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PubMed1991

Serine utilization as a precursor of phosphatidylserine and alkenyl-(plasmenyl)-, alkyl-, and acylethanolamine phosphoglycerides in cultured glioma cells.

In several tissues and cell lines, serine utilized for phosphatidylserine (PS) synthesis is an eventual precursor of the base moiety of ethanolamine phosphoglycerides (PE). We investigated the biosynthesis and decarboxylation of PS in cultured C6 glioma cells, with particular attention to 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine (plasmenylethanolamine) biosynthesis. Incorporation of [3H]serine into PS reached a maximum within 4-8 h, and label in nonplasmenylethanolamine phosphoglyceride (NP-PE) and plasmenylethanolamine was maximal by 12-24 h and 48 h, respectively. After 8 h, label in PS decreased even though 40-60% of initial label remained in the culture medium. Serial additions of fresh [3H]serine restored PS synthesis to higher levels of labeled PS accumulation followed by a subsequent decrease in 4-8 h. High performance liquid chromatographic analyses confirmed that medium serine was depleted by 8 h, and thereafter metabolites, including acetate and formate, accounted for radioactivity in the medium. The rapid but transient appearance of labeled glycine and ATP inside the cells indicated conversion of serine by hydroxymethyltransferase. 78-85% of label from serine was in headgroup of PS or of PE formed by decarboxylation. A precursor-product relationship was suggested for label from [3H]serine appearing in the headgroup of diacyl, alkylacyl, and alkenylacyl subclasses of PE. By 48 h, a constant specific activity, ratio of approximately 1:1 was reached between plasmenylethanolamine and NP-PE, similar to the molar distribution of these lipids. In contrast, equilibrium was not achieved in cells incubated with [1,2-14C]ethanolamine; plasmenylethanolamine had 2-fold greater specific activity than labeled NP-PE by 72-96 h. These observations indicate that in cultured glioma cells 1) serine serves as a precursor of the head group of PS and of both plasmenyl and non-plasmenyl species of PE; 2) exchange of headgroup between NP-PE and plasmenylethanolamine may involve different donor pools of PE depending on whether the headgroup originates with exogenous serine or ethanolamine; 3) serine is rapidly converted to other metabolites, which limits exogenous serine as a direct phospholipid precursor.

Animals↗

PubMed1994

Phorbol ester stimulates phosphorylation on serine 1327 of the human insulin receptor.

Phorbol esters stimulate the phosphorylation of the insulin receptor on discrete serine and threonine residues in intact cells. Phosphorylation of the insulin receptor cytoplasmic domain on serine, threonine, and tyrosine residues regulates receptor tyrosine kinase activity and signaling. In these studies, we demonstrate that phorbol ester treatment of intact COS-1 cells transiently expressing the human insulin receptor stimulates phosphorylation of serine 1327 within the carboxyl-terminal tail of the insulin receptor beta subunit. Phosphopeptide maps of wild-type (Ser1327) and mutant (Ala1327) human insulin receptors revealed the absence of a single phosphopeptide in the Ala1327 receptors when compared with wild-type receptors from phorbol ester-treated cells. Phosphoamino acid analysis revealed phosphoserine within the phosphopeptide from wild-type receptors that is absent in the Ala1327 receptor. The synthetic peptide 1327S (KRSYEEHIPYTHMNGGKK) corresponding to amino acids 1325-1342 of the human insulin receptor is phosphorylated on serine by protein kinase C. After digestion with trypsin, the phosphorylated synthetic peptide comigrated with the serine-phosphorylated peptide isolated from wild-type insulin receptors that was absent from the Ala1327 mutant. Ser1327 is proximal to autophosphorylation sites Tyr1328 and Tyr1334. The potential effects of serine phosphorylation at position 1327 on subsequent phosphorylation of these tyrosines by the insulin receptor kinase were examined using synthetic peptides. The chemically modified peptide 1327S(P) was synthesized with the stoichiometric addition of phosphate to the side chain hydroxyl of a serine corresponding to position 1327 of the insulin receptor. Kinetic analysis revealed that the addition of phosphate to the serine improved substrate recognition by the insulin receptor tyrosine kinase almost 2-fold. The average Km was 1.44 mM for the peptide 1327S(P) versus 2.64 mM for peptide 1327S. However, when compared with the unphosphorylated control peptide, 1327S, the serine-phosphorylated peptide 1327S(P) also reduced the Vmax of the insulin receptor tyrosine kinase 53%. Radiosequence analysis revealed that the chemical addition of phosphate to the serine in peptide 1327S(P) inhibited insulin receptor-catalyzed phosphorylation of the tyrosine on 1327S(P) corresponding to Tyr1334 but not of the tyrosine corresponding to Tyr1328. These data suggest that the juxtaposition of a serine phosphorylation site adjacent to receptor tyrosine phosphorylation sites provides the potential for regulation of insulin receptor autophosphorylation and signaling through its carboxyl-terminal tail.

