scholarly journals Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thanuja D. Sudasinghe ◽  
Michael T. Banco ◽  
Donald R. Ronning
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Binding Sites ◽  
Enzyme Inhibitor ◽  
Structural Information ◽  
Alkylating Agents ◽  
Enzyme Active Site ◽  
Treatment Regimens ◽  
Domains Of Life ◽  
Substrate Binding Sites

AbstractErgothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.

Membranous nephropathy

2020 ◽  
pp. 4928-4933
Author(s):  
An S. De Vriese ◽  
Fernando C. Fervenza
Keyword(s):  
High Risk ◽  
Membranous Nephropathy ◽  
Alkylating Agents ◽  
Calcineurin Inhibitors ◽  
Treatment Regimens ◽  
Phospholipase A2 Receptor ◽  
Risk Of Progression ◽  
Long Term Prognosis ◽  
Asymptomatic Proteinuria

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasians adults. It may also present with asymptomatic proteinuria. Its defining feature is the presence of subepithelial immune deposits, localized between the podocyte and the glomerular basement membrane. Aetiology—primary MN (80% of cases) is caused in most cases by antibodies against the M-type phospholipase A2 receptor (PLA2R). Secondary MN occurs as a consequence of drugs, malignancy, or autoimmune disease. Prognosis—the clinical course of primary MN is variable: spontaneous complete remission of proteinuria occurs in 20 to 30% and progressive kidney failure develops in 20 to 40% over 5 to 15 years. Patients with gross proteinuria (>8 g/day) are at high risk of progression, as are those with a high and rising anti-PLA2R antibody level. Management—patients at low risk of progression have an excellent long-term prognosis and should be treated conservatively without immunosuppression. Patients at medium and high risk for progression benefit from immunosuppression in addition to conservative treatment. Corticosteroid monotherapy is ineffective in primary MN and should not be used. Standard treatment regimens include corticosteroids with alkylating agents (chlorambucil, cyclophosphamide), corticosteroids with mycophenolate mofetil, and calcineurin inhibitors (ciclosporin, tacrolimus). Early experience with rituximab has given some promising results.

scholarly journals Development and Optimization of Chromosomally-Integrated Fluorescent Mycobacterium tuberculosis Reporter Constructs

2020 ◽  
Vol 11 ◽  
Author(s):  
Katharina Kolbe ◽  
Alice C. Bell ◽  
Gareth A. Prosser ◽  
Maike Assmann ◽  
Hee-Jeong Yang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Recombinant Dna ◽  
Optimization Techniques ◽  
Fluorescent Reporter ◽  
Stimulus Response ◽  
Response Characteristics ◽  
Treatment Regimens ◽  
Reporter Strains ◽  
Drug Efficiency

Mycobacterium tuberculosis resides in the lungs in various lesion types with unique microenvironmental conditions. This diversity is in line with heterogeneous disease progression and divergent drug efficiency. Fluorescent reporter strains can be used to decipher the micromilieu and to guide future treatment regimens. Current reporters using replicating plasmids, however, are not suitable for long-term mouse infections or studies in non-human primates. Using a combination of recombinant DNA and protein optimization techniques, we have developed reporter strains based on integrative plasmids, which exhibit stimulus-response characteristics and fluorescence intensities comparable to those based on replicating plasmids. We successfully applied the concepts by constructing a multi-color reporter strain able to detect simultaneous changes in environmental pH, Mg2+ concentrations, and protein expression levels.

m-[o-(2-Chloro-5-Fluorosulfonylphenylureido)Phenoxybutoxy]Benzamidine: Affinity Labeling Reagent Which Can Identify Secondary Binding Sites of Coagulation Complement and Fibrinolytic Serine Proteases

1979 ◽  
Author(s):  
D Bing ◽  
D Robison ◽  
J Andrews ◽  
R Laura
Keyword(s):  
Binding Sites ◽  
Serine Proteases ◽  
Enzyme Inhibitor ◽  
Molecular Model ◽  
Factor Xa ◽  
Affinity Labeling ◽  
Catalytic Center ◽  
Inhibitor Complex ◽  
Polypeptide Chains ◽  
Kinetics Of

