spinqualitylabelsall models 5u99, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5u99 is a 1 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ATP, MG, SO4 Gene: hisG, Rv2121c, MTCY261.17c (MYCTU) Activity: ATP phosphoribosyltransferase, with EC number 2.4.2.17 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HIS1_MYCTU] Catalyzes the condensation of ATP and 5-phosphoribose 1-diphosphate to form N'-(5'-phosphoribosyl)-ATP (PR-ATP). Has a crucial role in the pathway because the rate of histidine biosynthesis seems to be controlled primarily by regulation of HisG enzymatic activity (By similarity). Publication Abstract from PubMed Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first step in histidine biosynthesis, a pathway essential to microorganisms and a validated target for antimicrobial drug design. The ATP-PRT enzyme catalyzes the reversible substitution reaction between phosphoribosyl pyrophosphate and ATP. The enzyme exists in two structurally distinct forms, a short- and a long-form enzyme. These forms share a catalytic core dimer but bear completely different allosteric domains and thus distinct quaternary assemblies. Understanding enzymatic transition states can provide essential information on the reaction mechanisms and insight into how differences in domain structure influence the reaction chemistry, as well as providing a template for inhibitor design. In this study, the transition state structures for ATP-PRT enzymes from Campylobacter jejuni and Mycobacterium tuberculosis (long-form enzymes) and from Lactococcus lactis (short-form) were determined and compared. Intrinsic kinetic isotope effects (KIEs) were obtained at reaction sensitive positions for the reverse reaction using phosphonoacetic acid, an alternative substrate to the natural substrate pyrophosphate. The experimental KIEs demonstrated mechanistic similarities between the three enzymes and provided experimental boundaries for quantum chemical calculations to characterize the transition states. Predicted transition state structures support a dissociative reaction mechanism with a DN*ANdouble dagger transition state. Weak interactions from the incoming nucleophile and a fully dissociated ATP adenine are predicted regardless of the difference in overall structure and quaternary assembly. These studies establish that despite significant differences in the quaternary assembly and regulatory machinery between ATP-PRT enzymes from different sources, the reaction chemistry and catalytic mechanism are conserved. Transition State Analysis of Adenosine Triphosphate Phosphoribosyltransferase.,Moggre GJ, Poulin MB, Tyler PC, Schramm VL, Parker EJ ACS Chem Biol. 2017 Sep 19. doi: 10.1021/acschembio.7b00484. PMID:28872824 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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