David W Christianson

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Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is(More)
Oxidized low-density lipoproteins increase arginase activity and reciprocally decrease endothelial NO in human aortic endothelial cells. Here, we demonstrate that vascular endothelial arginase activity is increased in atherogenic-prone apolipoprotein E-null (ApoE(-/-)) and wild-type mice fed a high cholesterol diet. In ApoE(-/-) mice, selective arginase II(More)
The crystal structure of recombinant murine liver cytosolic epoxide hydrolase (EC has been determined at 2.8-A resolution. The binding of a nanomolar affinity inhibitor confirms the active site location in the C-terminal domain; this domain is similar to that of haloalkane dehalogenase and shares the alpha/beta hydrolase fold. A structure-based(More)
There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases(More)
The x-ray crystal structure of recombinant trichodiene synthase from Fusarium sporotrichioides has been determined to 2.5-A resolution, both unliganded and complexed with inorganic pyrophosphate. This reaction product coordinates to three Mg(2+) ions near the mouth of the active site cleft. A comparison of the liganded and unliganded structures reveals a(More)
The x-ray crystal structure of dimeric (+)-bornyl diphosphate synthase, a metal-requiring monoterpene cyclase from Salvia officinalis, is reported at 2.0-A resolution. Each monomer contains two alpha-helical domains: the C-terminal domain catalyzes the cyclization of geranyl diphosphate, orienting and stabilizing multiple reactive carbocation intermediates;(More)
Overexpression of the zinc enzyme carbonic anhydrase (CA; EC ) XII is observed in certain human cancers. This bitopic membrane protein contains an N-terminal extracellular catalytic domain, a membrane-spanning alpha-helix, and a small intracellular C-terminal domain. We have determined the three-dimensional structure of the extracellular catalytic domain of(More)
The structures of two alkylurea inhibitors complexed with murine soluble epoxide hydrolase have been determined by x-ray crystallographic methods. The alkyl substituents of each inhibitor make extensive hydrophobic contacts in the soluble epoxide hydrolase active site, and each urea carbonyl oxygen accepts hydrogen bonds from the phenolic hydroxyl groups of(More)
Although terpenoid synthases catalyze the most complex reactions in biology, these enzymes appear to play little role in the chemistry of catalysis other than to trigger the ionization and chaperone the conformation of flexible isoprenoid substrates and carbocation intermediates through multistep reaction cascades. Fidelity and promiscuity in this chemistry(More)