A5063910997- Sphingolipid Metabolism and Signaling
- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
- Lipid Membrane Structure and Behavior
- Lipid metabolism and biosynthesis
- Amyotrophic Lateral Sclerosis Research
- Ion channel regulation and function
- Lysosomal Storage Disorders Research
- Neurogenetic and Muscular Disorders Research
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Hemoglobinopathies and Related Disorders
- Fungal and yeast genetics research
- Erythrocyte Function and Pathophysiology
- Autophagy in Disease and Therapy
- Biochemical and Structural Characterization
- Trace Elements in Health
- Hereditary Neurological Disorders
- Adipose Tissue and Metabolism
- Amino Acid Enzymes and Metabolism
- Antimicrobial Peptides and Activities
- Neuroscience and Neuropharmacology Research
- Magnesium in Health and Disease
- Plant Micronutrient Interactions and Effects
- Glycogen Storage Diseases and Myoclonus
Uniformed Services University of the Health Sciences
2014-2024
University of Health Science
2024
University of Health Sciences
2024
Georgia Institute of Technology
2009
Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis. In yeast, SPT is composed of a heterodimer 2 highly-related subunits, Lcb1p and Lcb2p, third subunit, Tsc3p, which increases enzyme activity markedly required for growth at elevated temperatures. Higher eukaryotic orthologs Lcb2p have been identified, but not highly correlated with coexpression these subunits no ortholog Tsc3p has identified. Here, we report discovery proteins, ssSPTa ssSPTb,...
The role of vacuolar Ca2+ transport systems in regulating cellular was investigated by measuring the rate, free energy available to drive transport, ability vacuole buffer lumenal Ca2+, and efflux rate. magnitude gradient generated H+ best supports a 1 Ca2+:2 coupling ratio for Ca2+/H+ exchanger. This along with cytosolic concentration 125 nM would give approximately 30 microM. total is 2 mM due binding polyphosphate. rate from less than growth indicating that steady-state loading level...
Iron is an essential cofactor for enzymes involved in numerous cellular processes, yet little known about the impact of iron deficiency on metabolism or proteins. Previous studies have focused changes transcript and proteins levels iron-deficient cells, these may not reflect transport activity flux through a metabolic pathway. We analyzed metabolomes transcriptomes yeast grown iron-rich iron-poor media to determine which biosynthetic processes are altered when availability falls. led glucose...
Abstract Sphingolipid synthesis is initiated by condensation of Ser with palmitoyl-CoA producing 3-ketodihydrosphinganine (3-KDS), which reduced a 3-KDS reductase to dihydrosphinganine. palmitoyltransferase essential for plant viability. Arabidopsis thaliana contains two genes (At3g06060/TSC10A and At5g19200/TSC10B) encoding proteins significant similarity the yeast reductase, Tsc10p. Heterologous expression in either gene restored activity tsc10Δ mutant, confirming both as bona fide genes....
Sphingolipids compose a lipid family critical for membrane structure as well intra- and intercellular signaling. De novo sphingolipid biosynthesis is initiated by the enzyme serine palmitoyltransferase (SPT), which resides in endoplasmic reticulum (ER) membrane. In both yeast mammalian species, SPT activity homeostatically regulated through small ER proteins, Orms ORMDLs cells. These proteins form stable complexes with SPT. yeast, homeostatic regulation of relies, at least part, on...
ADVERTISEMENT RETURN TO ISSUEPREVArticleRaman spectroscopy of synthetic antimicrobial frog peptides magainin 2a and PGLaRobert W. Williams, Ruth Starman, Kenneth M. P. Taylor, Gable, Troy Beeler, Michael Zasloff, David CovellCite this: Biochemistry 1990, 29, 18, 4490–4496Publication Date (Print):May 8, 1990Publication History Published online1 May 2002Published inissue 8 1990https://pubs.acs.org/doi/10.1021/bi00470a031https://doi.org/10.1021/bi00470a031research-articleACS PublicationsRequest...
Several 3-keto-synthases have been studied, including the soluble fatty acid synthases, those involved in polyketide synthesis, and FAE1-like 3-ketoacyl-CoA synthases. All of these condensing enzymes a common ancestor an enzymatic mechanism that involves catalytic triad consisting Cys, His, His/Asn. In contrast to family mediate plant microsomal elongation, condensation step elongation animals fungi appears be mediated by Elop homologs. Curiously proteins bear no resemblance well...
Significance Sphingolipids are essential in eukaryotes and particularly important neural tissues. Generally, sphingolipids have an 18-carbon (C18) long chain base (LCB) backbone. However, low-abundance containing LCBs of 16 or 20 carbons also been discovered. Yet their specific functions biological significance is not known. This work demonstrates that elevation 20-carbon and/or C20 has detrimental neurodegenerative effects the brain retina, leading to perturbation protein homeostasis....
