Silvia Sacchi - Academia.edu (original) (raw)
Papers by Silvia Sacchi
Proceedings of the National Academy of Sciences, 2014
Author contributions: J.-M.B. and J.-P.M. designed research; M.L.B., M.M., S.S., N.Y., I.R., S.C.... more Author contributions: J.-M.B. and J.-P.M. designed research; M.L.B., M.M., S.S., N.Y., I.R., S.C., K.A.O., and J.-M.B. performed research; H.W. and L.P. contributed new reagents/ analytic tools; M.L.B., M.M., S.S., J.-M.B., and J.-P.M. analyzed data; and M.M., J.-M.B., and J.-P.M. wrote the paper.
Current Pharmaceutical Design, 2013
Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligan... more Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycinemodulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme (elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction). Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of Dserine improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics. This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DAAO-induced degradation of D-serine may alleviate symptoms in schizophrenic patients. Furthermore, it has been suggested that co-administration of D-serine with a human DAAO inhibitor may be a more effective means of increasing D-serine levels in the brain. Here, we present an overview of the current knowledge of the structure-function relationships in human DAAO and of the compounds recently developed to inhibit its activity (specifically the ones recently exploited for schizophrenia treatment).
Amino Acids
Since D-amino acids were identified in mammals, D-serine has been one of the most extensively stu... more Since D-amino acids were identified in mammals, D-serine has been one of the most extensively studied "unnatural amino acids". This brain-enriched transmitter-like molecule plays a pivotal role in the human central nervous system by modulating the activity of NMDA receptors. Physiological levels of D-serine are required for normal brain development and function; thus, any alterations in neuromodulator concentrations might result in NMDA receptor dysfunction, which is known to be involved in several pathological conditions, including neurodegeneration(s), epilepsy, schizophrenia, and bipolar disorder. In the brain, the concentration of D-serine stored in cells is defined by the activity of two enzymes: serine racemase (responsible for both the synthesis and degradation) and D-amino acid oxidase (which catalyzes D-serine degradation). Both enzymes emerged recently as new potential therapeutic targets for NMDA receptor-related diseases. In this review we have focused on human...
In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation o... more In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation of the neuromodulator D-serine, an important effector of NMDA-receptor mediated neurotransmission. Experimental evidence supports the concept that D-serine concentration increase by hDAAO inhibition may represent a valuable therapeutic approach to improve the symptoms in schizophrenia patients. This study investigated the effects on hDAAO conformation and stability of the substrate D-serine (or of the pseudo-substrate trifluoro-D-alanine), the FAD cofactor, and two inhibitors (benzoate, a classical substrate-competitive inhibitor and the drug chlorpromazine (CPZ), which competes with the cofactor). We demonstrated that all these compounds do not alter the interaction of hDAAO with its physiological partner pLG72. The ligands used affect the tertiary structure of hDAAO differently: benzoate or trifluoro-D-alanine binding increases the amount of the holoenzyme form in solution and stabilizes the flavoprotein, while CPZ binding favors a protein conformation resembling that of the apoprotein, which is more sensitive to degradation. Interestingly, the apoprotein form of hDAAO binds the substrate D-serine: this interaction increases FAD binding thus increasing the amount of active holoenzyme in solution. Benzoate and CPZ similarly modify the short-term cellular D-serine concentration but affect the cellular concentration of hDAAO differently. In conclusion, the different alteration of hDAAO conformation and stability by the ligands used represents a further parameter to take into consideration during the development of new drugs to cope schizophrenia.
Current pharmaceutical design, 2013
Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligan... more Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycine modulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme(elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction).Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of D-serine improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics.This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DA...
... 459 fiDAA 0-pLG72 interaction The interaction between hDAAO and pLG72 was inferred by yeast t... more ... 459 fiDAA 0-pLG72 interaction The interaction between hDAAO and pLG72 was inferred by yeast two-hybrid experiments and preliminary investigated by in vitro experiments using ... t *»' 400 ' / *4:1 !* 300 i ■* 200 F ; 100 i ■ 0.5:1 ■ ni nil 0 2 4 e e hDAAO:pLG72 ratio Figure 3 ...
Proceedings of the National Academy of Sciences, 2014
Author contributions: J.-M.B. and J.-P.M. designed research; M.L.B., M.M., S.S., N.Y., I.R., S.C.... more Author contributions: J.-M.B. and J.-P.M. designed research; M.L.B., M.M., S.S., N.Y., I.R., S.C., K.A.O., and J.-M.B. performed research; H.W. and L.P. contributed new reagents/ analytic tools; M.L.B., M.M., S.S., J.-M.B., and J.-P.M. analyzed data; and M.M., J.-M.B., and J.-P.M. wrote the paper.