Amino Acid Sequence↗

PubMed1993

Phosphorylation of the human vitamin D receptor by protein kinase C. Biochemical and functional evaluation of the serine 51 recognition site.

We have reported previously that the human vitamin D receptor (hVDR) is selectively phosphorylated by protein kinase C-beta (PKC-beta), in vitro, on a serine residue in the sequence RRS51MKRK, which is located between the two zinc fingers of hVDR and is potentially important to its transacting function (Hsieh, J.-C., Jurutka, P.W., Galligan, M.A., Terpening, C.M., Haussler, C.A., Samuels, D.S., Shimizu, Y., Shimizu, N., and Haussler, M.R. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 9315-9319). In the present experiments we evaluated this phosphorylation event using a series of hVDR mutants in which serine 51 or its flanking residues were modified. Alteration of serine 51 to a non-phosphorylatable residue resulted in an approximately 60% reduction in basal hVDR phosphorylation in intact cells but did not diminish 1,25-dihydroxyvitamin D3-stimulated phosphorylation. Such mutations also abolished subsequent phosphorylation of immunoprecipitated hVDR by purified PKC-beta, in vitro, as did replacement of basic residues on either side of serine 51. Mutation of serine 51 to glycine (S51G) or to aspartic acid (S51D), as well as altering the basic residues flanking serine 51, abolished the interaction of hVDR with the vitamin D-responsive element (VDRE) as monitored by gel mobility shift analysis. Thus, we conclude that unmodified serine 51 and its surrounding basic residues are crucial not only for PKC-beta substrate recognition but also for the optimal VDRE binding of native hVDR. In transactivation assays, S51G and S51D possessed only 35 and 10% of wild-type hVDR activity, respectively. Mutation of serine 51 to threonine (S51T) restored phosphorylation by PKC-beta, in vitro, to about 40% of wild-type and transactivation to 45% of that of wild-type hVDR. Alteration of serine 51 to alanine, which is the residue in the corresponding position of the glucocorticoid, progesterone, mineral-ocorticoid, and androgen receptors, eliminated PKC-beta phosphorylation but completely preserved the specific DNA binding activity and transactivation capacity of hVDR. Thus, phosphorylation of hVDR at serine 51 is not required for either VDRE binding or transactivation. Finally, incubation of Escherichia coli-expressed hVDR with PKC-beta elicits marked phosphorylation of the receptor and significantly inhibits its ability to complex with the VDRE. We therefore speculate that posttranslational modification of hVDR at serine 51 may constitute a negative regulatory loop which could be operative when target cells are subject to PKC activation events.

Amino Acid Sequence↗

PubMed1997

D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors.

