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Biochemical and Biophysical Research... Jul 2011It was hypothesized that residues Val44 and Val45 serve as important residues for human glutathione synthetase (hGS) function and stability given their location at the...
It was hypothesized that residues Val44 and Val45 serve as important residues for human glutathione synthetase (hGS) function and stability given their location at the dimer interface of this enzyme. Computational studies suggest that mutation at Val45 has more impact on the structure and stability of hGS than does mutation at Val44. Experimentally, enzymes with mutations at the 44 and or 45 positions of hGS were prepared, purified and assayed for initial activity. Val45 position mutations (either to alanine or tryptophan) have a greater impact on enzyme activity than do mutations at Val44. Differential scanning calorimetry experiments reveal a loss of stability in all mutant enzymes, with V45 mutations being less stable than the corresponding Val44 mutations. The γ-GluABA substrate affinity remains unaltered in V44A and V45A mutant enzymes, but increases when tryptophan is introduced at either of these positions. Hill coefficients trend towards less negative cooperativity with the exception of V45W mutant hGS. These results imply that residues V44 and V45 are located along the allosteric pathway of this negatively cooperative dimeric enzyme, that their mutation impacts the allosteric pathway more than it does the active site of hGS, and that these residues (and by extension the dimer interface in which they are located) are integral to the stability of human glutathione synthetase.
Topics: Allosteric Regulation; Catalytic Domain; Enzyme Stability; Glutathione Synthase; Humans; Isoenzymes; Mutation; Protein Multimerization; Protein Structure, Secondary; Valine
PubMed: 21683691
DOI: 10.1016/j.bbrc.2011.06.034 -
Cardiology 1999Valsartan is a specific angiotensin II receptor antagonist with high selectivity for the AT(1) receptor subtype. After oral administration of single or repeated... (Review)
Review
Valsartan is a specific angiotensin II receptor antagonist with high selectivity for the AT(1) receptor subtype. After oral administration of single or repeated once-daily doses, valsartan 40-80 mg inhibits the pressor response to angiotensin II for 24 hours. In patients with mild-to-moderate hypertension, efficacy of valsartan appears to be independent of age, sex, and race, and is at least equivalent to that of calcium antagonists, ACE inhibitors, or thiazide diuretics. Response rate to valsartan 160 mg o.d. is significantly greater than after receiving losartan 100 mg o.d. Valsartan has additive effects with other antihypertensive drugs and combination therapy is effective in severe hypertension and in hypertension with renal insufficiency, where renal function is well maintained. Valsartan has good tolerability with a side-effect profile indistinguishable from placebo and superior to that of comparable drugs. Valsartan does not cause cough or adverse metabolic effects; first dose hypotension and rebound hypertension on abrupt withdrawal have not been encountered. Valsartan has clear clinical advantage in the management of hypertension. Its impact on prognosis in patients with a high risk of cardiovascular morbidity and mortality is under evaluation.
Topics: Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Humans; Hypertension; Losartan; Tetrazoles; Valine; Valsartan
PubMed: 10449890
DOI: 10.1159/000047283 -
Journal of Clinical Hypertension... Apr 2006The angiotensin receptor blockers (ARBs) are very effective and safe antihypertensive drugs. They exert their antihypertensive effect through blockage of the angiotensin... (Review)
Review
The angiotensin receptor blockers (ARBs) are very effective and safe antihypertensive drugs. They exert their antihypertensive effect through blockage of the angiotensin II, type 1 receptor and quite possibly through stimulation by angiotensin II of the unoccupied type 2 receptor. Besides hypertension, the ARBs have been found recently to be of value in the treatment of heart failure and diabetic nephropathy. In addition, ARBs have emerged lately as being very effective and perhaps superior to other antihypertensive drugs in the prevention of de novo or recurrent strokes. Other actions that may account for their stroke-protective effects include their antiatherogenic, antidiabetic, antiplatelet aggregating, hypouricemic, and atrial antifibrillatory actions. All these actions make the ARBs a true pleiotropic class of drugs. Each of the foregoing effects will be discussed briefly in this concise review.
Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Diabetes Mellitus; Heart; Humans; Kidney; Losartan; Platelet Aggregation; Stroke; Tetrazoles; Uric Acid; Valine; Valsartan
PubMed: 16596029
DOI: 10.1111/j.1524-6175.2005.05264.x -
The Journal of International Medical... Jun 2020Numerous risk factors for heart disease or dementia harbor over 10% valine plus glycine content. Interestingly, TDP-43 contains 6.0% valine and 13.3% glycine, and the...
