Metabolism of the neuromodulator d-serine

Pollegioni, Loredano; Sacchi, Silvia

doi:10.1007/s00018-010-0307-9

Cited by 111 publications

(90 citation statements)

References 115 publications

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“…D-serine is synthesized from L-serine by SR, a pyridoxal 5¢-phosphatedependent enzyme that catalyzes also the elimination of water from L-serine and D-serine, generating pyruvate and ammonia (De Miranda et al, 2002). D-serine level is also regulated by DAAO, a peroxisomal enzyme whose function is to oxidize D-amino acids to the corresponding imino acids producing ammonia and hydrogen peroxide (Pollegioni & Sacchi, 2010).…”

Section: Introductionmentioning

confidence: 99%

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

et al. 2012

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SummaryRecent data indicate that age-related N-methyl-D-aspartate receptor (NMDAR) transmission impairment is correlated with the reduction in serine racemase (SR) expression and D-serine content. As apoptosis is associated with several diseases and conditions that generally occur with age, we investigated the modulation of SR ⁄ D-serine pathway during neuronal apoptosis and its impact on survival. We found that in cerebellar granule neurons (CGNs), undergoing apoptosis SR/D-serine pathway is crucially regulated. In the early phase of apoptosis, the expression of SR is reduced, both at the protein and RNA level through pathways, upstream of caspase activation, involving ubiquitin proteasome system (UPS) and c-Jun N-terminal kinases (JNKs). Forced expression of SR, together with treatment with NMDA and D-serine, blocks neuronal death, whereas pharmacological inhibition and Sh-RNA-mediated suppression of endogenous SR exacerbate neuronal death. In the late phase of apoptosis, the increased expression of SR contribute to the last, NMDAR-mediated, wave of cell death. These findings are relevant to our understanding of neuronal apoptosis and NMDAR activity regulation, raising further questions as to the role of SR/D-serine in those neuro-pathophysiological processes, such as aging and neurodegenerative diseases characterized by a convergence of apoptotic mechanisms and NMDAR dysfunction.

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Section: Introductionmentioning

confidence: 99%

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

et al. 2012

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“…In mammals, D-serine is produced by a bifunctional serine racemase/dehydratase (7) and is mainly degraded by D-amino acid oxidase (2,7). In rat brains, the localization of D-amino acid oxidase activity is reciprocal to that of D-serine (8,9), suggesting that D-amino acid oxidase determines the basal levels of D-serine in mammalian brains.…”

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Crystal Structure of a Zinc-dependent d-Serine Dehydratase from Chicken Kidney

Tanaka

Senda

Venugopalan

et al. 2011

Journal of Biological Chemistry

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D-Serine is a co-agonist of the NMDA receptor, an excitatory neurotransmitter receptor important for higher brain functions, including learning and memory (1, 2). The NMDA receptor is a glutamate-gated ion channel (3), and glutamate does not activate the receptor unless a co-agonist binding site is simultaneously occupied by D-serine or glycine (4). Because significant concentrations of D-serine exist in vertebrate brains (5), D-serine is believed to physiologically control the sensitivity of the NMDA receptor to glutamate (6).In mammals, D-serine is produced by a bifunctional serine racemase/dehydratase (7) and is mainly degraded by D-amino acid oxidase (2, 7). In rat brains, the localization of D-amino acid oxidase activity is reciprocal to that of D-serine (8, 9), suggesting that D-amino acid oxidase determines the basal levels of D-serine in mammalian brains. However, we have found recently that, in the chicken brain, D-serine is degraded mainly by a D-serine dehydratase (DSD) 4 (10), which catalyzes the ␣,␤-elimination of water from D-serine to form pyruvate and ammonia. In addition, we have found that the chicken DSD (chDSD) has a primary structure similar to those of metal-activated D-threonine aldolases (11-13), which are fold-type III PLP-dependent enzymes (14), and is distinct from a well known metal-independent bacterial DSD (dsdA) belonging to the foldtype II PLP-dependent enzyme family (14,15). Interestingly, a fold-type III family protein coded by gene YGL196W of Saccharomyces cerevisiae was recently identified as a zinc-dependent DSD (scDSD) (16). To understand why avian species use DSD to metabolize D-serine in the brain and its physiological functions, it is important to reveal the structural and enzymatic properties of this novel DSD family.In the present study, we showed that chDSD requires Zn 2ϩ just as scDSD does. Then, to reveal the catalytic roles of Zn 2ϩ in the dehydration of D-serine, we determined the crystal structures of chDSD, EDTA-treated chDSD, and the EDTA-treated chDSD⅐D-serine complex. Although there is only one DSD entry in the Protein Data Bank (PDB), DSD from Burkholderia xenovorans LB400 (PDB code 3GWQ), the structure contains neither PLP nor zinc, and the enzymatic properties of this DSD *