D-Serine is localized in mammalian brain to a discrete population of glial cells near NMDA receptors, suggesting that D-serine is an endogenous agonist of the receptor-associated glycine site. To explore this possibility, we have compared the immunohistochemical localizations of D-serine, glycine, and NMDA receptors in rat brain. In the telencephalon, D-serine is concentrated in protoplasmic astrocytes, which are abundant in neuropil in close vicinity to NMDA receptor 2A/B subunits. Ultrastructural examination of the CA1 region of hippocampus reveals D-serine in the cytosolic matrix of astrocytes that ensheath neurons and blood vessels, whereas NR2A/B is concentrated in dendritic spines. By contrast, glycine immunoreactivity in telencephalon is the lowest in brain. During postnatal week 2, D-serine levels in cerebellum are comparable to those in adult cerebral cortex but fall to undetectable levels by day 26. During week 2, we observe parallel ontogeny of D-serine in Bergmann glia and NR2A/B in Purkinje cells, suggesting a role for astrocytic D-serine in NMDA receptor-mediated synaptogenesis. D-Serine in the radial processes of Bergmann glia is also well positioned to regulate NMDA receptor-dependent granule cell migration. In the inner granule layer, D-serine is found transiently in protoplasmic astrocytes surrounding glomeruli, where it could regulate development of the mossy fiber/granule cell synapse. D-Serine seems to be the endogenous ligand of glycine sites in the telencephalon and developing cerebellum, whereas glycine predominates in the adult cerebellum, olfactory bulb, and hindbrain.

Animals↗

PubMed2004

Schwann cell and epineural fibroblast expression of serine racemase.

D-serine appears to be a natural agonist at the "glycine site" of the NMDA receptor and is created by conversion from L-serine by serine racemase. This racemase has been localized to protoplasmic astrocytes that ensheath synapses and modulate neuronal activity in the CNS, but serine racemase expression in the PNS has not been reported. Immunofluorescence indicated that Schwann cells and other endoneurial components of rat spinal nerve contain serine racemase, and western blot analysis detected the enzyme in lysates of sciatic nerve. Cultures from sciatic nerve contained Schwann cells and fibroblasts, and both cell types showed serine racemase expression by immunofluorescence and Western blot; the quantities per unit of total protein appeared slightly lower than that expressed in cultured astrocytes. Cultures enriched for each cell type were subjected to reverse transcriptase polymerase chain reaction, further confirming serine racemase mRNA in Schwann cells and fibroblasts. Finally, immunodetection of D-serine itself was observed in cultured Schwann cells and fibroblasts. These expression patterns of serine racemase may indicate roles for D-serine in peripheral nerve transduction.

Animals↗

PubMed2004

Possible role of D-serine in the pathophysiology of Alzheimer's disease.

Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimer's disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels of D-serine in the patients with AD were slightly (z=-1.77, p=0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z=-1.73, p=0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L+D) serine in the patients was significantly (z=-2.36, p=0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD.

Aged↗

PubMed1988

Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma.

The activities of 3-phosphoglycerate dehydrogenase, an enzyme of serine biosynthesis, and serine hydroxymethyltransferase, serine dehydratase and serine aminotransferase, which are competing enzymes of serine utilization, were assayed in human colon carcinomas from patients and in transplantable rat sarcomas. Serine dehydratase and serine aminotransferase activities were absent, whereas 3-phosphoglycerate dehydrogenase and serine hydroxymethyltransferase activities were markedly increased in both tumour types. Serine hydroxymethyltransferase catalyses the formation of glycine and methylene tetrahydrofolate which are important precursors for nucleotide biosynthesis. The observed enzymic imbalance in these tumours ensures that an increased capacity for the synthesis of serine is coupled to its utilisation for nucleotide biosynthesis as a part of the biochemical commitment to cellular replication in cancer cells. That this pattern is found in sarcomas and carcinomas, and in tumours of human and rodent origin, signifies its universal importance for the biochemistry of the cancer cell and singles it out as a potential target site for anti-cancer chemotherapy.

Aged↗

PubMed2003

Serine acetyltransferase of Escherichia coli: substrate specificity and feedback control by cysteine.