Numerous risk factors for heart disease or dementia harbor over 10% valine plus glycine content. Interestingly, TDP-43 contains 6.0% valine and 13.3% glycine, and the buildup of this protein in the brains of patients with limbic-predominant age-related TDP-43 encephalopathy has dire consequences. The two γ-methyl groups in valine enable hyperconjugation, which enhances the van der Waals interaction between its side group and the carbonyl carbon. This extends the C=O bond length, and this weakened C=O bond augments the secondary chemical bonding of the carbonyl oxygen atom to cations. This, in turn, promotes the formation and buildup of insoluble and rigid salts such as calcium oxalate, which is postulated to be a major cause of heart disease. Similarly, the long C=O bond length in glycine results in a weakened C=O bond with an enhanced affinity toward cations and the formation of insoluble salts. Further, several prion proteins possess a high glycine content of approximately 20%. The insoluble calcium salts produced may promote aggregate formation via secondary chemical bonding between calcium and glycine, as well as between calcium and valine. Chemical and biochemical insights will help us to better understand the etiology of disorders linked to protein aggregates.
Topics: Age Factors; Aged, 80 and over; Amino Acid Sequence; Brain; DNA-Binding Proteins; Glycine; Humans; Protein Aggregates; Risk Factors; TDP-43 Proteinopathies; Valine
PubMed: 32529876
DOI: 10.1177/0300060520929853 -
Skin Therapy Letter Feb 2005The Herpesviridae family (Types 1-8) continues to inflict considerable morbidity and social stigma upon humanity. Once infected with the herpes viruses, especially Types... (Review)
Review
The Herpesviridae family (Types 1-8) continues to inflict considerable morbidity and social stigma upon humanity. Once infected with the herpes viruses, especially Types 1-3, they establish permanent residence within our nervous system and reactivate during periods of stress, trauma, and/or other precipitating factors. To date, there is no cure for herpes viral infections but antivirals can attenuate the symptoms and duration of episodic outbreaks. Prophylactic therapy can suppress recurrences. The first antiviral with selective activity against virus-infected cells is considered to be acyclovir. Our article will highlight the clinical indications of the current generation, valacyclovir, which is a prodrug of acyclovir. We consider valacyclovir as a second-generation antiviral, having taken into account the initial selectivity and safety profile of its progenitor, acyclovir.
Topics: Acyclovir; Antiviral Agents; Herpesviridae Infections; Humans; Prodrugs; Valacyclovir; Valine
PubMed: 15776202
DOI: No ID Found -
Journal of the... Sep 2004The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial compared coronary heart disease outcome in two anti-hypertensive treatment strategies based on... (Review)
Review
The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial compared coronary heart disease outcome in two anti-hypertensive treatment strategies based on either an angiotensin receptor blocker, valsartan, or a calcium channel blocker (CCB), amlodipine. In both patient groups a diuretic was added, if necessary, in an attempt to achieve blood pressure (BP) goals. Follow-up of over 15,000 patients was maintained for 4.2 years. There were no differences in the primary composite endpoint of cardiac morbidity and mortality (which included interventional procedures, hospitalised heart failure, non-fatal myocardial infarction and fatal coronary heart disease, however myocardial infarction and stroke events occurred less commonly on amlodipine than on valsartan the former achieving statistical significance [p=0.02 and p=0.08 respectively]). There was a non-significant excess of hospitalised heart failure on amlodipine (p=0.012). However, lower BPs early in the trial probably accounted for most of the observed benefits in favour of the CCB. The angiotensin receptor blocker arm was associated with less new onset diabetes. The results of VALUE add further support to the evidence that blood pressure control is the major determinant in outcome in trials of antihypertensive therapy.
Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Drug Administration Schedule; Humans; Hypertension; Randomized Controlled Trials as Topic; Tetrazoles; Treatment Outcome; Valine; Valsartan
PubMed: 15526243
DOI: 10.3317/jraas.2004.033 -
Journal of Clinical Hypertension... Aug 2004The angiotensin II receptor blockers (ARBs), are highly selective for the AT1 subtype and will block the effects of angiotensin II on peripheral vessels. Several short-... (Review)
Review
