Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Much attention has focused on the development of protein kinases as drug targets to treat a variety of human diseases including diabetes, cancer, hypertension and arthritis. To date, Gleevec is one example of a drug targeting protein that has successfully treated human cancer. Several other protein kinase inhibitors are in clinical development. However, protein kinases are in fact part of a larger collection of some 2000 distinct proteins expressed by the genome that like the protein kinases also bind purines (the purinome), either to be utilized as substrates or as co-factors in the form of NAD, NADP and co-enzyme A. The solution structures of many representative gene family members within the purinome show these proteins bind purines in a similar orientations to that observed in all protein kinases. Several non-protein kinase purine utilizing proteins are established drug targets such as HMG CoA reductase, dihydrofolate reductase, phosphodiesterase and HSP90. Searches of OMIM identifies many purine utilizing enzymes that are associated with inborn errors in metabolism. Inhibition of any one of which by a drug could lead to an undesirable side effect. The purinome is therefore somewhat of a drug discovery mixed blessing. It is a rich source of therapeutic targets, but also contains a large collection of diverse proteins whose inhibition could result in an adverse outcome. Drug discovery within the purinome should therefore encompass strategies that enable broad assessment of selectivity across the entire purinome at the earliest stages of the discovery process. In this article we review the purinome within the context of drug discovery and discuss approaches for avoiding off target binding during the discovery/lead optimization process with particular emphasis on use of proteome mining technology.
 ...
PMID:The purinome, a complex mix of drug and toxicity targets. 1684 50

Glucocorticoid hormones play essential roles in adaptation to stress, regulation of metabolism and inflammatory responses. Their effects primarily depend on their binding to intracellular receptors leading to altered target gene transcription as well as on cell-type specific biotransformation between 11beta-hydroxy glucocorticoids and their 11-oxo metabolites. The latter effect is accomplished by two different 11beta-hydroxysteroid dehydrogenase isozymes, constituting a shuttle system between the receptor ligand cortisol and its non-binding precursor cortisone. Whereas the type 1 enzyme (11beta-HSD1) is in vitro a NADP(H)- dependent bidirectional enzyme, it reduces in most instances in vivo cortisone to active cortisol. The type 2 enzyme is an exclusive NAD+ dependent dehydrogenase of glucocorticoids, thus "protecting" the mineralocorticoid receptor against illicit occupation by cortisol. Inhibition of tissue-specific glucocorticoid activation by 11beta-HSD1 constitutes a promising target in the treatment of metabolic and cardiovascular diseases. Pharmacological inhibition leads in animal models to lowered hepatic glucose production and increased insulin sensitivity, the primary goals in therapy of diabetes mellitus. Importantly, 11beta-HSD1 activity appears to be intrinsically linked to all features of the metabolic syndrome, which could at least in animal experiments be modulated by use of synthetic selective inhibitors. Importantly, these features include not only insulin resistance but also dyslipidemia, obesity and arterial hypertension. Animal studies and pharmacological experiments suggest further unrelated target areas, for example improvement of cognitive function and treatment of glaucoma, due to the role of glucocorticoids and cellular activation by 11beta-HSD1 in these pathologies. The recent development of specific 11beta-HSD1 inhibitors coupled with advances on structural knowledge and regulation of the 11beta-HSD1 target has undoubtedly promoted the understanding of glucocorticoid control of metabolic regulation. Taken together, it appears that inhibitors against 11beta-HSD1 constitute a promising avenue for novel treatment strategies against the underlying causes of cardiovascular and other metabolic diseases.
 ...
PMID:Type 1 11beta-hydroxysteroid dehydrogenase as universal drug target in metabolic diseases? 1701 77