Although SAT (serine acetyltransferase) of Escherichia coli, which catalyses the first step in cysteine synthesis, proceeds via a random-order ternary complex reaction mechanism [Hindson and Shaw (2003) Biochemistry 42, 3113-3119], it has been suggested that the nearly identical enzyme from Salmonella typhimurium might involve an acetyl-enzyme intermediate [Leu and Cook (1994) Protein Peptide Lett. 1, 157-162]. In this study the alternative acetyl acceptor threonine and the alternative acyl donor, propionyl-CoA were used to further investigate the reaction mechanism of SAT from E. coli. Steady-state kinetic data and dead-end inhibition studies were again diagnostic of a random-order ternary complex reaction mechanism for alternative substrates. Since earlier kinetic studies with SAT from S. typhimurium suggested that cysteine competes with acetyl-CoA for binding, rather than serine with which it is isostructural, the specificity of the serine-binding pocket was assessed with three substrate mimics; beta-hydroxypropionic acid, glycine and ethanolamine. The data show that SAT interacts productively with the amino and hydroxymethyl moieties of serine, whereas the carboxyl group provides an essential contribution to binding strongly, supporting a view that cysteine will interact productively at the serine-binding site. Furthermore, since the hydroxymethyl contact region of the serine-binding site appears able to accommodate the methylene and acetyl moeties of threonine and O -acetyl-serine respectively, the site is unlikely to provide obligatory short-range contacts with the hydroxyl group of serine, a prerequisite for exclusion of cysteine. Such a proposal is supported by the results of micro-calorimetric studies which show that cysteine competes with serine for binding to SAT rather than with CoA. It follows that tight binding of cysteine at the serine-binding site near the catalytic centre may be the effector of a substantial reduction in the affinity of SAT for CoA, yielding the observed pattern of steady-state inhibition and the mechanism by which cysteine mediates effective end-product control of its synthesis.

Acetyl Coenzyme A↗

PubMed2001

MAP kinases mediate UVB-induced phosphorylation of histone H3 at serine 28.

Histone H3 phosphorylation is related closely to chromatin remodeling and chromosome condensation. H3 phosphorylation at serine 28 is coupled with mitotic chromosome condensation in diverse mammalian cell lines. However, the pathway that mediates phosphorylation of H3 at serine 28 is unknown. In the present study, ERK1, ERK2, or p38 kinase strongly phosphorylated H3 at serine 28 in vitro. JNK1 or JNK2 was able also to phosphorylate H3 at serine 28 in vitro but to a lesser degree. UVB irradiation markedly induced phosphorylation of H3 at serine 28 in JB6 Cl 41 cells. PD 98059, a MEK1 inhibitor, and SB 202190, a p38 kinase inhibitor, efficiently repressed UVB-induced H3 phosphorylation at serine 28. Expression of dominant negative mutant (DNM) ERK2 in JB6 Cl 41 cells totally blocked UVB-induced phosphorylation of H3 at serine 28. Additionally, DNM p38 kinase or DNM JNK1 partially blocked UVB-induced H3 phosphorylation at serine 28. Furthermore, UVB-induced H3 phosphorylation at serine 28 was inhibited in Jnk1(-/-) cells but not in Jnk2(-/-) cells. These results suggest that UVB-induced H3 phosphorylation at serine 28 may be mediated by mitogen-activated protein kinases.

Animals↗

PubMed1962

Effect of cultural conditions on growth and metabolite uptake by serine-glycine auxotrophs of Escherichia coli.

Levine, Elliot M. (Yale University, New Haven, Conn.) and Sofia Simmonds. Effect of cultural conditions on growth and metabolite uptake by serine-glycine auxotrophs of Escherichia coli. J. Bacteriol. 84:683-693. 1962.-A study was made of the effect of environmental conditions on the growth and metabolite uptake by Escherichia coli strain S/G (a serine-glycine auxotroph) and strain S (a serine-glycine auxotroph lacking a normal transport system for glycine). The induction in strain S of the glycine transport system, which occurs during growth in a glycine-containing medium, was prevented by l-asparagine; the "repression" appeared to result from the endogenous formation of glycine from asparagine (through homoserine and threonine) via a pathway in which serine was not an obligatory intermediate. The response of both strains to glycine appeared to be determined by the amount of l-serine or glycine present in the media (containing asparagine) in which the cells were grown prior to testing. Preliminary growth in the presence of low concentrations of exogenous glycine, which should produce cells with small endogenous "glycine-serine pools," favored the induction of a functional glycine transport system in cells of strain S. Cells of strain S/G grown under similar conditions subsequently showed an enhanced ability to take up C(14)-labeled glycine. With both strains, preliminary growth conditions leading to the formation of large endogenous "glycine-serine pools" (e.g., growth in the presence of high concentrations of exogenous serine) produced cells exhibiting a glycine uptake rate that was not commensurate with the rate at which these cells grew on glycine. The growth response apparently depends not only on the ability of the cells to transport glycine but also on the size of the endogenous "glycine-serine pools"; inocula composed of cells having a limited capacity to accumulate labeled glycine showed significant growth in glycine-containing media if the cells had large "glycine-serine pools." The growth and uptake responses to glycylglycine appear to be governed, in part, by the same factors that control the responses to free glycine.