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“…Modulation of glycine concentration is considered a main goal of modern neurochemistry since the relative contribution of glycine and D-serine to NMDAR activity in different brain regions is of central relevance for understanding neurotransmission mechanisms under both physiological and pathological conditions [2,21]. Accordingly, a specific biosensor for detecting glycine in biological fluids is of utmost importance.…”

Section: Discussionmentioning

confidence: 99%

“…The novel sensing assay shows a detection limit ≤ 0.5 lM (slightly lower than commercial assay kits) and was used to assay glycine and sarcosine in biological fluid, i.e. in a U87 glioblastoma cell line used to study the modulation of D-serine level by the catabolic enzyme D-amino acid oxidase [18,25]; D-serine and glycine are alternative ligands required, together with glutamate, to activate NMDARs [21,26]. The glycine concentration detected by the H244K GO-based assay was in good agreement with the value obtained by using the reference HPLC method (7.5 versus 6.7 lM, respectively) but in 1 s, compared with the 60 min required by chromatographic separation.…”

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Novel biosensors based on optimized glycine oxidase

et al. 2014

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Glycine is involved in several physiological functions, e.g. as a neurotransmitter in the central nervous system, and sarcosine has been identified as a differential metabolite greatly enhanced during prostate cancer progression and metastasis. Glycine oxidase from Bacillus subtilis (GO) was engineered with the final aim of producing specific analytical systems to detect these small achiral amino acids. Based on in silico analysis, site-saturation mutagenesis was independently performed at 11 positions: a total of 16 single-point GO variants were analyzed. Significantly improved kinetic parameters were observed on glycine for the A54R, H244K-N-Q-R, Y246W and M261R variants. The introduction of multiple mutations then identified the H244K/M261R variant showing a 5.4-fold increase in maximal activity on glycine. With sarcosine as substrate, a number of single-point variants showed increased maximal activity and/or affinity: the kinetic efficiency was increased 6-fold for the M49L variant. Two GO variants with a high substrate specificity ratio for glycine (versus sarcosine, i.e. H244K GO) or for sarcosine (versus glycine, i.e. M49L GO) combined with high substrate affinity were used to set up a simple fluorescence-based biosensor. This optical sensing assay represents a novel, inexpensive and fast tool to assay glycine or sarcosine concentrations in biological samples (detection limit ≤ 0.5 lM). IntroductionGlycine is the smallest and the only nonchiral natural a-amino acid used for protein biosynthesis. In addition to such a structural role, it possesses further physiological functions: it is an important biosynthetic precursor (i.e. it is used for de novo synthesis of porphyrins and purines) and it acts as a neurotransmitter in the central nervous system. Glycine is a coagonist, together with D-serine, of glutamate at glutamatergic N-methyl-Daspartate receptors (NMDARs) in the forebrain [1], thus serving both inhibitory and excitatory functions [2]. Due to this role, glycine is probably involved in the pathophysiology of schizophrenia and other neurological diseases. For example, a correlation exists between low levels of glycine and catatonia (a psychiatric disease), and the perturbation of the glycine deportation system is associated with ifosfamide encephalopathy and congenital nonketotic hyperglycinemia [2].Sarcosine, 2-(methylamino)acetic acid or N-methylglycine, is a natural, small, endogenous amino acid present in low concentrations in the blood and in urine. It has been proposed to play a role in the progression of prostate cancer, and assessing sarcosine concentrations in body fluids was suggested as a novel biomarker for prostate cancer [3]. With the final aim of developing a biosensor to assay glycine and sarcosine in biological fluids, we engineered glycine oxidase from Bacillus subtilis (GO) (EC 1.4.3.19) to improve its kinetic efficiency on these two compounds. GO is a homotetrameric flavoenzyme that contains one molecule of noncovalently bound FAD per 47 kDa protein monomer [4,5]. Purified recomb...

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Metabolism of the neuromodulator d-serine

Cited by 111 publications

References 115 publications

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

Crystal Structure of a Zinc-dependent d-Serine Dehydratase from Chicken Kidney

Novel biosensors based on optimized glycine oxidase

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