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Advances in Nutrition (Bethesda, Md.) Sep 2023Serine has been recently identified as an essential metabolite for oncogenesis, progression, and adaptive immunity. Influenced by many physiologic or tumor environmental... (Review)
Review
Serine has been recently identified as an essential metabolite for oncogenesis, progression, and adaptive immunity. Influenced by many physiologic or tumor environmental factors, the metabolic pathways of serine synthesis, uptake, and usage are heterogeneously reprogrammed and frequently amplified in tumor or tumor-associated cells. The hyperactivation of serine metabolism promotes abnormal cellular nucleotide/protein/lipid synthesis, mitochondrial function, and epigenetic modifications, which drive malignant transformation, unlimited proliferation, metastasis, immunosuppression, and drug resistance of tumor cells. Dietary restriction of serine or phosphoglycerate dehydrogenase depletion mitigates tumor growth and extends the survival of tumor patients. Correspondingly, these findings triggered a boom in the development of novel therapeutic agents targeting serine metabolism. In this study, recent discoveries in the underlying mechanism and cellular function of serine metabolic reprogramming are summarized. The vital role of serine metabolism in oncogenesis, tumor stemness, tumor immunity, and therapeutic resistance is outlined. Finally, some potential tumor therapeutic concepts, strategies, and limitations of targeting the serine metabolic pathway are described in detail. Taken together, this review underscores the importance of serine metabolic reprogramming in tumorigenesis and progression and highlights new opportunities for dietary restriction or selective pharmacologic intervention.
Topics: Humans; Serine; Carcinogenesis; Neoplasms; Proteins
PubMed: 37187454
DOI: 10.1016/j.advnut.2023.05.007 -
The Biochemical Journal Jan 2022Cellular function is based on protein-protein interactions. A large proportion of these interactions involves the binding of short linear motifs (SLiMs) by folded... (Review)
Review
Cellular function is based on protein-protein interactions. A large proportion of these interactions involves the binding of short linear motifs (SLiMs) by folded globular domains. These interactions are regulated by post-translational modifications, such as phosphorylation, that create and break motif binding sites or tune the affinity of the interactions. In addition, motif-based interactions are involved in targeting serine/threonine kinases and phosphatases to their substrate and contribute to the specificity of the enzymatic actions regulating which sites are phosphorylated. Here, we review how SLiM-based interactions assist in determining the specificity of serine/threonine kinases and phosphatases, and how phosphorylation, in turn, affects motif-based interactions. We provide examples of SLiM-based interactions that are turned on/off, or are tuned by serine/threonine phosphorylation and exemplify how this affects SLiM-based protein complex formation.
Topics: Binding Sites; Humans; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Serine; Substrate Specificity; Threonine
PubMed: 34989786
DOI: 10.1042/BCJ20200714 -
Cells Mar 2020In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two... (Review)
Review
In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily for its varied role throughout the central nervous system. The retina is one of the most complex neuronal tissues with a multitude of functions. Although recent studies have highlighted the importance of free serine and its derivatives to retinal homeostasis, currently few reviews exist that comprehensively analyze the topic. Here, we address this gap by emphasizing how and why the de novo production and demand for serine is exceptionally elevated in the retina. Many basic physiological functions of the retina require serine. Serine-derived sphingolipids and phosphatidylserine for phagocytosis by the retinal pigment epithelium (RPE) and neuronal crosstalk of the inner retina via D-serine require proper serine metabolism. Moreover, serine is involved in sphingolipid-ceramide balance for both the outer retina and the RPE and the reductive currency generation for the RPE via serine biosynthesis. Finally and perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and GSH. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies. Therefore, most critically, this review provides a strong argument for the exploration of serine-based clinical interventions for retinal pathologies.
Topics: Humans; Retinal Degeneration; Serine
PubMed: 32164325
DOI: 10.3390/cells9030674 -
Nature Communications May 2022Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling,...
Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.