Amino Acids↗

PubMed1980

Nitrate respiration of Klebsiella pneumoniae on amino acids, especially on serine.

Anaerobic growth on an amino acids mixture in the presence of nitrate of a strain of K. pneumoniae isolated from soil depended on the presence of serine in the mixture. This organism grew on serine as sole carbon source under anaerobic conditions in the presence of nitrate but not in its absence. Glycylglycine could replace serine. Serine was degraded to acetate, formate, pyruvate, acetone and acetoin with formation of nitrite under these conditions. These products were practically not different from those formed from glucose. Resting cells decomposed serine also in the absence of nitrate forming butanediol and a large amount of formate in place of decreased amounts of acetate and pyruvate. These cells also anaerobically decomposed alanine to products similar to those from serine and phenylalanine to phenylacetate and formate only in the presence of nitrate. Valine was not catabolized under the same conditions. Serine was decomposed to pyruvate and ammonia in the crude extract in the presence and absence of nitrate, indicating participation of serine dehydratase in its breakdown. Phenylalanine appears to be decomposed to phenylpyruvate by transamination coupled to glutamate oxidation and then to phenylacetate and formate. Little growth on serine under anaerobic conditions in the absence of nitrate may be accounted for by the small gain of ATP in the anaerobic breakdown of serine by this organism.

Amino Acids↗

PubMed1996

Role of cytosolic serine hydroxymethyltransferase in one-carbon metabolism in Neurospora crassa.

Conidiospores of wild type and two mutant strains of Neurospora crassa were grown on [3-13C]serine, [2-13C]glycine, or [13C]formate. Acid extracts of the mycelia were analyzed by 13C NMR for incorporation of the 13C label into choline, serine, and adenine. The goal was to elucidate the function of cytosolic serine hydroxymethyltransferase by comparison of a mutant strain lacking this activity and requiring formate for optimal growth (for mutant strain) to the wild-type strain and the ser3 strain which cannot convert glucose to serine. The results for both the wild-type and ser3 strains showed that the one-carbon adduct of the cytosolic pool of methylenetetrahydrofolate is formed primarily and preferably from C3 of serine. Both organisms could form methylenetetrahydrofolate from formate in the absence of serine and glycine. However, the for mutant strain was restricted in its ability to form methylenetetrahydrofolate from C3 of serine, preferring formate as the one-carbon source. All three strains had an active glycine cleavage complex and mitochondrial serine hydroxymethyltransferase. The formate requirement of the for mutant strain appears to be the result of the inability to form formate in the mitochondria from serine or glycine at a rate sufficient to sustain the biosynthetic pools of methylenetetrahydrofolate and 10-formyltetrahydrofolate in the cytosol. All three strains rapidly accumulated serine from the media to form high intracellular levels of this substrate. However, these strains did not accumulate either glycine or formate from the media at levels that could be detected by 13C NMR.

Carbon↗

PubMed1976

Utilization of L-serine in the in vivo biosynthesis of glycerophospholipids by rat liver.

