A5070368745- Amino Acid Enzymes and Metabolism
- Parkinson's Disease Mechanisms and Treatments
- Microbial metabolism and enzyme function
- Biotin and Related Studies
- Enzyme Catalysis and Immobilization
- Epigenetics and DNA Methylation
- Neurotransmitter Receptor Influence on Behavior
- Polyamine Metabolism and Applications
- Alcoholism and Thiamine Deficiency
- Biochemical and Molecular Research
- Electrochemical sensors and biosensors
- Cancer-related gene regulation
- Receptor Mechanisms and Signaling
- Enzyme Structure and Function
- Synthesis and Biological Evaluation
- Biochemical and biochemical processes
- Metabolism and Genetic Disorders
- Metal-Catalyzed Oxygenation Mechanisms
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Tuberculosis Research and Epidemiology
- Heme Oxygenase-1 and Carbon Monoxide
- Synthesis and biological activity
- Microbial Metabolic Engineering and Bioproduction
- Porphyrin Metabolism and Disorders
University of Pavia
2015-2025
Istituto Sperimentale Italiano Lazzaro Spallanzani
2018
Emory University
2003-2010
European Institute of Oncology
2010
University of Oxford
2008
Pharmaxis (Australia)
2008
Genomics (United Kingdom)
2008
Newron Pharmaceuticals (Italy)
2007
University of Bari Aldo Moro
2007
Virginia Tech
2006
Structures of human monoamine oxidase B (MAO B) in complex with safinamide and two coumarin derivatives, all sharing a common benzyloxy substituent, were determined by X-ray crystallography. These compounds competitively inhibit MAO Ki values the 0.1-0.5 microM range that are 30-700-fold lower than those observed A. The inhibitors bind noncovalently to B, occupying both entrance substrate cavities showing similarly oriented substituent.
The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold hMAO similar to that rat MAO and B B), unique in it crystallizes a monomer exhibits solution hydrodynamic behavior monomeric form rather than dimeric A. A's active site consists single hydrophobic cavity ≈550 Å 3 , which smaller determined from deprenyl-inhibited (≈700 ) but larger (≈450 ). An important component loop conformation residues...
Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound enzyme that catalyzes the oxidative deamination of arylalkylamine neurotransmitters and has been a target for number clinically used drug inhibitors. The 1.7-Å structure reversible isatin–MAO-B complex determined; it forms basis interpretation enzyme's when bound to either or irreversible 1,4-Diphenyl-2-butene found be MAO-B inhibitor, which occupies both entrance substrate cavity space in enzyme. Comparison these two...
LSD1 and LSD2 histone demethylases are implicated in a number of physiological pathological processes, ranging from tumorigenesis to herpes virus infection. A comprehensive structural, biochemical, cellular study is presented here probe the potential these enzymes for epigenetic therapies. This approach employs tranylcypromine as chemical scaffold design novel demethylase inhibitors. drug clinically validated antidepressant known target monoamine oxidases B. These two flavoenzymes...
Lysine‐specific histone demethylase 1 (LSD1) is a very recently discovered enzyme which specifically removes methyl groups from Lys4 of 3. We have addressed the functional properties protein demonstrating that demethylation involves flavin‐catalysed oxidation methylated lysine. The nature substrate acts as electron acceptor required to complete catalytic cycle was investigated. LSD1 converts oxygen hydrogen peroxide although this reactivity not pronounced other flavin‐dependent oxidases. Our...
Methylation of Lys residues on histone proteins is a well known and extensively characterized epigenetic mark. The recent discovery lysine-specific demethylase 1 (LSD1) demonstrated that lysine methylation can be dynamically controlled. Among the demethylases so far identified, LSD1 has unique feature functioning through flavin-dependent amine oxidation reaction. Data base analysis reveals mammalian genomes contain gene (AOF1, for amine-oxidase flavin-containing domain 1) homologous to...
Human histone demethylase LSD1 is a flavin-dependent amine oxidase that catalyzes the specific removal of methyl groups from mono- and dimethylated Lys4 H3. The N-terminal tail H3 subject to various covalent modifications, fundamental question in biology how these epigenetic marks affect activity. We show does not have strong preference for or Substrate recognition confined residues neighboring Lys4, but it requires sufficiently long peptide segment consisting 20 amino acids Electrostatic...
Histone demethylase LSD1 regulates transcription by demethylating Lys(4) of histone H3. The crystal structure the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network interactions folded conformation bound peptide. core is formed Arg(2), Gln(5), Ser(10), which are engaged specific intramolecular H-bonds. Several charged side chains on surface substrate-binding pocket establish electrostatic three-dimensional predicts that methylated binds...
Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, and trans,trans-farnesol are shown to competitively human, horse, rat, mouse with K(i) values low micromolar range but without effect on either bovine or sheep A. In contrast, competitive inhibitor isatin binds all known similar affinities. Sequence alignments crystal...
Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures MAO in complex with four N-propargylaminoindan class covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been determined at a resolution better than 2.1 Å. Rasagiline, N-methyl-N-propargyl-1(R)-aminoindan adopt essentially same conformation...
The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. targets the DprE1 catalytic component of essential enzyme decaprenylphosphoryl-β-D-ribofuranose-2'-epimerase, thus blocking biosynthesis arabinans, vital components mycobacterial cell walls. Crystal structures DprE1, in its native form and complex BTZ043, reveal formation semimercaptal adduct between an active-site cysteine, as well contacts to neighboring lysine residue. Kinetic studies confirm...
A variety of chromatin remodeling complexes are thought to orchestrate transcriptional programs that lead neuronal precursors from earliest commitment terminal differentiation. Here we show mammalian neurons have a specialized enzyme arising neurospecific splice variant LSD1/KDM1, histone lysine specific demethylase 1, whose activity on Lys4 H3 has been related gene repression. We found alternative splicing LSD1 transcript generates four full-length isoforms combinatorial retention two...
Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC 3.1 μM, is bactericidal active intracellular bacteria. To investigate its mechanism action, we isolated mutants resistant sequenced their genomes. Mutations were found in rv3405c, coding for transcriptional repressor divergently expressed rv3406 gene....
5-Hydroxymethylfurfural oxidase (HMFO) is a flavin-dependent enzyme that catalyzes the oxidation of many aldehydes, primary alcohols, and thiols. The three-step conversion 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid relevant for industrial production biobased polymers. remarkable wide substrate scope HMFO contrasts with enzyme's precision in positioning perform catalysis. We have solved crystal structure at 1.6 Å resolution, which guided mutagenesis experiments probe role...
Abstract Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated process primarily because they are both sources and targets reactive oxygen species (ROS). In heart, oxidative stress contributes to pathological cardiac ageing, but mechanisms underlying ROS production still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) a relevant source heart...
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) monoamine oxidases (hMAO-A/B) for therapy neurodegenerative diseases. identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly...