-
Journal of Peptide Science : An... Jan 2016Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale... (Review)
Review
Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications.
Topics: Amino Acids; Aspartic Acid; Cell Line; Epithelial Cells; Fluorenes; Glycosylation; Humans; Methylation; Peptides; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; Solid-Phase Synthesis Techniques
PubMed: 26785684
DOI: 10.1002/psc.2836 -
Circulation Research Jan 2020Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation...
RATIONALE
Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics.
OBJECTIVE
The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.
METHODS AND RESULTS
We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy.
CONCLUSIONS
Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.
Topics: Acetyl-CoA Carboxylase; Animals; Aspartic Acid; Cardiomegaly; Cells, Cultured; Fatty Acids; Glucose; Male; Mice; Myocytes, Cardiac; Rats; Rats, Wistar
PubMed: 31709908
DOI: 10.1161/CIRCRESAHA.119.315483 -
Circulation Research Jan 2020
Topics: Aspartic Acid; Cardiomegaly; Glucose; Humans; Myocardium
PubMed: 31944916
DOI: 10.1161/CIRCRESAHA.119.316358 -
Nature Reviews. Endocrinology Feb 2019Cancer cells consume and utilize glucose at a higher rate than normal cells. However, some microenvironments limit the availability of nutrients and glucose. In 2018,... (Comparative Study)
Comparative Study Review
Cancer cells consume and utilize glucose at a higher rate than normal cells. However, some microenvironments limit the availability of nutrients and glucose. In 2018, researchers found that tumours depend on a variety of different nutrient sources, both locally and systemically, to overcome metabolic limitations and promote tumour progression and metastasis.
Topics: Asparagine; Aspartic Acid; Disease Progression; Female; Humans; Lactic Acid; Male; Neoplasms; Oxygen Consumption; Proteins; Reference Values; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 30560891
DOI: 10.1038/s41574-018-0146-6 -
Cell Jul 2015The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well...
The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.
Topics: Aspartate Aminotransferase, Cytoplasmic; Aspartic Acid; Cell Proliferation; DNA, Mitochondrial; Electron Transport; Humans; Jurkat Cells; Mitochondria; Mutation; Phenformin; Pyruvic Acid
PubMed: 26232224
DOI: 10.1016/j.cell.2015.07.016 -
Nutrients Dec 2018A diet rich in B-group vitamins is essential for optimal body and brain function, and insufficient amounts of such vitamins have been associated with higher levels of... (Randomized Controlled Trial)
Randomized Controlled Trial
The Effect of a High-Dose Vitamin B Multivitamin Supplement on the Relationship between Brain Metabolism and Blood Biomarkers of Oxidative Stress: A Randomized Control Trial.
A diet rich in B-group vitamins is essential for optimal body and brain function, and insufficient amounts of such vitamins have been associated with higher levels of neural inflammation and oxidative stress, as marked by increased blood plasma homocysteine. Neural biomarkers of oxidative stress quantified through proton magnetic spectroscopy (1H-MRS) are not well understood, and the relationship between such neural and blood biomarkers is seldom studied. The current study addresses this gap by investigating the direct effect of 6-month high-dose B-group vitamin supplementation on neural and blood biomarkers of metabolism. Using a randomized, double-blind, placebo-controlled design, 32 healthy adults (20 female, 12 male) aged 30⁻65 years underwent blood tests (vitamin B6, vitamin B12, folate, and homocysteine levels) and 1H-MRS of the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) before and after supplementation. Results confirmed the supplement was effective in increasing vitamin B6 and vitamin B12 levels and reducing homocysteine, whereas there was no change in folate levels. There were significant relationships between vitamin B6 and -acetylaspartate (NAA), choline, and creatine, as well as between vitamin B12 and creatine (s < 0.05), whereas NAA in the PCC increased, albeit not significantly ( > 0.05). Together these data provide preliminary evidence for the efficacy of high-dose B-group supplementation in reducing oxidative stress and inflammation through increasing oxidative metabolism. It may also promote myelination, cellular metabolism, and energy storage.
Topics: Adult; Aged; Antioxidants; Aspartic Acid; Biomarkers; Brain; Cognition; Cognition Disorders; Creatine; Dietary Supplements; Double-Blind Method; Female; Homocysteine; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Vitamin B Complex
PubMed: 30513795
DOI: 10.3390/nu10121860 -
Molecular Systems Biology Jul 2023While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be...
While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.
Topics: Aspartic Acid; DNA Damage; Oxidative Stress; Peroxiredoxins; Reactive Oxygen Species; Humans
PubMed: 37259925
DOI: 10.15252/msb.202211267 -
Molecules (Basel, Switzerland) Apr 2023Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 () are presented. NPe6, also designated as Laserphyrin, Talaporfin,... (Review)
Review
Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 () are presented. NPe6, also designated as Laserphyrin, Talaporfin, and LS-11, is a second-generation photosensitizer derived from chlorophyll-a, currently used in Japan for the treatment of human lung, esophageal, and brain cancers. After the initial misidentification of the structure of this chlorin-e aspartic acid conjugate as (), NMR and other synthetic procedures described herein arrived at the correct structure (), confirmed using single crystal X-ray crystallography. Interesting new features of chlorin-e chemistry (including the intramolecular formation of an anhydride ()) are reported, allowing chemists to regioselectively conjugate amino acids to each available carboxylic acid on positions 13 (formic), 15 (acetic), and 17 (propionic) of chlorin e (). Cellular investigations of several amino acid conjugates of chlorin-e revealed that the 13-aspartylchlorin-e derivative is more phototoxic than its 15- and 17-regioisomers, in part due to its nearly linear molecular conformation.
Topics: Humans; Photosensitizing Agents; Photochemotherapy; Porphyrins; Amino Acids; Aspartic Acid; Chlorophyllides
PubMed: 37110713
DOI: 10.3390/molecules28083479 -
Aging Nov 2022
Topics: Isoaspartic Acid; Amino Acid Sequence; Aspartic Acid
PubMed: 36446387
DOI: 10.18632/aging.204420 -
The Neuroscientist : a Review Journal... Aug 2019The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person's total energy intake. Cellular bioenergetics in the central nervous... (Review)
Review
The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person's total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, -acetylaspartate, and biotin, in regulating oligodendrocyte function.
Topics: Animals; Aspartic Acid; Axons; Brain; Energy Metabolism; Glucose; Humans; Lactic Acid; Mitochondria; Multiple Sclerosis; Myelin Sheath; Oligodendroglia
PubMed: 30122106
DOI: 10.1177/1073858418793077