Current Pharmaceutical Design, 2013
Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligan... more Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycinemodulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme (elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction). Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of Dserine improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics. This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DAAO-induced degradation of D-serine may alleviate symptoms in schizophrenic patients. Furthermore, it has been suggested that co-administration of D-serine with a human DAAO inhibitor may be a more effective means of increasing D-serine levels in the brain. Here, we present an overview of the current knowledge of the structure-function relationships in human DAAO and of the compounds recently developed to inhibit its activity (specifically the ones recently exploited for schizophrenia treatment).
Amino Acids
Since D-amino acids were identified in mammals, D-serine has been one of the most extensively stu... more Since D-amino acids were identified in mammals, D-serine has been one of the most extensively studied "unnatural amino acids". This brain-enriched transmitter-like molecule plays a pivotal role in the human central nervous system by modulating the activity of NMDA receptors. Physiological levels of D-serine are required for normal brain development and function; thus, any alterations in neuromodulator concentrations might result in NMDA receptor dysfunction, which is known to be involved in several pathological conditions, including neurodegeneration(s), epilepsy, schizophrenia, and bipolar disorder. In the brain, the concentration of D-serine stored in cells is defined by the activity of two enzymes: serine racemase (responsible for both the synthesis and degradation) and D-amino acid oxidase (which catalyzes D-serine degradation). Both enzymes emerged recently as new potential therapeutic targets for NMDA receptor-related diseases. In this review we have focused on human...
In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation o... more In human brain the flavoprotein D-amino acid oxidase (hDAAO) is responsible for the degradation of the neuromodulator D-serine, an important effector of NMDA-receptor mediated neurotransmission. Experimental evidence supports the concept that D-serine concentration increase by hDAAO inhibition may represent a valuable therapeutic approach to improve the symptoms in schizophrenia patients. This study investigated the effects on hDAAO conformation and stability of the substrate D-serine (or of the pseudo-substrate trifluoro-D-alanine), the FAD cofactor, and two inhibitors (benzoate, a classical substrate-competitive inhibitor and the drug chlorpromazine (CPZ), which competes with the cofactor). We demonstrated that all these compounds do not alter the interaction of hDAAO with its physiological partner pLG72. The ligands used affect the tertiary structure of hDAAO differently: benzoate or trifluoro-D-alanine binding increases the amount of the holoenzyme form in solution and stabilizes the flavoprotein, while CPZ binding favors a protein conformation resembling that of the apoprotein, which is more sensitive to degradation. Interestingly, the apoprotein form of hDAAO binds the substrate D-serine: this interaction increases FAD binding thus increasing the amount of active holoenzyme in solution. Benzoate and CPZ similarly modify the short-term cellular D-serine concentration but affect the cellular concentration of hDAAO differently. In conclusion, the different alteration of hDAAO conformation and stability by the ligands used represents a further parameter to take into consideration during the development of new drugs to cope schizophrenia.
Current pharmaceutical design, 2013
Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligan... more Over the years, accumulating evidence has indicated that D-serine represents the endogenous ligand for the glycine modulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas. Cellular concentrations of D-serine are regulated by synthesis due to the enzyme serine racemase (isomerization reaction) and by degradation due to the same enzyme(elimination reaction) as well as by the FAD-containing flavoenzyme D-amino acid oxidase (DAAO, oxidative deamination reaction).Several findings have linked low levels of D-serine to schizophrenia: D-serine concentrations in serum and cerebrospinal fluid have been reported to be decreased in schizophrenia patients while human DAAO activity and expression are increased; oral administration of D-serine improved positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics.This evidence indicates that increasing NMDA receptor function, perhaps by inhibiting DA...
... 459 fiDAA 0-pLG72 interaction The interaction between hDAAO and pLG72 was inferred by yeast t... more ... 459 fiDAA 0-pLG72 interaction The interaction between hDAAO and pLG72 was inferred by yeast two-hybrid experiments and preliminary investigated by in vitro experiments using ... t *»' 400 ' / *4:1 !* 300 i ■* 200 F ; 100 i ■ 0.5:1 ■ ni nil 0 2 4 e e hDAAO:pLG72 ratio Figure 3 ...