A5076448680- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Mitochondrial Function and Pathology
- Autophagy in Disease and Therapy
- RNA and protein synthesis mechanisms
- Lipid Membrane Structure and Behavior
- Genomics and Rare Diseases
- Porphyrin Metabolism and Disorders
- Lipid metabolism and biosynthesis
- Fungal and yeast genetics research
- Metabolism and Genetic Disorders
- Folate and B Vitamins Research
- Protein Kinase Regulation and GTPase Signaling
- Neonatal Health and Biochemistry
- Hereditary Neurological Disorders
- Genetic Neurodegenerative Diseases
- Photosynthetic Processes and Mechanisms
- Adipose Tissue and Metabolism
- Advanced Proteomics Techniques and Applications
- Microbial Natural Products and Biosynthesis
- Protein Structure and Dynamics
- Neurogenetic and Muscular Disorders Research
- Lysosomal Storage Disorders Research
- Genomics and Phylogenetic Studies
- Antibiotic Resistance in Bacteria
Dalhousie University
2006-2024
Mutations in genes involved lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group neurodegenerative motor neuron disorders characterized by paraparesis. Here, we report an unusual autosomal recessive condition, best classified as complicated form mutation the ethanolaminephosphotransferase 1 (EPT1) gene (now known SELENOI), responsible for final step Kennedy pathway forming phosphatidylethanolamine from...
Sideroblastic anemias are acquired or inherited that result in a decreased ability to synthesize hemoglobin red blood cells and the presence of iron deposits mitochondria cell precursors. A common subtype congenital sideroblastic anemia is due autosomal recessive mutations SLC25A38 gene. The current treatment for chronic transfusion coupled with chelation. function not known. Here we report protein, its yeast homolog Hem25, mitochondrial glycine transporters required initiation heme...
In eukaryotes, neuropathy target esterase (Nte1p in yeast) deacylates phosphatidylcholine derived exclusively from the CDP-choline pathway to produce glycerophosphocholine (GroPCho) and release two fatty acids. The metabolic fate of GroPCho eukaryotic cells is currently not known. Saccharomyces cerevisiae contains open reading frames predicted contain glycerophosphodiester phosphodiesterase domains, YPL110c YPL206c. Pulse-chase experiments were conducted monitor under conditions known alter...
Abstract CHKB encodes one of two mammalian choline kinase enzymes that catalyze the first step in synthesis membrane phospholipid phosphatidylcholine. In humans and mice, inactivation gene ( Chkb mice) causes a recessive rostral-to-caudal muscular dystrophy. Using knockout we reveal at no stage disease is phosphatidylcholine level significantly altered. We observe affected muscle temporal change lipid metabolism occurs with an initial inability to utilize fatty acids for energy via...
The Saccharomyces cerevisiae NTE1 gene encodes an evolutionarily conserved phospholipase B localized to the endoplasmic reticulum (ER) that degrades phosphatidylcholine (PC) generating glycerophosphocholine and free fatty acids. We show here activity of NTE1-encoded (Nte1p) prevents attenuation transcription genes encoding enzymes involved in phospholipid synthesis response increased rates PC by affecting nuclear localization transcriptional repressor Opi1p. Nte1p becomes necessary for cells...
Phosphatidylcholine is the major phospholipid in eukaryotic cells. There are two main pathways for synthesis of phosphatidylcholine: CDP-choline pathway present all eukaryotes and phosphatidylethanolamine methylation mammalian hepatocytes some single celled eukaryotes, including yeast Saccharomyces cerevisiae. In S. cerevisiae, rate-determining step phosphatidylcholine via catalyzed by Pct1. Pct1 converts phosphocholine CTP to pyrophosphate. this study, we determined that nucleoplasm at...
Choline is a precursor for the synthesis of phosphatidylcholine through CDP-choline pathway. Saccharomyces cerevisiae expresses single high affinity choline transporter at plasma membrane, encoded by HNM1 gene. We show that exposing cells to increasing levels results in two different regulatory mechanisms impacting Hnm1 activity. Initial exposure rapid decrease Hnm1-mediated transport level activity, whereas chronic degradation an endocytic mechanism depends on ubiquitin ligase Rsp5 and...
The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, most abundant components eukaryotic cell membranes. In recent years, these have moved into clinical focus because four ten genes involved been associated with a range autosomal recessive rare diseases such as neurodevelopmental disorder muscular dystrophy (CHKB), bone abnormalities cone-rod (PCYT1A) spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families...
A proteomics approach was used to search for novel phospholipid binding proteins in Saccharomyces cerevisiae . Phospholipids were immobilized on a solid support and the lipids probed with soluble yeast protein extracts. From this, phosphatidic acid eluted identified by mass spectrometry. Thirteen 11 of these previously unknown lipid proteins. The protein–lipid interactions would not have been predicted using bioinformatics approaches as none possessed known motif. subset purified homogeneity...
Abstract The SLC25 family member SLC25A38 (Hem25 in yeast) was recently identified as a mitochondrial glycine transporter that provides substrate to initiate heme/hemoglobin synthesis. Mutations the human gene cause congenital sideroblastic anemia. full extent which members coregulate heme synthesis with other functions is not clear. In this study, we surveyed 29 nonessential Saccharomyces cerevisiae for their ability support growth presence and absence of HEM25. Six were required or cells...
In Saccharomyces cerevisiae, the transcriptional repressor Opi1 regulates expression of genes involved in phospholipid synthesis responding to abundance precursor phosphatidic acid at endoplasmic reticulum. We report here identification conserved leucine zipper (LZ) domain as a hot spot for gain function mutations and characterization strongest variant identified,
Cells regulate the biophysical properties of membranes through coordinated synthesis many lipid classes. In Saccharomyces cerevisiae, transcriptional repressor Opi1 regulates expression genes involved in phospholipid (PL) by responding to abundance PL precursor phosphatidic acid (PA) at endoplasmic reticulum (ER). recruitment PA-enriched allows gene toward synthesis, while a decrease PA level signals need reduce rate resulting release from and its translocation into nucleus where is...
Abstract The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, most abundant components eukaryotic cell membranes. In recent years, these have moved into clinical focus since four out ten genes involved been associated with a range autosomal recessive rare diseases such as neurodevelopmental disorder muscular dystrophy ( CHKB ), bone abnormalities cone-rod PCYT1A spastic paraplegia PCYT2, SELENOI ). We identified six individuals from five...