The crystal structure of free human hypoxanthineguanine phosphoribosyltransferase reveals extensive conformational plasticity throughout the catalytic cycle

Human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) catalyses the synthesis of the purine nucleoside monophosphates, IMP and GMP, by the addition of a 6-oxopurine base, either hypoxanthine or guanine, to the 1-beta-position of 5-phospho-U-D-ribosyl-1-pyrophosphate (PRib-PP). The mechanism is sequential, with PRib-PP binding to the free enzyme prior to the base. After the covalent reaction, pyrophosphate is released followed by the nucleoside monophosphate. A number of snapshots of the structure of this enzyme along the reaction pathway have been captured. These include the structure in the presence of the inactive purine base analogue, 7-hydroxy [4,3-d] pyrazolo pyrimidine (HPP) and PRib-PP. Mg2+, and in complex with IMP or GMP. The third structure is that of the immucillinHP.Mg2+.PPi complex, a transition-state analogue. Here, the first crystal structure of free human HGPRT is reported to 1.9 angstrom resolution, showing that significant conformational changes have to occur for the substrate(s) to bind and for catalysis to proceed. Included in these changes are relative movement of subunits within the tetramer, rotation and extension of an active-site alpha-helix (D137-D153), reorientation of key active-site residues K68, D137 and K165, and the rearrangement of three active-site loops (100-128, 165-173 and 186-196). Toxoplasina gondii HGXPRT is the only other 6-oxopurine phosphoribosyltransferase structure solved in the absence of ligands. Comparison of this structure with human HGPRT reveals significant differences in the two active sites, including the structure of the flexible loop containing K68 (human) or K79 (T gondii). (c) 2005 Elsevier Ltd. All rights reserved

Lead compounds for antimalarial chemotherapy: Purine base analogs discriminate between human and P-falciparum 6-oxopurine phosphoribosyltransferases

The malarial parasite Plasmodium falciparum depends on the purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) to convert purine bases from the host to nucleotides needed for DNA and RNA synthesis. An approach to developing antimalarial drugs is to use HGXPRT to convert introduced purine base analogs to nucleotides that are toxic to the parasite. This strategy requires that these compounds be good substrates for the parasite enzyme but poor substrates for the human counterpart, HGPRT. Bases with a chlorine atom in the 6-position or a nitrogen in the 8-position exhibited strong discrimination between P. falciparum HGXPRT and human HGPRT. The k(cat)/K-m values for the Plasmodium enzyme using 6-chloroguanine and 8-azaguanine as substrates were 50-80-fold and 336-fold higher than for the human enzyme, respectively. These and other bases were effective in inhibiting the growth of the parasite in vitro, giving IC50 values as low as 1 mu M

Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase: A target for anti-malarial chemotherapy

The malarial parasite. Plasmodium vivax (Pv), causes a serious infectious disease found primarily in Asia and the Americas. For protozoan parasites, 6-oxopurine phosphoribosyltransferases (PRTases) provide the only metabolic pathway to synthesize the purine nucleoside monophosphates essential for DNA/RNA production. We have purified the recombinant Pv 6-oxopurine (PRTase) and compared its properties with the human and Pf enzymes. The Pv enzyme uses hypoxanthine and guanine with similar catalytic efficiency to the Pf enzyme but xanthine is not a substrate, hence we identify this enzyme as PvHGPRT. Mass spectrometry suggests that PvHGPRT contains bound magnesium ions that are removed by EDTA resulting in loss of activity. However, the addition of Mg(2+) restores activity. Acyclic nucleoside phosphonates (ANPs) are good inhibitors of PvHGPRT having K(i) values as low as 3 mu M. These compounds can form the basis for the design of new drugs aimed at combating malaria caused by Pv. (C) 2010 Elsevier B.V. All rights reserved

Design of Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase inhibitors as potential antimalarial therapeutics

Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Kvalues of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an ICof 11.7 ± 3.2 μM against Pf lines grown in culture and a CCin human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index.status: publishe

Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics

Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 ± 3.2 μM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index

tpaviot/pythonocc-core: 7.7.2

<p>This release requires opencascade-7.7.2</p> <ul> <li><p>wrapper: port to opencascade-7.7.2</p> </li> <li><p>wrapper: bump swig version to 4.1.1</p> </li> <li><p>wrapper: new wrappers for RWPly, Unitsmethod, XDE</p> </li> <li><p>wrapper: handle TCollection_AsciiString, Standard_CString, TCollection_ExtendedString as python strings</p> </li> <li><p>wrapper: pickle objects that provide json serializer</p> </li> <li><p>wrapper: improve docstrings</p> </li> <li><p>dataexchange: gltf importer/exporter, ply exporter, obj exporter</p> </li> <li><p>display: support for PyQt6 and PySide6</p> </li> <li><p>webgl: refactored threejs and x3dom renderer to stay sync with latest releases</p> </li> <li><p>display: new tkinter renderer, making PyQt or wx GUI managers optional</p> </li> <li><p>cmake installer: respect CMake install prefix</p> </li> </ul&gt

Design of <i>Plasmodium vivax</i> Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics

Plasmodium falciparum (<i>Pf</i>) and Plasmodium vivax (<i>Pv</i>) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG­[X]­PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3<i>R</i>,4<i>R</i>]-4-guanin-9-yl-3-((<i>S</i>)-2-hydroxy-2-phosphonoethyl)­oxy-1-<i>N</i>-(phosphonopropionyl)­pyrrolidine, of <i>Pv</i>HGPRT and <i>Pf</i>HGXPRT that has <i>K</i>_i values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of <i>Pv</i>HGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC₅₀ of 11.7 ± 3.2 μM against <i>Pf</i> lines grown in culture and a CC₅₀ in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

International audienc