Structural studies of the human glyoxylate reductase/hydroxypyruvate reductase (GRHPR) and other proteins

Human glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is a D-2-hydroxyacid dehydrogenase found predominantly within the liver, and is essential for the removal of the reactive metabolic product glyoxylate. Primary hyperoxaluria type 2 (PH2) disease, which is characterised by increased urinary oxalate and L-glycerate levels leading to calcium oxalate deposition and decreased renal function, is caused by mutations in the gene for GRHPR. In this study the first crystal structures of the human GRHPR enzyme are reported. Structures of apo, binary and ternary forms of GRHPR are reported, the latter being the first structure of a true ternary complex of an enzyme from the D-2-hydroxyacid dehydrogenase family.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Crystal Structure of DIM-1, an Acquired Subclass B1 Metallo-β-Lactamase from Pseudomonas stutzeri

Metallo-β-lactamases (MBLs) hydrolyze almost all classes of β-lactam antibiotic, including carbapenems—currently first choice drugs for opportunistic infections by Gram-negative bacterial pathogens. MBL inhibitor development is complicated by the diversity within this group of enzymes, and by the appearance of new enzymes that continue to be identified both as chromosomal genes and on mobile genetic elements. One such newly discovered MBL is DIM-1, a mobile enzyme originally discovered in the opportunist pathogen Pseudomonas stutzeri but subsequently identified in other species and locations. DIM-1 is a subclass B1 MBL more closely related to the TMB-1, GIM-1 and IMP enzymes than to other clinically encountered MBLs such as VIM and NDM; and possesses Arg, rather than the more usual Lys, at position 224 in the putative substrate binding site. Here we report the crystallization and structure determination of DIM-1. DIM-1 possesses a binuclear metal center with a 5 (rather than the more usual 4) co-ordinate tri-histidine (Zn1) site and both 4- and 5-co-ordinate Cys-His-Asp- (Zn2) sites observed in the two molecules of the crystallographic asymmetric unit. These data indicate a degree of variability in metal co-ordination geometry in the DIM-1 active site, as well as facilitating inclusion of DIM-1 in structure-based MBL inhibitor discovery programmes

Can a Logarithmically Running Coupling Mimic a String Tension?

It is shown that a Coulomb potential using a running coupling slightly modified from the perturbative form can produce an interquark potential that appears nearly linear over a large distance range. Recent high-statistics SU(2) lattice gauge theory data fit well to this potential without the need for a linear string-tension term. This calls into question the accuracy of string tension measurements which are based on the assumption of a constant coefficient for the Coulomb term. It also opens up the possibility of obtaining an effectively confining potential from gluon exchange alone.Comment: 13 pages, LaTeX, two figures not included, available from author. revision - Line lengths fixed so it will tex properl

The Hyperfine Splitting in Charmonium: Lattice Computations Using the Wilson and Clover Fermion Actions

We compute the hyperfine splitting $m_{J/\psi}-m_{\eta_c}$ on the lattice, using both the Wilson and $O(a)$-improved (clover) actions for quenched quarks. The computations are performed on a $24^3\times48$ lattice at $\beta = 6.2$, using the same set of 18 gluon configurations for both fermion actions. We find that the splitting is 1.83\err{13}{15} times larger with the clover action than with the Wilson action, demonstrating the sensitivity of the spin-splitting to the magnetic moment term which is present in the clover action. However, even with the clover action the result is less than half of the physical mass-splitting. We also compute the decay constants $f_{\eta_c}$ and $f^{-1}_{J/\psi}$, both of which are considerably larger when computed using the clover action than with the Wilson action. For example for the ratio $f^{-1}_{J/\psi}/f^{-1}_{\rho}$ we find 0.32\err{1}{2} with the Wilson action and $0.48\pm 3$ with the clover action (the physical value is 0.44(2)).Comment: LaTeX file, 8 pages and two postscript figures. Southampton Preprint: SHEP 91/92-27 Edinburgh Preprint: 92/51

Topological Structure of the SU(3) Vacuum

We investigate the topological structure of the vacuum in SU(3) lattice gauge theory. We use under-relaxed cooling to remove the high-frequency fluctuations and a variety of "filters" to identify the topological charges in the resulting smoothened field configurations. We find a densely packed vacuum with an average instanton size, in the continuum limit, of about 0.5 fm. The density at large sizes decreases as a large inverse power of the size. At small sizes we see some sign of a trend towards the asymptotic perturbative behaviour. We find that an interesting polarisation phenomenon occurs: the large topological charges tend to have, on the average, the same sign and are over-screened by the smaller charges which tend to have, again on the average, the opposite sign to the larger instantons. We also calculate the topological susceptibility for which we obtain a continuum value of about 187 MeV. We perform the calculations for various volumes, lattice spacings and numbers of cooling sweeps, so as to obtain some control over the associated systematic errors. The coupling range is from beta=6.0 to beta=6.4 and the lattice volumes range from 16x16x16x48 to 32x32x32x64.Comment: LaTeX. Self-unpacking, uuencoded tar-compressed fil

Heavy Quark Free Energies and Screening in SU(2) Gauge Theory

We investigate the singlet, triplet and colour average heavy quark free energies in SU(2) pure gauge theory at various temperatures T. We focus on the long distance behaviour of the free energies, studying in particular the temperature dependence of the string tension and the screening masses. The results are qualitatively similar to the SU(3) scenario, except near the critical temperature Tc of the deconfining transition. Finally we test a recently proposed method to renormalize the Polyakov loop.Comment: 5 pages, 4 figures, contribution to the Proceedings of SEWM 2002 (Heidelberg

Light hadron spectroscopy with O(a) improved dynamical fermions

We present the first results for the static quark potential and the light hadron spectrum using dynamical fermions at $\beta=5.2$ using an O(a) improved Wilson fermion action together with the standard Wilson plaquette action for the gauge part. Sea quark masses were chosen such that the pseudoscalar-vector mass ratio, m_PS/m_V$, varies from 0.86 to 0.67. Finite-size effects are studied by using three different volumes, 8^3\cdot 24, 12^3\cdot 24 and 16^3\cdot 24. Comparing our results to previous ones obtained using the quenched approximation, we find evidence for sea quark effects in quantities like the static quark potential and the vector-pseudoscalar hyperfine splitting.Comment: 38 pages, 14 Postscript figure, LaTe

Tadpole-improved SU(2) lattice gauge theory

A comprehensive analysis of tadpole-improved SU(2) lattice gauge theory is made. Simulations are done on isotropic and anisotropic lattices, with and without improvement. Two tadpole renormalization schemes are employed, one using average plaquettes, the other using mean links in Landau gauge. Simulations are done with spatial lattice spacings $a_s$ in the range of about 0.1--0.4 fm. Results are presented for the static quark potential, the renormalized lattice anisotropy $a_t/a_s$ (where $a_t$ is the ``temporal'' lattice spacing), and for the scalar and tensor glueball masses. Tadpole improvement significantly reduces discretization errors in the static quark potential and in the scalar glueball mass, and results in very little renormalization of the bare anisotropy that is input to the action. We also find that tadpole improvement using mean links in Landau gauge results in smaller discretization errors in the scalar glueball mass (as well as in the static quark potential), compared to when average plaquettes are used. The possibility is also raised that further improvement in the scalar glueball mass may result when the coefficients of the operators which correct for discretization errors in the action are computed beyond tree level.Comment: 14 pages, 7 figures (minor changes to overall scales in Fig.1; typos removed from Eqs. (3),(4),(15); some rewording of Introduction