The incorporation of L-serine-U-14C, L-serine-3-14C, and D,L-serine-1-14-C into the glycerophospholipids of rat liver in vivo was determined over a period of 3 min to 13 hr following intravenous injection. The radioactivity from these serines was transferred to variable extent into the glycerol, fatty acid, and nitrogenous base parts of all the glycerophospholipids and neutral lipids. The half-lives and turnover rates of phosphatidylserine calculated from the precursor-product specific activity curves obtained with L-serine-U-14C were 14 min and 0.28 mumol/min/liver, respectively. The half-lives and turnover rates of phosphatidylserine as measured from the decay data of lipid serine from all markers averaged, respectively, 8.2 hr and 0.0008 mumol/min/liver. The discrepancy between these turnover rates was attributed to an understimation of degradation of phosphatidylserine due to its continued biosynthesis and/or an extensive reutilization of L-serine. By monitoring the formation of radioactive lipid ethanolamine, it was found that phosphatidylserine was decarboxylated at one-half the rate of lipid serine biosynthesis. It is suggested that as much as one-half of total phosphatidylserine may be degraded by other mechanisms, such as base exchange with choline, ethanolamine, and serine, as already demonstrated in vitro by other workers. The time course and nature of labeling of phosphatidylcholine was consistent with an extensive conversion of radioactive L-serine to 1-carbon fragments and a rapid methylation of phosphatidylethanolamine to phosphatidylcholine.

Animals↗

PubMed1985

Metabolism of an ingested serine load in psychotic and nonpsychotic subjects.

Our previous studies have shown that in psychotics, the plasma serine level is abnormally high and that plasma serine hydroxymethyltransferase (which cleaves serine to glycine) activity is abnormally low as compared with that in nonpsychotic subjects. In this study, psychotic and nonpsychotic subjects ingested a large bolus of L-serine (4 mM/kg) at breakfast and blood was drawn before breakfast, 2 hr, 4 hr, and 6 hr after serine ingestion. Baseline serine and SHMT activity differentiated between psychotics and nonpsychotics with high degrees of significance (p less than 0.0001) and p less than 0.01, respectively). Plasma serine levels 2 hr after serine ingestion were significantly higher (p less than 0.01) in nonpsychotics as compared with psychotics. Elimination of serine in psychotics was bimodal and was significantly different from that of nonpsychotics (p less than 0.0079, Moses test). These findings provide additional evidence for abnormal serine metabolism in psychotic patients.

Age Factors↗

PubMed1990

Metabolic control analysis of mammalian serine metabolism.

(1) Mammalian serine metabolism is discussed in relation to its synthesis and utilization in proliferating cells, particularly during the nonmalignant proliferation of lymphocytes. (2) An analysis of the control of serine biosynthesis de novo under conditions of high pathway flux has been carried out using metabolic control theory. (3) The important and novel conclusions are that control of pathway flux is localized exclusively at the final step of this biosynthetic pathway, phosphoserine phosphatase. This conclusion challenges the frequently stated maxim that control of biosynthetic pathways is always directed at the first pathway enzyme in a sequence. In the case of phosphoserine phosphatase, the enzyme is inhibited uncompetitively by its product serine, and this feedback control mechanism has the most significant controlling influence on overall pathway flux. Thus, the serine biosynthesis pathway, under these conditions, is controlled by product demand (serine utilization) and not by substrate supply (glycolytic provision of 3-phosphoglycerate), despite the high rate of glycolysis associated with cell proliferation. (4) The control structure of the pathway is not immutable. As has been observed with other pathways analyzed by metabolic control theory, the key points of control in the pathway can shift according to physiological circumstances. At low pathway flux, the control of serine biosynthesis is shared between all the component enzymes of the pathway, and the responsiveness of flux shifts from product demand to substrate supply. (5) Serine utilization has been studied in mitogenically-stimulated human peripheral lymphocytes. Cell proliferation and serine utilization for nucleic acid synthesis have been shown to be responsive to serine concentrations in the normal plasma range. (6) It is concluded that the maintenance of normal plasma serine concentrations is an important factor in the rate of lymphocyte proliferation and hence the effectiveness with which the body can mount an immune response to an antigenic challenge, such as in infection.

Animals↗

PubMedDate not supplied

Comparison of the effects of central administration of serine and glycine on body temperature of the rabbit.

