A5007855619- Sirtuins and Resveratrol in Medicine
- Adipose Tissue and Metabolism
- Biochemical effects in animals
- Autophagy in Disease and Therapy
- Lysosomal Storage Disorders Research
- Trypanosoma species research and implications
- Sleep and Wakefulness Research
- Carbohydrate Chemistry and Synthesis
- Neuroscience of respiration and sleep
- Circadian rhythm and melatonin
- Mitochondrial Function and Pathology
- Histone Deacetylase Inhibitors Research
- RNA Research and Splicing
- Folate and B Vitamins Research
- Studies on Chitinases and Chitosanases
- Neurological disorders and treatments
- HIV Research and Treatment
- Biochemical and Molecular Research
- Mechanical Circulatory Support Devices
- Migraine and Headache Studies
- Advanced MRI Techniques and Applications
- Child Development and Digital Technology
- Photoreceptor and optogenetics research
- RNA regulation and disease
- PARP inhibition in cancer therapy
Codexis (United States)
2023
University of California, San Francisco
2013-2016
University of Wisconsin–Madison
2006-2014
Silent Information Regulator 2 (Sir2) enzymes (or sirtuins) are NAD + -dependent deacetylases that modulate gene silencing, aging and energy metabolism. Previous work has implicated several transcription factors as sirtuin targets. Here, we investigated whether mammalian sirtuins could directly control the activity of metabolic enzymes. We demonstrate Acetyl-CoA synthetases (AceCSs) regulated by reversible acetylation activate AceCSs deacetylation. Site-specific mouse AceCS1 on Lys-661 was...
Mutations in casein kinase Iδ that are associated with migraine patients cause changes enzymatic function, pain behavior, cortical excitability, and astrocyte signaling mice.
Emerging proteomic evidence suggests that acetylation of metabolic enzymes is a prevalent post-translational modification. In few recent reports, down-regulated activity specific in fatty acid oxidation, urea cycle, electron transport, and anti-oxidant pathways. Here, we reveal the glycolytic enzyme phosphoglycerate mutase-1 (PGAM1) negatively regulated by Sirt1, member NAD(+)-dependent protein deacetylases. Acetylated PGAM1 displays enhanced activity, although Sirt1-mediated deacetylation...
Familial Advanced Sleep Phase (FASP) is a heritable human sleep phenotype characterized by very early and wake times. We identified missense mutation in the Cryptochrome 2 ( CRY2 ) gene that co-segregates with FASP one family. The leads to replacement of an alanine residue at position 260 threonine (A260T). In mice, causes shortened circadian period reduced phase-shift early-night light pulse associated phase-advanced behavioral rhythms light-dark cycle. A260T located phosphate loop flavin...
Accumulating evidence suggests that reversible protein acetylation may be a major regulatory mechanism rivals phosphorylation. With the recent cataloging of thousands sites on hundreds proteins comes challenge identifying acetyltransferases and deacetylases regulate levels. Sirtuins are conserved family NAD(+)-dependent implicated in genome maintenance, metabolism, cell survival, lifespan. SIRT3 is dominant deacetylase mitochondria, emerging control pathways by deacetylation central...
Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from concentrated metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A a key building block for lipid synthesis, we postulated inability to catabolize NAA leads deficiency during critical period CNS development, impairing myelination and possibly other aspects development. We tested...
Acetyl coenzyme A synthetase-1 (AceCS1) catalyzes the synthesis of acetyl from acetate and is thought to play diverse roles ranging fatty acid gene regulation. By using an affinity-purified antibody generated against 18-mer peptide sequence AceCS1 a polyclonal directed recombinant protein, we examined expression in rat brain. immunoreactivity adult brain was present predominantly cell nuclei, with only light moderate cytoplasmic staining some neurons, axons, oligodendrocytes. Some...
Fabry disease is caused by a deficiency of α-galactosidase A (GLA) leading to the lysosomal accumulation globotriaosylceramide (Gb3) and other glycosphingolipids. patients experience significant damage heart, kidney, blood vessels that can be fatal. Here we apply directed evolution generate more stable GLA variants as potential next generation treatments for disease. GLAv05 GLAv09 were identified after screening than 12,000 through 8 rounds evolution. Both exhibit increased stability at both...
Reversible protein acetylation is now recognized as a major regulatory mechanism for controlling diverse cellular processes. With the recent cataloging of ~1000 sites on hundreds proteins comes challenge assigning functional roles to specific lysine acetylation, identifying acetyltransferases and deaceytlases responsible, elucidating physiological cause effect. The sirtuin family deacetylases represents class enzymes that are linked variety metabolic pathways. Sirtuins catalyze NAD‐dependent...
Identifying the substrates for SIRT3 is paramount to understanding how reversible acetylation can modulate mitochondrial metabolism. Here we utilize a SPOT peptide library containing ~250 unique 9‐mer sequences of previously identified acetylated proteins. Within nine residue peptides, central thiotrifluoro‐acetyl‐lysine was used as tight‐binding mimic acetyl‐lysine. Library screening revealed wide range in binding affinity, which validated by measuring catalytic efficiency deacetylation...
The Silent Information Regulator 2 (Sir2) enzyme family are conserved NAD-dependant deacetylases that include seven human homologues (SirT1-7). Sir2 in bacteria and yeast have been implicated the regulation of Acetyl CoA synthetase (AceCS) activity by reversible acetylation. AceCS is evolutionarily utilizes acetate, ATP, for production acetyl CoA. Mammals contain two homologues, AceCS1 AceCS2, which produce fatty acid metabolism TCA cycle, respectively. acetylation site bacterial shows...