The galactose-fed beagle develops diabetes-like microvascular changes that are histologically and clinically similar in appearance to all stages of human diabetic retinopathy. This animal model is extremely useful for evaluating drugs for the treatment of diabetic retinopathy; however, the time required to develop the various retinal lesions (24-72 months for background to the proliferative stage) may be considered prohibitive. Retinal vascular changes begin with an initial degeneration of capillary pericytes, which has been linked to the aldose reductase catalyzed formation of galactitol. Because aldose reductase-linked sugar cataract formation is known to be age dependent, with the onset and severity of cataract higher in younger diabetic and galactose-fed animals, retinal capillary changes in the eyes of initially 2- versus 9-month-old beagles fed a diet containing 30% galactose were compared. Eyes were enucleated after 36 months of galactose feeding, the intact retinal capillaries were isolated by trypsin digestion, and defined retinal regions were evaluated by computer image analysis. Nicotinamide adenine dinucleotide phosphate-dependent reductase activity, using DL-glyceraldehyde and D-xylose as substrates, was also compared in the lenses and whole retinas of eyes from the 2- and 9-month-old beagles. Significantly (P<or=0.05) increased pericyte degeneration, expressed as either the number of pericytes/mm capillary length or the ratio of endothelial cells versus pericytes (E/P ratio) was observed in the retinas of the younger dogs. The number of microaneurysms per eye was also significantly increased in the younger dogs, but no difference in acellular capillary areas was observed. This correlates with a threefold higher level of reductase activity in the retinas of the 2-month-old dogs. Because retinal capillary pericyte destruction is age dependent similar to the formation of sugar cataracts, the use of younger dogs may shorten the time period required for evaluating the efficacy of drugs for diabetic retinopathy in this animal model.
 ...
PMID:Age-dependent retinal capillary pericyte degeneration in galactose-fed dogs. 1734 Nov 53

During the past several decades, the incidence of obesity has significantly increased worldwide. Enormous efforts have been devoted to understanding the molecular mechanisms underlying obesity and its related metabolic disorders such as type 2 diabetes, cardiovascular disease, atherosclerosis, and hypertension. It is now well-established that altered adipocyte metabolism in obese patients is closely associated with the induction of various metabolic stresses including hyperglycemia, hyperlipidemia, hyperinsulinemia, and chronic inflammation. However, the cellular factor(s) which sense metabolic changes and/or initiate the pathological progression of obesity-induced metabolic disorders remain to be elucidated. In this review, we will discuss the possible roles of cellular NADP(+)/NADPH, which function as redox potential regulators, in the induction of obesity-associated oxidative stress, chronic inflammation, and insulin resistance and suggest G6PD, a NADPH-generating enzyme, as a novel target for treating metabolic disorders.
Diabetes Res Clin Pract 2007 Sep
PMID:New evaluations of redox regulating system in adipose tissue of obesity. 1745 57

NAD(P)H-dependent d-xylose reductase is a homodimeric oxidoreductase that belongs to the aldo-keto reductase superfamily. The enzyme has the special function to catalyze the first step in the assimilation of xylose into yeast metabolic pathways. Performing this function via reducing the open chain xylose to xylitol, the xylose reductase of Pichia stipitis is one of the most important enzymes that can be used to construct recombinant Saccharomyces cerevisiae strain for utilizing xylose and producing alcohol. To investigate into the interaction mechanism of the enzyme with its ligand NAD and NADP, the 3D structure was developed for the NAD(P)H-dependent d-xylose reductase from P. stipitis. With the 3D structure, the molecular docking operations were conducted to find the most stable bindings of the enzyme with NAD and NADP, respectively. Based on these results, the binding pockets of the enzyme for NAD and NADP have been explicitly defined. It has been found that the residues in forming the binding pockets for both NAD and NADP are almost the same and mainly hydrophilic. These findings may be used to guide mutagenesis studies, providing useful clues to modify the enzyme to improve the utilization of xylose for producing alcohol. Also, because human aldose reductases have the function to reduce the open chain form of glucose to sorbitol, a process physiologically significant for diabetic patients at the time that their blood glucose levels are elevated, the information gained through this study may also stimulate the development of new strategies for therapeutic treatment of diabetes.
 ...
PMID:Insights from modeling the 3D structure of NAD(P)H-dependent D-xylose reductase of Pichia stipitis and its binding interactions with NAD and NADP. 1754 74

AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions. In vitro, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase in vivo. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both in vitro and in vivo activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10-NADP(+)-tolrestat was determined at 1.25-A resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments.
 ...
PMID:Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10. 1808 47

In diabetes the exposure of the vascular endothelium to high glucose levels results in increased oxidative insult and in vascular dysfunction. We have investigated the effects of rosuvastatin on oxidative stress and apoptosis induced in human umbilical vein endothelial cells (HUVECs) by constant and intermittent high glucose levels. HUVECs were incubated for 14 days in either low (5 mM) or high (20 mM) glucose concentrations, or intermittent high and low glucose on a daily basis. Constant high glucose levels increased p47-phox, p67-phox, and p22-phox expression [components of the Nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase complex]; endothelial nitric oxide synthase, nitric oxide, and O(2)(-) production; nitrotyrosine, 8-hydroxy-2'-deoxyguanosine, and caspase-3 expression; and reduced Bcl-2 expression. These effects were significantly greater under intermittent compared to constant high/low glucose conditions. The effect of rosuvastatin (1 microM) in the presence or absence of mevalonate (200 microM) was evaluated in the cells under both constant and intermittent glucose conditions. Rosuvastatin almost normalized all these parameters. These effects of rosuvastatin were prevented when mevalonate was also added, demonstrating the link to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. These data suggest that rosuvastatin has the potential to prevent damage to and apoptosis of HUVECs induced by high glucose exposure, by reducing oxidative stress. The action of rosuvastatin on antioxidant pathways is related to the inhibition of the overexpression of components of NAD(P)H oxidase induced by the two conditions of high glucose.
J Diabetes Complications
PMID:The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose. 1819 Oct 76

Recent studies have shown that glucose-6-phosphate dehydrogenase (G6PD) is an effectual therapeutic target for metabolic disorders, including obesity and diabetes. In this study, we used in silico and conventional screening approaches to identify putative inhibitors of G6PD and found that gallated catechins (EGCG, GCG, ECG, CG), but not ungallated catechins (ECG, GC, EC, C), were NADP(+)-competitive inhibitors of G6PD and other enzymes that employ NADP(+) as a coenzyme, such as IDH and 6PGD.
 ...
PMID:Catechin gallates are NADP+-competitive inhibitors of glucose-6-phosphate dehydrogenase and other enzymes that employ NADP+ as a coenzyme. 1831 8

Mounting evidence attests to the paramount importance of the non-redox NAD functions. Indeed, NAD homeostasis is related to the free radicals-mediated production of reactive oxygen species responsible for irreversible cellular damage in infectious disease, diabetes, inflammatory syndromes, neurodegeneration and cancer. Because the cellular redox status depends on both the absolute concentration of pyridine dinucleotides and their respective ratios of oxidized and reduced forms (i.e., NAD/NADH and NADP/NADPH), it is conceivable that an altered regulation of the synthesis and degradation of NAD impairs the cell redox state and likely contributes to the mechanisms underlying the pathogenesis of the above mentioned diseases. Taking into account the recent appearance in the literature of comprehensive reviews covering different aspects of the significance of NAD metabolism, with particular attention to the enzymes involved in NAD cleavage, this monograph includes the most recent results on NAD biosynthesis in mammals and humans. Due to recent findings on nicotinamide riboside as a nutrient, its inclusion under "niacins" is proposed. Here, the enzymes involved in the de novo and reutilization pathways are overviewed.
 ...
PMID:Enzymology of mammalian NAD metabolism in health and disease. 1850 49

11beta-Hydroxysteroid dehydrogenase1(11beta-HSD1) can serve either as an oxo-reductase or dehydrogenase determined by the redox state in the endoplasmic reticulum (ER). This bidirectional enzyme governs paracrine glucocorticoid production. Recent in vitro studies have underscored the key role of cytoplasmic glucose-6-phosphate (G6P) in controlling the flux direction of 11betaHSD-1 by altering the intraluminal ER NADPH/NADP ratio. The hypothesis that other hexose phosphoesters or the plentiful cellular oxidative protector glutathione could also regulate microsomal 11betaHSD-1 activity was tested. Fructose-6-phosphate increased the activity of 11beta-HSD1 reductase in isolated rat and porcine liver microsomes but not porcine fat microsomes. Moreover, oxidized glutathione (GSSG) attenuated 11beta-HSD1 reductase activity by 40% while reduced glutathione (GSH) activated the reductase in liver. Fat microsomes were unaffected because they lack glutathione reductase. Nonetheless, another oxidizing agent, hydrogen peroxide (0.5mM), inhibited both fat and liver 11beta-HSD1 reductase. Consistent with the major role of the redox state, 2.5mM GSSG and hydrogen peroxide augmented the 11beta-HSD1 dehydrogenase, antithetical to the reductase, by 20-30% in liver microsomes. Given the key role of reactive oxygen species and hexose phosphate accumulation in the pathoetiology of obesity and diabetes, these compounds might also modify 11beta-HSD1 in these conditions.
 ...
PMID:Modification of microsomal 11beta-HSD1 activity by cytosolic compounds: glutathione and hexose phosphoesters. 1855 Mar 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>