A5089032199- Aldose Reductase and Taurine
- Prenatal Substance Exposure Effects
- Heme Oxygenase-1 and Carbon Monoxide
- Neonatal Health and Biochemistry
- Biochemical effects in animals
- Polyamine Metabolism and Applications
- Pancreatic function and diabetes
- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- Folate and B Vitamins Research
- Alcohol Consumption and Health Effects
- Ubiquitin and proteasome pathways
- Cannabis and Cannabinoid Research
- Metabolism and Genetic Disorders
- Fatty Acid Research and Health
- Catalytic Cross-Coupling Reactions
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- Estrogen and related hormone effects
- Pharmacogenetics and Drug Metabolism
- Immune Cell Function and Interaction
- Catalytic C–H Functionalization Methods
- Nitric Oxide and Endothelin Effects
- RNA Interference and Gene Delivery
Baylor College of Medicine
2004-2024
Arkansas Children's Nutrition Center
2018
Children's Nutrition Research Center at Baylor College of Medicine
2010-2017
Agricultural Research Service
2013-2015
United States Department of Agriculture
2013
SignalRx Pharmaceuticals (United States)
2000
National Heart Lung and Blood Institute
1999
Brandeis University
1996-1997
University Hospital of Bern
1993-1994
Weatherford College
1993
Aldehyde reductase [EC 1.1.1.2] and aldose 1.1.1.21] are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl compounds. These enzymes implicated in the development of diabetic complications by catalyzing reduction glucose to sorbitol. Enzyme inhibition as a direct pharmacokinetic approach prevention resulting from hyperglycemia diabetes has not been effective because nonspecificity inhibitors some appreciable side effects. To understand structural...
Aldose reductase, which catalyzes the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction a wide variety aromatic and aliphatic carbonyl compounds, is implicated in development diabetic galactosemic complications involving lens, retina, nerves, kidney. A 1.65 angstrom refined structure recombinant human placenta aldose reductase reveals that enzyme contains parallel β8/α8-barrel motif establishes new for NADP-binding oxidoreductases. The substrate-binding...
Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless gene, SUMO-4, that encodes 95-amino acid having an 86% amino homology with SUMO-2. In contrast SUMO-2, is highly expressed all tissues examined, SUMO-4 mRNA was detected mainly kidney. A single nucleotide polymorphism substituting conserved methionine valine...
Aldose reductase (AR) has been implicated in osmoregulation the kidney because it reduces glucose to sorbitol, which can serve as an osmolite. Under hyperosmotic stress, transcription of this gene is induced increase enzyme level. This mode osmotic regulation AR expression observed a number nonrenal cells well, suggesting that common response stress. We have identified 132-base pair sequence ∼1 kilobase pairs upstream start site enhances activity promoter well SV40 when are under Within...
Local control of sperm maturation Newly produced spermatozoa within the testis do not have fertilizing ability but become fully functional when they mature in epididymis. The development epididymis itself is dependent on testicular factors arriving via luminal flow. Improper signaling between and hypothesized to result male infertility. Kiyozumi et al. identified NELL2 as a protein that binds its receptor, ROS1, surface induces epididymal differentiation (see Perspective by Lord Oatley). In...
Men or mice with homozygous serine/threonine kinase 33 (
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTyrosine-48 Is the Proton Donor and Histidine-110 Directs Substrate Stereochemical Selectivity in Reduction Reaction of Human Aldose Reductase: Enzyme Kinetics Crystal Structure Y48H Mutant EnzymeKurt M. Bohren, Charles E. Grimshaw, Chung Jeng Lai, David H. Harrison, Dagmar Ringe, Gregory A. Petsko, Kenneth GabbayCite this: Biochemistry 1994, 33, 8, 2021–2032Publication Date (Print):March 1, 1994Publication History Published online1 May...
Aldose reductase (EC 1.1.1.21) from human brain has been purified to apparent homogeneity. The enzyme catalyzes the NADPH‐dependent reduction of several physiological and xenobiotic aldehydes. Isocortico‐steroids, e.g. isocortisol isocorticosterone, are best substrates ( K m < 1 μm), followed by aromatic arylalkylaldehydes, including biogenic aldehydes = 3–15 μM). activity towards aldoses is highest with glyceraldehyde 25 μM) decreases increasing number carbon atoms sugar. Flavonoids,...
Aldose reductase is a NADPH-dependent aldo-keto involved in the pathogenesis of some diabetic and galactosemic complications. The published crystal structure human aldose [Wilson et al. (1992) Science 257, 81-84] contains hitherto unexplained electron density positioned within active site pocket facing nicotinamide ring NADPH other key residues (Tyr48, His110, Cys298). In this paper we identify as citrate, which present crystallization buffer (pH 5.0), provide confirmatory evidence by both...
Carbonyl reductase (EC 1.1.1.184)is one of several monomeric, NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds that are generally referred to as the aldoketoreductases.The grouping enzyme into family has been proposed on basis functional similarities and in absence structural data.Here, we describe isolation characterization a cDNA clone complementary human mRNA from placenta library constructed phage Xgtl 1.The consists 1199 base pairs contains an open reading...