Abstract Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they abundant myelin membranes. Serine palmitoyltransferase, enzyme that catalyses rate-limiting reaction sphingolipid synthesis, is composed multiple subunits including an activating subunit, SPTSSA. both essential cytotoxic their synthesis must therefore be tightly regulated. Key to homeostatic regulation ORMDL proteins bound serine...
The homeostatic regulation of serine palmitoyltransferase (SPT) activity in yeast involves N-terminal phosphorylation Orm proteins, while higher eukaryotes lack these sites. Although recent studies have indicated a conserved ceramide-mediated feedback inhibition the SPT-ORM/ORMDL complex eukaryotes, its conservation and relationship with remain unclear. Here, we determine structure SPT-Orm2 dephosphomimetic state identify an evolutionarily ceramide-sensing site. Ceramide stabilizes Orm2...
Significance It is well known that because of constant metabolic flow and interconnectivity, alteration any one step in lipid metabolism can lead to changes many metabolites. Therefore, the exact metabolites causing diseases are often elusive. By creating a new genetic model, we uncoupled long-chain bases ceramide caused by synthase 1 deficiency. This work sheds light on neurotoxicity sphingolipid precursors, bases, neurodegenerative diseases.
The serine palmitoyltransferase (SPT) complex catalyzes the first and rate-limiting step in sphingolipid biosynthesis all eukaryotes. ORM/ORMDL proteins are negative regulators of SPT that respond to cellular levels. However, molecular basis underlying ORM/ORMDL-dependent homeostatic regulation is not well understood. We determined cryo-electron microscopy structure Arabidopsis SPT-ORM1 complex, composed LCB1, LCB2a, SPTssa, ORM1, an inhibited state. A ceramide molecule sandwiched between...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanism of magainin 2a induced permeabilization phospholipid vesiclesEarl Grant, Jr., Troy J. Beeler, Kenneth M. P. Taylor, Gable, and Mark A. RosemanCite this: Biochemistry 1992, 31, 41, 9912–9918Publication Date (Print):October 1, 1992Publication History Published online1 May 2002Published inissue 1 October 1992https://pubs.acs.org/doi/10.1021/bi00156a008https://doi.org/10.1021/bi00156a008research-articleACS PublicationsRequest reuse...
TSC13 is required for the biosynthesis of very-long-chain fatty acids (VLCFAs) in yeast. Tsc13p a polytopic endoplasmic reticulum (ER) membrane protein that accumulates at nucleus-vacuole (NV) junctions, which are formed through Velcro-like interactions between Nvj1p perinuclear ER and Vac8p on vacuole membrane. NV junctions mediate piecemeal microautophagy nucleus (PMN), during bleb-like portions extruded into invaginations degraded lumen. We report sequestered from peripheral...
The relationship between serine palmitoyltransferase (SPT) activity and ORMDL regulation of sphingolipid biosynthesis was investigated in mammalian HEK293 cells. Each the three human ORMDLs reduced increase long-chain base synthesis seen after overexpression wild-type SPT or containing C133W mutation hLCB1, which produces non-catabolizable sphingoid base, 1-deoxySa. ORMDL-dependent repression occurred whether expressed as individual subunits a heterotrimeric single-chain fusion protein....
Very long chain fatty acids (VLCFAs) are essential with multiple functions, including ceramide synthesis. Although the components of VLCFA biosynthetic machinery have been elucidated, how their activity is regulated to meet cell's metabolic demand remains unknown. The goal this study was identify mechanisms that regulate rate synthesis, and we discovered acid elongase Elo2 by phosphorylation. phosphorylation induced upon inhibition TORC1 requires GSK3. Expression nonphosphorylatable...
Serine palmitoyltransferase (SPT), an endoplasmic reticulum-localized membrane enzymecomposed of acatalytic LCB1/LCB2 heterodimer and a small activating subunit (Tsc3 in yeast; ssSPTs mammals), is negatively regulated by the evolutionarily conserved family proteins known as ORMs. In yeast, SPT, ORMs, PI4P phosphatase Sac1, copurify "SPOTs" complex. However, neither mechanism ORM inhibition SPT nor details interactions ORMs Sac1 with are known. Here we report that first transmembrane domain...
The genus Coccolithovirus is a recently discovered group of viruses that infect the globally important marine calcifying microalga Emiliania huxleyi. Surprisingly, viral genome contains cluster putative sphingolipid biosynthetic genes not found in other genus. To address role these pathogenesis, ehv050 gene predicted to encode serine palmitoyltransferase (SPT), first and rate-limiting enzyme biosynthesis, was expressed characterized Saccharomyces cerevisiae. We show encoded protein indeed...
Abstract Fundamental changes in the composition and distribution of lipids within brain are believed to contribute cognitive decline associated with Alzheimer’s disease (AD). The mechanisms by which these lipid affect cellular function ultimately cognition not well understood. Although “candidate gene” approaches can provide insight into effects dysregulated metabolism they require a preexisting understanding molecular targets individual species. In this report we combine unbiased gene...