34-1114: 1IA8 , 1NVQ , 1NVR , 1NVS , 1ZLT , 1ZYS , 2AYP , 2BR1 , 2BRB , 2BRG , 2BRH , 2BRM , 2BRN , 2BRO , 2C3J , 2C3K , 2C3L , 2CGU , 2CGV , 2CGW , 2CGX , 2E9N , 2E9O , 2E9P , 2E9U , 2E9V , 2GDO , 2GHG , 2HOG , 2HXL , 2HXQ , 2HY0 , 2QHM , 2QHN , 2R0U , 2WMQ , 2WMR , 2WMS , 2WMT , 2WMU , 2WMV , 2WMW , 2WMX , 2X8D , 2X8E , 2X8I , 2XEY , 2XEZ , 2XF0 , 2YDI , 2YDJ , 2YDK , 2YER , 2YEX , 2YM3 , 2YM4 , 2YM5 , 2YM6 , 2YM7 , 2YM8 , 2YWP , 3F9N , 3JVR , 3JVS , 3NLB , 3OT3 , 3OT8 , 3PA3 , 3PA4 , 3PA5 , 3TKH , 3TKI , 3U9N , 4FSM , 4FSN , 4FSQ , 4FSR , 4FST , 4FSU , 4FSW , 4FSY , 4FSZ , 4FT0 , 4FT3 , 4FT5 , 4FT7 , 4FT9 , 4FTA , 4FTC , 4FTI , 4FTJ , 4FTK , 4FTL , 4FTM , 4FTN , 4FTO , 4FTQ , 4FTR , 4FTT , 4FTU , 4GH2 , 4HYH , 4HYI , 4JIK , 4QYE , 4QYF , 4QYG , 4QYH , 4RVK , 4RVL , 4RVM , 5DLS , 5F4N 1111 12649 ENSG00000149554 ENSMUSG00000032113 O14757 O35280 NM_001330428 NM_007691 NP_001317357 NP_031717 Checkpoint kinase 1 , commonly referred to as Chk1 ,
68-436: A combined computational approach, a set of in-house plant-based semi-synthetic aminoarylbenzosuberene molecules selected for analysis, from these Bch10 regarded as a potential CHK1 inhibitor compared to the top five co-crystallized inhibitors based on their binding affinity and toxicity profile. During meiosis in human and mouse, CHEK1 protein kinase is important for integrating DNA damage repair with cell cycle arrest. CHEK1
102-765: A higher level of DNA damage. Therefore, Chk1 may contribute to chemotherapy resistance. In order to optimize chemotherapies, Chk1 must be inhibited to reduce the survival advantage. Chk1 gene can be effectively silenced by siRNA knockdown for further analysis based on an independent validation. By inhibiting Chk1, cancer cells lose the ability to repair damaged DNA which allows chemotherapeutic agents to work more effectively. Combining DNA damaging therapies such as chemotherapy or radiation treatment with Chk1 inhibition enhances targeted cell death and provides synthetic lethality. Many cancers rely on Chk1 mediated cell cycle arrest heavily especially if cancers are deficient in p53. Approximately 50% of cancers possess p53 mutations illustrating
136-405: A medium effect size for negative and total symptoms of schizophrenia. There also is evidence that L ‐serine could acquire a therapeutic role in diabetes. D -Serine is being studied in rodents as a potential treatment for schizophrenia. D -Serine also has been described as a potential biomarker for early Alzheimer's disease (AD) diagnosis, due to a relatively high concentration of it in
170-414: A neuromodulator by coactivating NMDA receptors , making them able to open if they then also bind glutamate . D -serine is a potent agonist at the glycine site (NR1) of canonical diheteromeric NMDA receptors . For the receptor to open, glutamate and either glycine or D -serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg or Zn ). Some research has shown that D -serine
204-471: A non-essential amino acid has come to be considered as conditional, since vertebrates such as humans cannot always synthesize optimal quantities over entire lifespans. Safety of L -serine has been demonstrated in an FDA-approved human phase I clinical trial with Amyotrophic Lateral Sclerosis, ALS , patients (ClinicalTrials.gov identifier: NCT01835782), but treatment of ALS symptoms has yet to be shown. A 2011 meta-analysis found adjunctive sarcosine to have
238-446: A patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). Besides disruption of serine biosynthesis, its transport may also become disrupted. One example is spastic tetraplegia, thin corpus callosum, and progressive microcephaly , a disease caused by mutations that affect the function of the neutral amino acid transporter A . The classification of L -serine as