Topics: Carbon; Cell Movement; Purine Nucleotides; Purines; Serine
PubMed: 35577785
DOI: 10.1038/s41467-022-30362-z -
ELife Aug 2017The modification of serines by molecules of ADP-ribose plays an important role in signaling that the DNA in a cell has been damaged and needs to be repaired.
The modification of serines by molecules of ADP-ribose plays an important role in signaling that the DNA in a cell has been damaged and needs to be repaired.
Topics: ADP-Ribosylation; Adenosine Diphosphate Ribose; Hydrolases; Serine; Signal Transduction
PubMed: 28796599
DOI: 10.7554/eLife.29942 -
The Biochemical Journal May 2003The amino acid L-serine, one of the so-called non-essential amino acids, plays a central role in cellular proliferation. L-Serine is the predominant source of one-carbon... (Review)
Review
The amino acid L-serine, one of the so-called non-essential amino acids, plays a central role in cellular proliferation. L-Serine is the predominant source of one-carbon groups for the de novo synthesis of purine nucleotides and deoxythymidine monophosphate. It has long been recognized that, in cell cultures, L-serine is a conditional essential amino acid, because it cannot be synthesized in sufficient quantities to meet the cellular demands for its utilization. In recent years, L-serine and the products of its metabolism have been recognized not only to be essential for cell proliferation, but also to be necessary for specific functions in the central nervous system. The findings of altered levels of serine and glycine in patients with psychiatric disorders and the severe neurological abnormalities in patients with defects of L-serine synthesis underscore the importance of L-serine in brain development and function. This paper reviews these recent insights into the role of L-serine and the pathways of L-serine utilization in disease and during development, in particular of the central nervous system.
Topics: Amino Acid Metabolism, Inborn Errors; Central Nervous System; Gluconeogenesis; Humans; Serine
PubMed: 12534373
DOI: 10.1042/BJ20021785 -
The Journal of Cell Biology Aug 2016Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine... (Review)
Review
Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer.
Topics: Animals; Biosynthetic Pathways; Humans; Models, Biological; Neoplasms; Nucleotides; Phosphoglycerate Dehydrogenase; Serine
PubMed: 27458133
DOI: 10.1083/jcb.201604085 -
Bioorganic & Medicinal Chemistry May 2019Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can...
Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine - the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.
Topics: Amino Acids; Cysteine; Kinetics; Magnetic Resonance Spectroscopy; Pharmaceutical Preparations; Serine
PubMed: 30975501
DOI: 10.1016/j.bmc.2019.04.002 -
Biological & Pharmaceutical Bulletin Sep 2005It has now been well established that D-serine, a coagonist for the N-methyl-D-aspartate (NMDA) glutamate receptors (NR1/NR2 type), is maintained at a high concentration... (Review)
Review
It has now been well established that D-serine, a coagonist for the N-methyl-D-aspartate (NMDA) glutamate receptors (NR1/NR2 type), is maintained at a high concentration in mammalian brains for life and shows a brain-selective and NMDA receptor R2B subunit-related distribution, overturning the hitherto generally accepted theory that D-amino acid is not always present in mammalian tissues. D-Serine in the brain has been shown to be contained in both the glia and neurons and to have specific processes of biosynthesis, extracellular release, uptake, and degradation. Moreover, the selective elimination of D-serine reduces the NMDA receptor-mediated intracellular signaling and long-term potentiation of synaptic connections. Together with the anti-psychotic and anti-ataxic property of D-serine and the pivotal roles of the NMDA receptor in divergent higher brain functions, these observations support the view that the D-amino acid may be involved as an endogenous modulator for the NMDA receptor in various neuropsychiatric functions and their pathological conditions.
Topics: Animals; Brain; Brain Chemistry; Humans; Mental Disorders; Nervous System Diseases; Receptors, N-Methyl-D-Aspartate; Serine
PubMed: 16141516
DOI: 10.1248/bpb.28.1561 -
The Journal of Biological Chemistry Jan 1955
Topics: Phosphatidylserines; Serine
PubMed: 13233205
DOI: No ID Found