Serine deficiencies
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Psychomotor retardation, microcephaly and seizures of neonatal or childhood origin, progressive polyneuropathy in adults, low concentrations of serine in blood and cerebrospinal fluid, and deficiency of 3-phosphogylcerate dehydrogenase, 3-phosphoserineaminotransferase, or phosphoserine-phosphatase. The biochemical characteristic of the disease is a low concentration of serine in the cerebrospinal fluid. Serine racemase converts L-serine to D-serine, which is a neuromodulator binding to and activating the N-Methyl-D-aspartate subtype of glutamate receptors. Information is not available on pathogenesis, but serine is a precursor of phospholipids and glycolipids, important constituents of the central nervous system. Failure of improvement in many patients has been attributed to intra-uterine deficiency of serine and its effect on prenatal development. All of the serine deficiency diseases are inherited in an autosomal recessive pattern. The patient with phosphoserine phosphatase deficiency had pre- and postnatal retardation of growth, psychomotor retardation and features of Williams syndrome, which was considered to be unrelated, although both genes are on chromosome 7.
The mitotic phase of spermatogenesis
C. Yan Cheng in Spermatogenesis, 2018
In healthy men, millions of sperm are produced daily in the testis through a process known as spermatogenesis, owing to the tremendous replenishing power of spermatogonia, a heterogeneous population consisting of both spermatogonial stem cells and committed progenitors. The spermatogonia need to undergo three phases—the mitotic phase, the meiotic phase, and the postmeiotic differentiation phase—to give rise to spermatozoa. In the mitotic phase, spermatogonia undergo a series of mitosis to expand the number of daughter cells. The cultured spermatogonia remain heterogeneous and the stem cell activity is maintained in a subpopulation of cells. The spermatogonial niche comprises of various cell types and extracellular matrix proteins. In contrast with the paracrine growth factors, little is known about the autocrine regulation in spermatogonia. Studies suggest that the metabolism of spermatogonia also affects the fate decision. The mammalian target of rapamycin, an atypical serine/threonine kinase, is a master regulator of cell growth and metabolism.
Protein Phosphorylation
Enrique Pimentel in Handbook of Growth Factors, 2017
Covalent reversible phosphorylation of cellular proteins is an important regulatory mechanism involved in the control of metabolism as well as in the regulation of cell proliferation and differentiation. 1 - 3 The phosphorylations regulated by protein kinases occur most frequently on serine/threonine residues, but phosphorylation on tyrosine, although less frequent, is very important for the functional modification of cellular proteins. Some of the phosphorylated cellular proteins are located in the nucleus and are directly involved in the control of RNA synthesis and DNA replication. Nuclear proteins whose functions are regulated by phosphorylation at specific amino acid residues include proto-oncogene products such as Myc, Myb, Fos, Jun, and Ets, as well as the products of tumor suppressor genes such as the p53 and RB proteins. Transcription factors such as CREB and NF-κB are substrates for kinases involved in the control of cell growth.
Phase I clinical trial of safety of L-serine for ALS patients
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2017
Todd D. Levine, Robert G. Miller, Walter G. Bradley, Dan H. Moore, David S. Saperstein, Lynne E. Flynn, Jonathan S. Katz, Dallas A. Forshew, James S. Metcalf, Sandra A. Banack, Paul A. Cox
We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18–85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.
Urinary D-serine level as a predictive biomarker for deterioration of renal function in patients with atherosclerotic risk factors
Published in Biomarkers, 2019
Hidehiro Iwakawa, Shin Makabe, Tomokazu Ito, Tohru Yoshimura, Hiroyuki Watanabe
Background: D-serine, the enantiomer of L-serine, was identified in mammals 20 years ago. Although a close relationship between D-serine and renal dysfunction has been shown, the clinical implications of urinary D- and L-serine in humans are poorly understood. The aim of this study was to evaluate the relationship between urinary D- and L-serine with well-known renal biomarkers, and clarify the prognostic value of D- and L-serine for renal events. Methods: This cross-sectional, prospective study included 65 patients with atherosclerotic risk factors, who were followed up for a median of 16 months. The primary endpoint was a composite of end-stage renal disease and a decline in estimated glomerular filtration rate (eGFR) ≥ 25% from baseline. Results: Urinary D-serine concentrations showed a better correlation with eGFR than did urinary L-serine, whereas neither urinary D- nor L-serine correlated with tubular markers such as urinary liver-type fatty acid-binding protein and N-acetyl-beta-D-glucosaminidase. A Cox regression analysis revealed that low urinary D-serine levels were significantly associated with the primary endpoint after adjusting for confounding factors (hazard ratio 12.60; 95% confidence interval, 3.49–45.51). Conclusions: Urinary D-serine is associated with glomerular filtration and can be a prognostic biomarker of renal dysfunction in patients with atherosclerotic risk factors.
Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies
Published in Expert Opinion on Drug Discovery, 2018
Bence Szilágyi, György G. Ferenczy, György M. Keserű
Introduction: D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia. The inhibition of DAAO appears to be a viable strategy to increase D-serine level and to have therapeutic potential in schizophrenia. Areas covered: This review describes the efforts to develop DAAO inhibitors and to optimize their in vitro and in vivo effects in preclinical settings. The structural evolution of DAAO inhibitors is presented from simple carboxylic acid derivatives via small, planar compounds with carboxylic acid mimetics to extended compounds whose binding is possible owing to DAAO flexibility. Inhibitory potency and pharmacokinetic properties are discussed in the context of compounds’ ability to increase D-serine level and to show efficacy in animal models of schizophrenia. Expert opinion: The accumulated knowledge on the structural requirements of DAAO inhibitors and on their in vitro and in vivo effects provides appropriate basis to develop inhibitors with optimized potency, selectivity and pharmacokinetic profile including blood-brain penetration. In addition, the validation of DAAO inhibition therapy in alleviating the symptoms of schizophrenia requires further studies on the efficacy of DAAO inhibitors in behavioral assays of animals and on the species differences in D-serine metabolism.
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