Using mouse gene knock-out models, we identify aldehyde reductase (EC 1.1.1.2, Akr1a4 (GR)) and aldose 1.1.1.21, Akr1b3 (AR)) as the enzymes responsible for conversion of D-glucuronate to L-gulonate, a key step in ascorbate (ASC) synthesis pathway mice. The (KO) mice show that two enzymes, GR AR, provide approximately 85 15% respectively. GRKO/ARKO double are unable synthesize ASC (>95% deficit) develop scurvy. GRKO ( 85% grow normally when fed regular chow (ASC content = 0) but suffer...
Significance To rapidly identify small-molecule lead compounds to target healthcare-associated proteases, we constructed a unique 9.8-million-membered protease-focused DNA-encoded chemical library. Affinity selection of this library with healthcare-relevant protease (i.e., thrombin, key protein necessary for blood coagulation) revealed potent inhibitors in the first screening attempt. Our results emphasize utility structurally focused approach uncover hits healthcare targets (e.g.,...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery poorly suited producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen billion DNA-encoded molecules en masse identify a potent class virus-specific inhibitors SARS-CoV-2...
The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by human genome share highly conserved catalytic domains. Until now, no selective unique a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein type 2 (BMPR2), have been reported. This dearth receptor-specific kinase hinders therapeutic options skeletal defects and cancer as result an overactivated BMP signaling...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanism of Human Aldehyde Reductase: Characterization the Active Site PocketOleg A. Barski, Kenneth H. Gabbay, Charles E. Grimshaw, and Kurt M. BohrenCite this: Biochemistry 1995, 34, 35, 11264–11275Publication Date (Print):September 5, 1995Publication History Published online1 May 2002Published inissue 5 September 1995https://pubs.acs.org/doi/10.1021/bi00035a036https://doi.org/10.1021/bi00035a036research-articleACS PublicationsRequest reuse...
Human aldose reductase (EC 1.1.1.21) and aldehyde 1.1.1.2) are implicated in the development of diabetic complications by a variety mechanisms, number drugs to inhibit these enzymes have been proposed for therapy prevention complications. To probe structure function two enzymes, we used site-directed mutagenesis cDNAs both replace lysine 262 with methionine. Wild-type mutant were overexpressed Escherichia coli purified anion exchange affinity chromatography. N-terminal sequence analysis,...
DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify starting points for drug discovery. As robust transformation discovery, palladium-catalyzed C–N coupling is valuable synthetic method the construction of DECL matter; however, currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide bromide electrophiles. We developed conditions utilizing an N-heterocyclic carbene–palladium catalyst that extends this reaction...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHuman Aldose Reductase: Rate Constants for a Mechanism Including Interconversion of Ternary Complexes by Recombinant Wild-Type EnzymeCharles E. Grimshaw, Kurt M. Bohren, Chung-Jeng Lai, and Kenneth H. GabbayCite this: Biochemistry 1995, 34, 44, 14356–14365Publication Date (Print):November 1, 1995Publication History Published online1 May 2002Published inissue 1 November...
Human aldose reductase and aldehyde are members of the aldo-keto superfamily that share three domains homology a nonhomologous COOH-terminal region. The two enzymes catalyze NADPH-dependent reduction wide variety carbonyl compounds. To probe function investigate basis for substrate specificity, we interchanged cDNA fragments encoding NH2-terminal reductase. A chimeric enzyme (CH1, 317 residues) was constructed in which first 71 residues were replaced with 73 Catalytic effectiveness (kcat/Km)...
Hypertonicity induces a group of genes that are responsible for the intracellular accumulation protective organic osmolytes such as sorbitol and betaine. Two representative aldose reductase enzyme (AR, EC 1.1.1.21), which is conversion glucose to sorbitol, betaine transporter (BGT1), mediates Na+-coupled uptake in response osmotic stress. We recently reported induction BGT1 mRNA renal epithelial Madin-Darby canine kidney cell line inhibited by SB203580, specific p38 kinase inhibitor. In...
Aldose reductase (EC 1.1.1.21) catalyzes the NADPH-mediated conversion of glucose to sorbitol. The hyperglycemia diabetes increases sorbitol production primarily through substrate availability and is thought contribute pathogenesis many diabetic complications. Increased can also occur at normoglycemic levels via rapid in aldose transcription expression, which have been shown upon exposure cell types hyperosmotic conditions. induction accumulation sorbitol, an organic osmolyte, be part...
Aldose reductase enfolds NADP+/NADPH via a complex loop mechanism, with cofactor exchange being the rate-limiting step for overall reaction. This study measures binding constants of these cofactors in wild-type enzyme, as well variety active-site mutants (C298A, Y48H, Y48F, Y209F, H110A, W219A, and W20A), seeks to identify site mechanism aldose inhibitor alrestatin recombinant human enzyme. All mutant enzymes, regardless their enzyme activities, have normal or only slightly elevated coenzyme...
BackgroundNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and risk factor for cirrhosis, hepatocellular carcinoma failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. MethodsUsing livers from our previous study, carried out global non-targeted metabolomic approach to quantify diet-induced changes...
Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis pulmonary arterial hypertension (PAH). Multiple factors may contribute decreased bioavailability, including increased activity arginase, enzyme that converts arginine ornithine and urea, which compete with NOS for arginine; inadequate de novo production from citrulline; concentration asymmetric dimethylarginine (ADMA), endogenous inhibitor NOS. We hypothesized PAH patients...