The angiotensin II receptor blockers (ARBs), are highly selective for the AT1 subtype and will block the effects of angiotensin II on peripheral vessels. Several short- and long-term studies have shown these agents to be safe and effective antihypertensive drugs. Since monotherapy of hypertension may be ineffective in lowering the blood pressure to goal, the use of an ARB, especially in combination with a diuretic or another medication, is frequently necessary to bring the blood pressure <140/90 mm Hg (<130/80 mm Hg among people with diabetes mellitus or chronic renal failure), according to JNC 7 guidelines. Besides hypertension, the ARBs have been shown to reduce left ventricular hypertrophy in hypertensive patients. Other benefits of these medications, as well as the angiotensin I converting enzyme inhibitors (ACEIs), include a decrease in cardiovascular morbidity and mortality in patients with heart failure, or hypertensive diabetic nephropathy with proteinuria. Some of the beneficial effects noted with the ACEIs and ARBs (congestive heart failure, left ventricular hypertrophy), have also been demonstrated with the use of b blockers alone and in combination with a diuretic. These drugs, i.e., b blockers, ARBs, and ACEIs, seem to exert their beneficial action through the blockade of the renin-angiotensin-aldosterone system. The role of this system in cardiovascular remodeling and its blockade will be discussed in this review, which will specifically summarize data with the ARB, valsartan.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Cardiovascular Diseases; Drug Interactions; Drug Therapy, Combination; Humans; Hypertension; Tetrazoles; Valine; Valsartan
PubMed: 15308883
DOI: 10.1111/j.1524-6175.2004.03449.x -
The American Journal of Managed Care Nov 2005Angiotensin II, the principal effector peptide of the renin-angiotensin-aldosterone system (RAAS), has potent vasoconstrictive and other effects that can lead to cardiac... (Review)
Review
Angiotensin II, the principal effector peptide of the renin-angiotensin-aldosterone system (RAAS), has potent vasoconstrictive and other effects that can lead to cardiac and renal complications. Angiotensin receptor blockers (ARBs), which block the effects of angiotensin II at the receptor level, antagonize angiotensin II's vasoconstrictive and prooxidant effects, decrease aldosterone secretion, and mitigate sympathetic activity. The antihypertensive efficacy of the ARBs has been demonstrated in large clinical trials. In addition to their blood pressure-lowering effect, these agents also provide cardiovascular (CV) protection and reduce CV mortality as effectively as other classes of antihypertensive agents. By inhibiting the RAAS, the ARBs also have renoprotective effects and are indicated for the treatment of hypertension in patients with diabetes. They have also been shown to lower the incidence of new-onset diabetes in high-risk hypertensive patients. Combining ARBs with other antihypertensive drugs increases their antihypertensive efficacy.
Topics: Angiotensin Receptor Antagonists; Antihypertensive Agents; Captopril; Diabetes Complications; Drug Evaluation; Humans; Hypertension; Losartan; Tetrazoles; Treatment Outcome; Valine; Valsartan
PubMed: 16300453
DOI: No ID Found -
Journal of Bacteriology Jul 1966Norton, J. E. (University of Oklahoma School of Medicine, Oklahoma City), and J. R. Sokatch. Oxidation of d- and l-valine by enzymes of Pseudomonas aeruginosa. J....
Norton, J. E. (University of Oklahoma School of Medicine, Oklahoma City), and J. R. Sokatch. Oxidation of d- and l-valine by enzymes of Pseudomonas aeruginosa. J. Bacteriol. 92:116-120. 1966.-Cell-free extracts prepared from Pseudomonas aeruginosa grown on dl-valine catalyzed the consumption of oxygen with several d-amino acids, but not with the corresponding l-amino acids. The product of d-valine oxidation was identified as 2-oxoisovalerate by the preparation and characterization of 2-oxoisovalerate 2,4-dinitrophenylhydrazone. The enzyme catalyzing d-amino acid oxidation was present in extracts of cells grown on valine, but not on glucose, had a pH optimum of approximately 9.0, consumed 1 atom of oxygen per mole of keto acid produced, and was not stimulated by any of the usual electron transport cofactors. It was not possible to demonstrate either the direct oxidation of l-valine or the conversion of l- to d-valine by these enzyme preparations. However, a possible route of l-valine metabolism by transamination with 2-oxoglutarate with regeneration of the amino group acceptor by glutamate oxidation was established by identification of the transaminase and l-glutamate dehydrogenase in these enzyme preparations.
Topics: Amino Acids; Enzymes; Hydrogen-Ion Concentration; In Vitro Techniques; Oxidation-Reduction; Oxygen Consumption; Pseudomonas aeruginosa; Valine
PubMed: 4957429
DOI: 10.1128/jb.92.1.116-120.1966 -
Communications Biology Jan 2023Although Clostridium novyi-NT is an anti-cancer bacterial therapeutic which germinates within hypoxic tumors to kill cancer cells, the actual germination triggers for C....
Although Clostridium novyi-NT is an anti-cancer bacterial therapeutic which germinates within hypoxic tumors to kill cancer cells, the actual germination triggers for C. novyi-NT are still unknown. In this study, we screen candidate germinants using combinatorial experimental designs and discover by serendipity that D-valine is a potent germinant, inducing 50% spore germination at 4.2 mM concentration. Further investigation revealed that five D-valine analogs are also germinants and four of these analogs are enantiomeric pairs. This stereoflexible effect of L- and D-amino acids shows that spore germination is a complex process where enantiomeric interactions can be confounders. This study also identifies L-cysteine as a germinant, and hypoxanthine and inosine as co-germinants. Several other amino acids promote (L-valine, L-histidine, L-threonine and L-alanine) or inhibit (L-arginine, L-glycine, L-lysine, L-tryptophan) germination in an interaction-dependent manner. D-alanine inhibits all germination, even in complex growth media. This work lays the foundation for improving the germination efficacy of C. novyi-NT spores in tumors.
Topics: Valine; Spores, Bacterial; Amino Acids; Alanine; Spores
PubMed: 36709236
DOI: 10.1038/s42003-023-04496-9