272-783: A result of abnormal replication during S phase through the uncoupling of replication enzymes helicase and DNA polymerase. These ssDNA structures attract ATR and eventually activates the checkpoint pathway. However, activation of Chk1 is not solely dependent on ATR, intermediate proteins involved in DNA replication are often necessary. Regulatory proteins such as replication protein A, Claspin, Tim/Tipin, Rad 17, TopBP1 may be involved to facilitate Chk1 activation. Additional protein interactions are involved to induce maximal phosphorylation of Chk1. Chk1 activation can also be ATR-independent through interactions with other protein kinases such as PKB/AKT, MAPKAPK and p90/RSK. Also, Chk1 has been shown to be activated by
306-450: A serine/threonine kinase which regulates the G2/M phase transition in fission yeast. Constitutive expression of Chk1 in fission yeast was shown to induce cell cycle arrest. The same gene called Rad27 was identified in budding yeast by Carr and associates. In 1997, homologs were identified in more complex organisms including the fruit fly, human and mouse. Through these findings, it is apparent Chk1
340-417: A variable degree to treatment with L -serine, sometimes combined with glycine. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, as well as for evaluating diagnostic and therapeutic strategies
374-522: A very faint musty aroma. D -Serine is sweet with an additional minor sour taste at medium and high concentrations. Serine deficiency disorders are rare defects in the biosynthesis of the amino acid L -serine. At present three disorders have been reported: These enzyme defects lead to severe neurological symptoms such as congenital microcephaly and severe psychomotor retardation and in addition, in patients with 3-phosphoglycerate dehydrogenase deficiency to intractable seizures. These symptoms respond to
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#1732855063755408-472: Is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene . Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle. In 1993, Beach and associates initially identified Chk1 as
442-584: Is a central component of genome surveillance pathways and is a key regulator of the cell cycle and cell survival. Chk1 is required for the initiation of DNA damage checkpoints and has recently been shown to play a role in the normal (unperturbed) cell cycle. Chk1 impacts various stages of the cell cycle including the S phase, G2/M transition and M phase. In addition to mediating cell cycle checkpoints, Chk1 also contributes to DNA repair processes, gene transcription, egg production, embryo development, cellular responses to HIV infection and somatic cell viability. Chk1
476-518: Is a more potent agonist at the NMDAR glycine site than glycine itself. However, D-serine has been shown to work as an antagonist/inverse co-agonist of t -NMDA receptors through the glycine binding site on the GluN3 subunit. D -serine was thought to exist only in bacteria until relatively recently; it was the second D amino acid discovered to naturally exist in humans, present as a signaling molecule in
510-463: Is a network of signaling pathways that leads to activation of checkpoints, DNA repair and apoptosis to inhibit damaged cells from progressing through the cell cycle. Chk1 is regulated by ATR through phosphorylation, forming the ATR-Chk1 pathway. This pathway recognizes single strand DNA (ssDNA) which can be a result of UV-induced damage, replication stress and inter-strand cross linking. Often ssDNA can be
544-577: Is a positive correlation with Chk1 expression and tumor grade and disease recurrence suggesting Chk1 may promote tumor growth. Chk1 is essential for cell survival and through high levels of expressions in tumors the function may be inducing tumor cell proliferation. Further, a study has demonstrated that targeting Chk1 reactivates the tumour suppressive activity of protein phosphtase 2A (PP2A) complex in cancer cells. Studies have shown complete loss of Chk1 suppresses chemically induce carcinogenesis however Chk1 haploinsufficiency results in tumor progression. Due to
578-399: Is an α- amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − NH 3 form under biological conditions), a carboxyl group (which is in the deprotonated − COO form under biological conditions), and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in
