A5051766961- Sirtuins and Resveratrol in Medicine
- Autophagy in Disease and Therapy
- Calcium signaling and nucleotide metabolism
- PARP inhibition in cancer therapy
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Toxin Mechanisms and Immunotoxins
- Phosphodiesterase function and regulation
- Mitochondrial Function and Pathology
- Adenosine and Purinergic Signaling
- Receptor Mechanisms and Signaling
- Cancer, Hypoxia, and Metabolism
- Biochemical effects in animals
- Eicosanoids and Hypertension Pharmacology
- Thyroid Disorders and Treatments
- Adipose Tissue and Metabolism
- Peptidase Inhibition and Analysis
- Enzyme function and inhibition
- Protein Structure and Dynamics
- Bacterial Genetics and Biotechnology
- Folate and B Vitamins Research
- Redox biology and oxidative stress
- Signaling Pathways in Disease
- Protein Kinase Regulation and GTPase Signaling
- Enzyme Catalysis and Immobilization
University of Bayreuth
2015-2024
Software (Spain)
2023
Cornell University
2003-2021
Micron (United States)
2021
Micron Biomedical (United States)
2021
Harm Reduction Services
2021
Robert Bosch (Germany)
2021
University of Bonn
2015
Weatherford College
2014
Ruhr University Bochum
2006-2012
Significance Sirtuin enzymes regulate metabolism and stress responses through deacetylation of specific protein lysine residues. Sirtuins are considered attractive drug targets, but selective inhibitors rare, their mechanisms mostly unknown. We report the mechanism inhibition by Ex-527, a potent Sirt1 inhibitor widely used in physiological studies. A set Sirtuin/ligand crystal structures, together with activity binding data, reveals that compound inhibits forming trimeric complex NAD +...
In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, first enzyme of urea cycle. However, while SIRT5 is ubiquitously expressed, cycle and CPS1 are only present in and, to a minor extent, kidney. To address possibility that involved production also nonliver cells, clones human breast cancer cell lines MDA-MB-231 mouse myoblast C2C12, overexpressing or silenced for were produced. Our results show increased SIRT5-silenced decreased SIRT5-overexpressing...
Abstract Sirtuins are a highly conserved class of NAD + -dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis cancer, inflammation and neurodegeneration, which makes modulation activity promising strategy for pharmaceutical intervention. A rational basis development optimized inhibitors is lacking so far. Here we present high-resolution structures complex with selective drug-like that show unique inhibitory mechanism. Potency unprecedented selectivity...
Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by polyphenol resveratrol can mimic such effects alleviate metabolic diseases. The mechanism stimulation is unknown, hindering development improved activators. Here we show that inhibits human Sirt3 stimulates Sirt5, in addition Sirt1, against fluorophore-labeled peptide substrates but also...
Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. 2 was previously shown modulate proteotoxicity age-associated neurodegenerative disorders such as Alzheimer Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into interplay between sirtuin α-synuclein, major component of pathognomonic protein inclusions in PD other synucleinopathies. We found that α-synuclein is...
Abstract Nearly half of all pregnancies are unintended; thus, existing family planning options inadequate. For men, the only choices condoms and vasectomy, most current efforts to develop new contraceptives for men impact sperm development, meaning that contraception requires months continuous pretreatment. Here, we provide proof-of-concept an innovative strategy on-demand contraception, where a man would take birth control pill shortly before sex, as needed. Soluble adenylyl cyclase (sAC)...
NAD + can influence DNA repair by modulating protein interactions.
ABSTRACT Cryptococcus neoformans , a fungal pathogen of humans, causes fatal meningitis in immunocompromised patients. Its virulence is mainly determined by the elaboration polysaccharide capsule surrounding its cell wall. During life, C. confronted with and responds to dramatic variations CO 2 concentrations; one important morphological change triggered shift from natural habitat (0.033% ) infected hosts (5% induction biosynthesis. In cells, hydrated bicarbonate spontaneous reaction that...
Sirtuins are protein deacylases regulating metabolism and stress responses, implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 sought as chemical tools potential therapeutics, such cancer. Activators available Sirt1 exploit its unique N-terminus, whereas drug-like Sirt2-7 lacking. We synthesized screened pyrrolo[1,2-a]quinoxaline derivatives, yielding first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound...
Significance Soluble adenylyl cyclase (sAC) generates the ubiquitous signaling molecule cAMP in response to bicarbonate. In physiological systems, bicarbonate is nearly instantaneous equilibrium with carbon dioxide and pH; therefore, sAC, its evolutionarily related cyclases, serve as nature’s dioxide/bicarbonate/pH sensors. particular, regulation of mammalian sAC mediates numerous cellular processes, from sperm activation pH homeostasis mitochondrial ATP synthesis. We solved crystal...
Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In present study, we characterize SIRT2 inhibition activity of brain-permeable compound AK7 examine efficacy this small molecule in models Parkinson's disease, amyotrophic lateral sclerosis cerebral ischemia. results demonstrate that is neuroprotective disease; it...
Significance Chronic neuroinflammation and oxidative stress are likely complicit in driving disease progression Huntington's (HD). Here, we describe the mechanism of action a unique chemical scaffold that is highly selective for activation NRF2, master transcriptional regulator cellular antiinflammatory antioxidant defense genes. The use this revealed NRF2 responses were muted HD patient-derived neural stem cells, suggesting increased susceptibility critical renewable cell population to...
Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested influence substrate sequence by analyzing effects on Sirt1-dependent 6802 acetylation sites using peptide microarrays. Resveratrol stimulated a small set and inhibited another set, whereas most substrates were hardly affected. Solution assays confirmed these...
Sirt2 is a target for the treatment of neurological, metabolic, and age-related diseases including cancer. Here we report series inhibitors based on 1,2,4-oxadiazole scaffold. These compounds are potent active at single-digit μM level by using substrate α-tubulin-acetylLys40 peptide inactive up to 100 against Sirt1, -3, -5 (deacetylase desuccinylase activities). Their mechanism inhibition uncompetitive toward both NAD+, crystal structure analog in complex with ADP-ribose reveals its...
Sirtuins are evolutionary conserved NAD+-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria regulates fatty acid apoptosis. In contrast the mitochondrial deacetylase Sirt3 desuccinylase Sirt5, no prominent deacylase activity structural information available Sirt4. Here we describe acyl substrates crystal structures enzyme shows...