L-Serine regulates the activities of microglial cells that express very low level of 3-phosphoglycerate dehydrogenase, an enzyme forL-serine biosynthesis

2001 ◽  
Vol 64 (4) ◽  
pp. 392-401 ◽  
Author(s):  
Hiroki Sugishita ◽  
Yasuhide Kuwabara ◽  
Kazuko Toku ◽  
Lisa Doi ◽  
Lihua Yang ◽  
...  
Keyword(s):  
Microglial Cells ◽  
Low Level ◽  
Phosphoglycerate Dehydrogenase ◽  
Serine Biosynthesis

scholarly journals Molecular Characterization of 3-Phosphoglycerate Dehydrogenase Deficiency—a Neurometabolic Disorder Associated with Reduced L-Serine Biosynthesis

2000 ◽  
Vol 67 (6) ◽  
pp. 1389-1399 ◽  
Author(s):  
Leo W.J. Klomp ◽  
Tom J. de Koning ◽  
Helga E.M. Malingré ◽  
Ellen A.C.M. van Beurden ◽  
Miny Brink ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Dehydrogenase Deficiency ◽  
Neurometabolic Disorder ◽  
Phosphoglycerate Dehydrogenase ◽  
Serine Biosynthesis

scholarly journals The biosynthesis of serine and glycine in Pseudomonas AM1 with special reference to growth on carbon sources other than C1 compounds

1971 ◽  
Vol 121 (5) ◽  
pp. 753-762 ◽  
Author(s):  
W. Harder ◽  
J. R. Quayle
Keyword(s):  
Essential Role ◽  
Carbon Sources ◽  
Enzymic Activity ◽  
Serine Hydroxymethyltransferase ◽  
The Other ◽  
Wild Type ◽  
Phosphoserine Phosphatase ◽  
Wild Type Phenotype ◽  
Phosphoglycerate Dehydrogenase ◽  
Serine Biosynthesis

1. A mutant, 20S, of Pseudomonas AM1 was obtained that requires a supplement of serine to grow on succinate, lactate or ethanol. This mutant lacks phosphoserine phosphatase and revertants to wild-type phenotype regained this enzymic activity showing that the phosphorylated pathway of serine biosynthesis is necessary for growth on these three substrates. 2. The requirement for supplemental serine by mutant 20S could be met by glycine, suggesting that Pseudomonas AM1 can obtain C1 units from glycine. 3. Mutant 20S grows on C1 compounds at a lower rate compared with the wild type. Supplementation with serine stimulated the growth rate of the mutant suggesting that the phosphorylated pathway of serine biosynthesis plays some role, but not an essential role, during growth on C1 compounds. 4. A mutant, 82G, was obtained that requires a supplement of glycine to grow on succinate, lactate or ethanol. When grown in such supplemented media, the mutant lacks serine hydroxymethyltransferase and revertants to wild-type phenotype regained enzymic activity showing that during growth on succinate, lactate or ethanol, glycine is made from serine via serine hydroxymethyltransferase, and that the organism can obtain C1 units from glycine. 5. Mutant 82G grew on methanol and then contained serine hydroxymethyltransferase suggesting that this enzyme is necessary for growth on C1 compounds and that Pseudomonas AM1 may synthesize two such enzymes, one used in growth on C1 compounds, the other used in growth on other substrates. Mutant 82G might lack the latter enzyme. 6. Phosphoglycerate dehydrogenase is specifically inhibited by l-serine and the regulatory implications of this are discussed.

scholarly journals Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers

2016 ◽  
Vol 113 (7) ◽  
pp. 1778-1783 ◽  
Author(s):  
Edouard Mullarky ◽  
Natasha C. Lucki ◽  
Reza Beheshti Zavareh ◽  
Justin L. Anglin ◽  
Ana P. Gomes ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Small Molecule ◽  
Cancer Cell Lines ◽  
Small Molecule Inhibitor ◽  
Genetic Ablation ◽  
Molecule Inhibitor ◽  
Phosphoglycerate Dehydrogenase ◽  
Serine Biosynthesis

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism.

scholarly journals Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway

2015 ◽  
Vol 59 (8) ◽  
pp. 4680-4688 ◽  
Author(s):  
Yihong Deng ◽  
Wei Ran ◽  
Suqin Man ◽  
Xueping Li ◽  
Hongjian Gao ◽  
...  
Keyword(s):  
Acanthamoeba Castellanii ◽  
Dependent Manner ◽  
Biosynthesis Pathway ◽  
Content Type ◽  
Phosphoserine Aminotransferase ◽  
Proteomic Approach ◽  
Phosphoglycerate Dehydrogenase ◽  
Serine Biosynthesis ◽  
Amoebicidal Activity

ABSTRACTAcanthamoebasp. parasites are the causative agents ofAcanthamoebakeratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether againstAcanthamoeba castellaniitrophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibitedin vitroamoebicidal activity in a time- and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins inAcanthamoebawas validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether againstAcanthamoebatrophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment ofAcanthamoebainfections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or blockAcanthamoebainfections.