612-495: Is essential for the maintenance of genomic integrity. Chk1 monitors DNA replication in unperturbed cell cycles and responds to genotoxic stress if present. Chk1 recognizes DNA strand instability during replication and can stall DNA replication in order to allow time for DNA repair mechanisms to restore the genome. Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating various repair factors. Furthermore, Chk1 has been associated with three particular aspects of
646-468: Is expressed in the testes and associates with meiotic synaptonemal complexes during the zygonema and pachynema stages. CHEK1 likely acts as an integrator for ATM and ATR signals and may be involved in monitoring meiotic recombination . In mouse oocytes CHEK1 appears to be indispensable for prophase I arrest and to function at the G2/M checkpoint . Serine Serine (symbol Ser or S )
680-548: Is highly conserved from yeast to humans. Human Chk1 is located on chromosome 11 on the cytogenic band 11q22-23. Chk1 has a N-terminal kinase domain, a linker region, a regulatory SQ/TQ domain and a C-terminal domain. Chk1 contains four Ser/Gln residues. Chk 1 activation occurs primarily through the phosphorylation of the conserved sites, Ser-317, Ser-345 and less often at Ser-366. Checkpoint kinases (Chks) are protein kinases that are involved in cell cycle control. Two checkpoint kinase subtypes have been identified, Chk1 and Chk2. Chk1
714-440: Is hydrolyzed to serine by phosphoserine phosphatase ( EC 3.1.3.3 ). In bacteria such as E. coli these enzymes are encoded by the genes serA (EC 1.1.1.95), serC (EC 2.6.1.52), and serB (EC 3.1.3.3). Serine hydroxymethyltransferase (SMHT) also catalyzes the biosynthesis of glycine (retro-aldol cleavage) from serine, transferring the resulting formalddehyde synthon to 5,6,7,8-tetrahydrofolate . However, that reaction
SECTION 20
#1732855063755748-656: Is irreversible. Chk1 must inactivate in order for the cell to transition from the G2 phase into mitosis, Chk1 expression levels are mediated by regulatory proteins. Chk1 has a regulatory role in the spindle checkpoint however the relationship is less clear as compared to checkpoints in other cell cycle stages. During this phase the Chk1 activating element of ssDNA can not be generated suggesting an alternate form of activation. Studies on Chk1 deficient chicken lymphoma cells have shown increased levels of genomic instability and failure to arrest during
782-590: Is necessary to define the underlying interactions. Chk1 has a central role in coordinating the DNA damage response and therefore is an area of great interest in oncology and the development of cancer therapeutics. Initially Chk1 was thought to function as a tumor suppressor due to the regulatory role it serves amongst cells with DNA damage. However, there has been no evidence of homozygous loss of function mutants for Chk1 in human tumors. Instead, Chk1 has been shown to be overexpressed in numerous tumors including breast, colon, liver, gastric and nasopharyngeal carcinoma. There
816-434: Is reversible, and will convert excess glycine to serine. SHMT is a pyridoxal phosphate (PLP) dependent enzyme. Industrially, L -serine is produced from glycine and methanol catalyzed by hydroxymethyltransferase . Racemic serine can be prepared in the laboratory from methyl acrylate in several steps: Hydrogenation of serine gives the diol serinol : Serine is important in metabolism in that it participates in
850-441: The biosynthesis of purines and pyrimidines . It is the precursor to several amino acids including glycine and cysteine , as well as tryptophan in bacteria. It is also the precursor to numerous other metabolites, including sphingolipids and folate , which is the principal donor of one-carbon fragments in biosynthesis. D -Serine, synthesized in neurons by serine racemase from L -serine (its enantiomer ), serves as