We have determined that m-[o-(2-chloro-5-fluorosulfonylphenylureido)phenoxybutoxy]benza-midine [mCP(PBA)-F] is an affinity labeling reagent which labels both polypeptide chains of thrombin, factor Xa, complement component CIS and plasmin. As this means it is reacting outside of the catalytic center, we have called this reagent an exo-site affinity labeling reagent. Progressive irreversible inhibition of these enzymes by this reagent is rapid (k1st 2.5-4.6 x 10-3sec-1), the kinetics of inactivation are consistent with inhibition proceding via formation of a specific enzyme-inhibitor complex analogous to a Michaelis-Menton complex (KL - 115-26 μM), and diisopropylfluorophosphate or p-amidino-phenylmethanesulfonyfluoride Prevent labeling by [3H]mCP(PBA)-F. A molecular model of mCP(PBA)-F shows that the reactive SO2F group can be 17 A from the cationic amidine. The data are consistent with the hypothesis that both peptide chains are required for the specific proteolytic activity exhibited by these proteases and that the peptide chain which does not contain the active site serine is close to the catalytic center. (Supported by NIH and AHA grants

Considering a Potential Role of Linalool as a Mood Stabilizer for Bipolar Disorder

2020 ◽  
Vol 26 (40) ◽  
pp. 5128-5133
Author(s):  
Kate Levenberg ◽  
Wade Edris ◽  
Martha Levine ◽  
Daniel R. George
Keyword(s):  
Bipolar Disorder ◽  
Treatment Options ◽  
Mood Stabilizer ◽  
Well Being ◽  
Epidemiologic Studies ◽  
Treatment Regimens ◽  
Bipolar Spectrum Disorders ◽  
Short And Long Term

Epidemiologic studies suggest that the lifetime prevalence of bipolar spectrum disorders ranges from 2.8 to 6.5 percent of the population. To decrease morbidity and mortality associated with disease progression, pharmacologic intervention is indicated for the majority of these patients. While a number of effective treatment regimens exist, many conventional medications have significant side effect profiles that adversely impact patients’ short and long-term well-being. It is thus important to continue advancing and improving therapeutic options available to patients. This paper reviews the limitations of current treatments and examines the chemical compound Linalool, an alcohol found in many plant species, that may serve as an effective mood stabilizer. While relatively little is known about Linalool and bipolar disorder, the compound has been shown to have antiepileptic, anti-inflammatory, anxiolytic, anti-depressive, and neurotrophic effects, with mechanisms that are comparable to current bipolar disorder treatment options.

scholarly journals Vasculitis: From Target Molecules to Novel Therapeutic Approaches

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 757
Author(s):  
Sang-Wan Chung
Keyword(s):  
Systemic Vasculitis ◽  
Alkylating Agents ◽  
Large Vessel Vasculitis ◽  
Large Vessel ◽  
Biologic Therapies ◽  
Therapeutic Approaches ◽  
Novel Treatments ◽  
Treatment Regimens ◽  
Immune Mediated ◽  
Target Molecules

Systemic vasculitis is a group of diverse diseases characterized by immune-mediated inflammation of blood vessels. Current treatments for vasculitis, such as glucocorticoids and alkylating agents, are associated with significant side effects. In addition, the management of both small and large vessel vasculitis is challenging due to a lack of robust markers of disease activity. Recent research has advanced our understanding of the pathogenesis of both small and large vessel vasculitis, and this has led to the development of novel biologic therapies capable of targeting key cytokine and cellular effectors of the inflammatory cascade. It is anticipated that these novel treatments will lead to more effective and less toxic treatment regimens for patients with systemic vasculitis.

Substrate-binding sites in acetylcholinesterase

1991 ◽  
Vol 12 ◽  
pp. 422-426 ◽  
Author(s):  
Ferdinand Hucko ◽  
Jaak Järv ◽  
Christoph Weise
Keyword(s):  
Binding Sites ◽  
Substrate Binding ◽  
Substrate Binding Sites
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