In previous research, intracerebroventricular (ICV) injection of serine (1-4 mg) caused dose-related hypothermia in rabbits and reduced rises in body temperature caused by leukocytic pyrogen (LP) and prostaglandin E2 (PGEs). Since serine is the major precursor of the putative neurotransmitter glycine, these effects of serine may be due to its conversion to glycine. To assess this possibility, glycine was administered centrally to see if its effects on body temperature are similar to those of serine. ICV injections of glycine (0.25-1.0 mg) caused dose-related decreased in body temperature in a 10 degrees C environment but had no significant effect at 23 degrees C. Glycine (1 mg) delayed the normal rise in temperature in 30 degrees C environment and reduced LP fever and PGE2 hyperthermia. ICV glycine and serine in combination were, however, subadditive in producing hypothermia, which suggests that these amino acids act at different central sites. A difference in the interaction of serine and glycine with strychnine in producing hypothermia also suggests that the action of serine is not entirely mediated by glycine. Since serine and glycine have similar effects on normal body temperature and fever some portion of the effects of serine may be caused by its conversion to glycine. The subadditivity data and the difference in temperature effects when the amino acids are given with strychnine suggest that serine and glycine probably have separate central sites of action.

Animals↗

PubMed2006

Intracerebroventricular injection of L-serine analogs and derivatives induces sedative and hypnotic effects under an acute stressful condition in neonatal chicks.

Four experiments were conducted to clarify the central functions of L-serine and its analogs on an acute stressful condition. Intracerebroventricular (i.c.v.) injection of L-serine (0.21, 0.42 and 0.84 micromol) attenuated stress responses in a dose-dependent fashion, as well as induced sleep, in Experiment 1. The effects of L- and D-serine in Experiment 2, those of L-serine, phosphoserine, acetylserine and L-cysteine in Experiment 3 and those of L-serine, glycine and lysophosphatidylserine in Experiment 4 were compared at an equimolar basis (0.84 micromol). D-Serine, proposed as an endogenous agonist of N-methyl-D-aspatate (NMDA) receptor, did not have sedative and hypnotic effects as observed with L-serine. In contrast, all the analogs and derivatives of L-serine had a sedative effect, although with a different manner in several behavioral markers of stress such as spontaneous activity and distress vocalizations. No significant changes in plasma corticosterone concentration were observed in any experiment. Taken together, the i.c.v. injection of L-serine analogs and its derivatives have sedative and hypnotic effects under an acute stressful condition, which does not involve the hypothalamic-pituitary-adrenal axis. In conclusion, L-serine may be effective in improving anxiety or sleep disorders induced by psychological stressor.

Age Factors↗

PubMed2006

L-serine uptake by human placental microvillous membrane vesicles.

The human fetus requires more glycine than any other amino acid but placental glycine transfer to the fetus is insufficient to meet fetal demand. L-Serine could represent a major metabolic source of glycine for the human fetus but little is known about the kinetics and physiology of L-serine uptake by the human placenta. We have characterised the amino acid transport systems involved in the uptake of L-serine by the microvillous membrane of the human placental syncytiotrophoblast and compared the uptake rates to those of glycine. L-Serine uptake into microvillous membrane (MVM) vesicles was primarily mediated by system A (MeAIB inhibitable) and system L (BCH inhibitable). Further characterisation using specific substrates of LAT1 and LAT2 found the pattern of L-serine uptake was consistent with that expected for uptake mediated by LAT2. Uptakes were performed with tracer levels of (14)C-L-serine, physiological levels of L-serine, or with physiological levels of amino acids. As amino acid concentrations rose, the proportion of uptake by System L decreased while uptake by uncharacterised Na(+)-independent systems increased. Uptake of Lserine into MVM vesicles had a V(max) of 2.1+/-0.4 nmol/mg protein/min, which was significantly higher than for glycine (V(max) 1.0+/-0.2 nmol/mg protein/min). This indicates that MVM vesicles have a higher uptake capacity for L-serine than glycine, despite a greater demand for glycine over serine for fetal protein synthesis. Further studies are now required to define the fate of L-serine taken up by the placenta and its importance for the fetus.

Amino Acid Transport System A↗