2-Phosphoglycerate phosphatase and serine biosynthesis in Veillonella alcalescens

1981 ◽  
Vol 27 (8) ◽  
pp. 808-814 ◽  
Author(s):  
J. J. Pestka ◽  
E. A. Delwiche
Keyword(s):  
Biosynthetic Pathway ◽  
Gel Filtration ◽  
Deae Cellulose ◽  
Apparent Molecular Weight ◽  
Ammonium Sulfate Precipitation ◽  
Ph Optimum ◽  
Phosphoserine Aminotransferase ◽  
Cell Extracts ◽  
Phosphoglycerate Dehydrogenase ◽  
Serine Biosynthesis

The constituent enzymes for the phosphorylated and nonphosphorylated serine biosynthetic pathways in Veillonella alcalescens were identified and included phosphoserine phosphatase, 3-phosphoglycerate dehydrogenase, glycerate dehydrogenase, phosphoserine aminotransferase, and serine–pyruvate aminotransferase. Cell extracts of the organism were also found to cause the specific dephosphorylation of 2-phosphoglycerate. The phosphatase was purified 39-fold by manganese chloride precipitation, ammonium sulfate precipitation, and DEAE-cellulose chromatography. Sephadex G-200 gel filtration data established an apparent molecular weight of 50 000 for the enzyme. The 2-phosphoglycerate phosphatase had a pH optimum of 5.5 and was distinct from phosphoglyceromutase. Assays conducted with the purified enzyme on a number of other phosphorylated intermediates indicated that the phosphatase was most specific for 2-phosphoglycerate. Glucerate, hydroxypyruvate, and serine inhibited the enzyme, whereas succinate stimulated activity. Veillonella 2-phosphoglycerate phosphatase is the first such enzyme to be described in a prokaryote and is probably involved in glycerate generation for the nonphosphorylated serine biosynthetic pathway.

scholarly journals Pathways leading to and from serine during growth of Pseudomonas AM1 in C1 compounds or succinate

1970 ◽  
Vol 117 (3) ◽  
pp. 563-572 ◽  
Author(s):  
J. Heptinstall ◽  
J. R. Quayle
Keyword(s):  
Dehydrogenase Activity ◽  
Reductase Activity ◽  
Methanol Dehydrogenase ◽  
Wild Type ◽  
Hydroxypyruvate Reductase ◽  
Phosphoglycerate Dehydrogenase ◽  
Specific Activities ◽  
Phenazine Methosulphate ◽  
Serine Biosynthesis ◽  
Enrichment Step

1. The following enzymes of the phosphorylated pathway of serine biosynthesis have been found in methanol- and succinate-grown Pseudomonas AM1: phosphoglycerate dehydrogenase, phosphoserine-α-oxoglutarate aminotransferase and phosphoserine phosphohydrolase. Their specific activities were similar in the organism grown on either substrate. 2. A procedure for preparation of auxotrophic mutants of Pseudomonas AM1 is described involving N-methyl-N′-nitro-N-nitrosoguanidine as mutagen and a penicillin enrichment step. 3. A mutant, M-15A, has been isolated that is unable to grow on methanol and that lacks phenazine methosulphate-linked methanol dehydrogenase. The mutant is able to grow on methylamine, showing that the amine is not oxidized by way of methanol. 4. Loss of methanol dehydrogenase activity in mutant M-15A led to loss of phenazine methosulphate-linked formaldehyde dehydrogenase activity showing that the same enzyme is probably responsible for both activities. 5. A mutant, 20B-L, has been isolated that cannot grow on any C1 compound tested but can grow on succinate. 6. Mutant 20B-L lacks hydroxypyruvate reductase, and revertants that regained the ability to grow on methanol, methylamine and formate contained hydroxypyruvate reductase activity at specific activities similar to that of the wild-type organism. This shows that hydroxypyruvate reductase is necessary for growth on methanol, methylamine and formate but not for growth on succinate. 7. The results suggest that during growth of Pseudomonas AM1 on C1 compounds, serine is converted into 3-phosphoglycerate by a non-phosphorylated pathway, whereas during growth on succinate, phosphoglycerate is converted into serine by a phosphorylated pathway.

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