A5006393292- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Biochemical and Molecular Research
- RNA regulation and disease
- Lysosomal Storage Disorders Research
- Neurological diseases and metabolism
- Enzyme Structure and Function
- Cellular transport and secretion
- Microbial Natural Products and Biosynthesis
- melanin and skin pigmentation
- Protein Structure and Dynamics
- Cytomegalovirus and herpesvirus research
- Glycosylation and Glycoproteins Research
- Trace Elements in Health
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Supramolecular Self-Assembly in Materials
- Botulinum Toxin and Related Neurological Disorders
- Advanced NMR Techniques and Applications
- Viral-associated cancers and disorders
- RNA Research and Splicing
- Peptidase Inhibition and Analysis
- Metal-Catalyzed Oxygenation Mechanisms
- Cancer Research and Treatments
National Institutes of Health
2012-2025
National Heart Lung and Blood Institute
2014-2025
National Institute of Diabetes and Digestive and Kidney Diseases
2010-2018
University of St Andrews
2004-2012
Scripps Institution of Oceanography
2008-2011
University of California, San Diego
2009
University of Montana
2008
Significance Identifying factors that regulate the degradation of α-synuclein, protein at center Parkinson’s disease etiology, is vital in designing therapeutic strategies. This study provides new mechanistic insights into α-synuclein clearance lysosome, a cellular site for proteolysis by using purified mouse lysosomes and lysosomal proteases. Cathepsins B L are identified to be through peptide mapping mass spectrometry. Importantly, cathepsin degrades amyloid fibrils, materials associated...
[ PSI + ] is a prion of the essential translation termination factor Sup35p. Although mammalian infections are uniformly fatal, commonly studied variants do not impair growth, leading to suggestions that may protect against stress conditions. We report here over half sick or lethal. These “killer ]s” compatible with cell growth only when also expressing minimal Sup35C, lacking N-terminal domain. The severe detriment killer results in rapid selection nonkiller loss prion. [URE3], nitrogen...
Polyketides are among the major classes of bioactive natural products used to treat microbial infections, cancer, and other diseases. Here we describe a pathway chloroethylmalonyl-CoA as polyketide synthase building block in biosynthesis salinosporamide A, marine metabolite whose chlorine atom is crucial for potent proteasome inhibition anticancer activity. S-adenosyl-L-methionine (SAM) converted 5'-chloro-5'-deoxyadenosine (5'-ClDA) reaction catalyzed by SAM-dependent chlorinase previously...
Pmel17 is a melanocyte protein necessary for eumelanin deposition 1 in mammals and found melanosomes filamentous form. The luminal part of human includes region (RPT) with 10 copies partial repeat sequence, pt.e.gttp.qv., known to be essential vivo filament formation. We show that this RPT readily forms amyloid vitro, but only under the mildly acidic conditions typical lysosome-like melanosome lumen, filaments quickly become soluble at neutral pH. Under same conditions, Pmel promote Electron...
The generation of α-synuclein (α-syn) truncations from incomplete proteolysis plays a significant role in the pathogenesis Parkinson's disease. It is well established that C-terminal exhibit accelerated aggregation and serve as potent seeds fibril propagation. In contrast, mechanistic understanding N-terminal remains ill defined. Previously, we found disease-related resulted increased fibrillar twist, accompanied by modest conformational changes more compact core, suggesting region could be...
The extracellular curli proteins of Enterobacteriaceae form fibrous structures that are involved in biofilm formation and adhesion to host cells. These fibrils considered a functional amyloid because they not consequence misfolding, but have many the properties protein amyloid. We confirm formed by CsgA CsgB, primary Escherichia coli, possess hallmarks typical Moreover we demonstrate cross-beta structure distinguishes However, solid state NMR experiments indicate is based on an in-register...
Pmel17 is a functional amyloidogenic protein whose fibrils act as scaffolds for pigment deposition in human skin and eyes. We have used the repeat domain (RPT, residues 315-444), an essential luminal polypeptide region of Pmel17, model system to study conformational changes from soluble unstructured monomers β-sheet-containing fibrils. Specifically, we report on effects solution pH (4 → 7) mimicking conditions melanosomes, acidic organelles where are formed. Local, secondary, fibril...
While astrocytes, the most abundant cells found in brain, have many diverse functions, their role lysosomal storage disorder Gaucher disease (GD) has not been explored. GD, resulting from inherited deficiency of enzyme glucocerebrosidase and subsequent accumulation glucosylceramide its acylated derivative glucosylsphingosine, both non-neuronopathic (GD1) neuronopathic forms (GD2 3). Furthermore, mutations GBA1, gene mutated are an important risk factor for Parkinson's (PD). To elucidate...
Choices choices: The fluorinase enzyme from Streptomyces cattleya (catalyzes the formation of a CF bond fluoride ions) also has capacity to utilize chloride ion although it clear preference for ion. mediates nucleophilic chlorination reaction, which is an unusual mechanism enzymatic chlorination. Supporting information this article available on WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z503582_s.pdf or author. Please note: publisher not responsible content functionality any...
The fluorinase enzyme from S. cattleya is applied as a catalyst for the efficient incorporation of [18F]-fluoride into [18F]-5'-fluoro-5'-deoxyadenosine, [18F]-5'-fluoro-5'-deoxyinosine and [18F]-5-fluoro-5-deoxyribose positron emission tomography (PET) applications.
A new shunt in the phenylalanine biosynthetic pathway to nonproteinogenic amino acid L-3-cyclohex-2'-enylalanine was exploited marine bacterium Salinispora tropica by mutagenesis allow for genetic engineering of unnatural derivatives potent proteasome inhibitor salinosporamide (2) such as antiprotealide (1).
Sporolides A and B (1) are polycyclic macrolides from the marine actinomycete Salinispora tropica with a previously undescribed molecular architecture. Sequencing of 5 183 331 bp S. CNB-440 genome has shed light into sporolide biosynthesis, which is highlighted by an enediyne polyketide synthase unexpected tyrosine degradation pathway. In this paper, we describe in vitro characterization biosynthetic gene spoT1, involved initial biochemical reaction to highly functionalized cyclohexenone unit 1.
Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy, but susceptibility to drug resistance limits their efficacy. The marine actinobacterium Salinispora tropica produces salinosporamide A (NPI-0052, marizomib), potent proteasome inhibitor and promising clinical agent the treatment of multiple myeloma. Actinobacteria also possess 20S machinery, raising question self-resistance. We identified redundant β-subunit, SalI, encoded within biosynthetic gene...
Abstract Fibrils derived from Pmel17 are functional amyloids upon which melanin is deposited. of the repeat domain (RPT) form under strict melanosomal pH (4.5–5.5) and completely dissolve at pH≥6. To determine Glu residue responsible for this reversibility, aggregation single, double, quadruple Ala Gln mutants were examined by intrinsic Trp fluorescence, circular dichroism spectroscopy, transmission electron microscopy. Charge neutralization E404, E422, E425, or E430, located in putative...