884-768: The G1/S transition, S phase and G2/M transition. Furthermore, Chk1 can target Cdc25 indirectly through phosphorylating Nek11. WEE1 kinase and PLK1 are also targeted by Chk1 to induce cell cycle arrest. Phosphorylation of WEE1 kinase inhibits cdk1 which results in cell cycle arrest at the G2 phase. Chk1 has a role in the spindle checkpoint during mitosis thus interacts with spindle assembly proteins Aurora A kinase and Aurora B kinase. Recently, Chk1 has shown to mediate DNA repair mechanisms and does so by activating repair factors such as proliferating cell nuclear antigen (PCNA), FANCE, Rad51 and TLK. Chk1 facilitates replication fork stabilization during DNA replication and repair however more research
918-469: The S-phase, which includes the regulation of late origin firing, controlling the elongation process and maintenance of DNA replication fork stability. In response to DNA damage, Chk1 is an important signal transducer for G2/M checkpoint activation. Activation of Chk1 holds the cell in the G2 phase until ready to enter the mitotic phase. This delay allows time for DNA to repair or cell death to occur if DNA damage
952-509: The Scc1 subunit of the protein cohesin, in zygotes. Chk1 interacts with many downstream effectors to induce cell cycle arrest. In response to DNA damage, Chk1 primarily phosphorylates Cdc25 which results in its proteasomal degradation. The degradation has an inhibitory effect on the formation of cyclin-dependent kinase complexes, which are key drivers of the cell cycle. Through targeting Cdc25, cell cycle arrest can occur at multiple time points including
986-462: The brain, soon after the discovery of D -aspartate . Had D amino acids been discovered in humans sooner, the glycine site on the NMDA receptor might instead be named the D -serine site. Apart from central nervous system, D -serine plays a signaling role in peripheral tissues and organs such as cartilage, kidney, and corpus cavernosum. Pure D -serine is an off-white crystalline powder with
1020-514: The dependence that many cancers may have on the Chk1 pathway. Inhibition of Chk1 allows selective targeting of p53 mutant cells as Chk1 levels are more likely to highly expressed in tumor cells with p53 deficiencies. Even though this method of inhibition is highly targeted, recent research has shown Chk1 also has a role in the normal cell cycle. Therefore, off-target effects and toxicity associated with combination therapies using Chk1 inhibitors must be considered during development of novel therapies. In
1054-407: The human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC. This compound is one of the proteinogenic amino acids . Only the L - stereoisomer appears naturally in proteins. It is not essential to the human diet, since it is synthesized in the body from other metabolites , including glycine . Serine
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1088-409: The possibility of Chk1 involvement in tumor promotion, the kinase and related signaling molecules may be potentially effective therapeutic targets. Cancer therapies utilize DNA damaging therapies such as chemotherapies and ionizing radiation to inhibit tumor cell proliferation and induce cell cycle arrest. Tumor cells with increased levels of Chk1 acquire survival advantages due to the ability to tolerate
1122-438: The spindle checkpoint phase in mitosis. Furthermore, haploinsufficient mammary epithelial cells illustrated misaligned chromosomes and abnormal segregation. These studies suggest Chk1 depletion can lead to defects in the spindle checkpoint resulting in mitotic abnormalities. DNA damage induces the activation of Chk1 which facilitates the initiation of the DNA damage response (DDR) and cell cycle checkpoints. The DNA damage response
1156-614: Was first obtained from silk protein, a particularly rich source, in 1865 by Emil Cramer. Its name is derived from the Latin for silk, sericum . Serine's structure was established in 1902. The biosynthesis of serine starts with the oxidation of 3-phosphoglycerate (an intermediate from glycolysis ) to 3-phosphohydroxypyruvate and NADH by phosphoglycerate dehydrogenase ( EC 1.1.1.95 ). Reductive amination (transamination) of this ketone by phosphoserine transaminase ( EC 2.6.1.52 ) yields 3-phosphoserine ( O -phosphoserine) which
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