serine racemase
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2021 ◽  
Vol 41 (12) ◽  
Author(s):  
Fabio K. Tamaki

Abstract The analysis of the urine contents can be informative of physiological homoeostasis, and it has been speculated that the levels of urinary d-serine (d-ser) could inform about neurological and renal disorders. By analysing the levels of urinary d-ser using a d-ser dehydratase (DSD) enzyme, Ito et al. (Biosci. Rep.(2021) 41, BSR20210260) have described abundant levels of l-erythro-β-hydroxyasparagine (l-β-EHAsn), a non-proteogenic amino acid which is also a newly described substrate for DSD. The data presented support the endogenous production l-β-EHAsn, with its concentration significantly correlating with the concentration of creatinine in urine. Taken together, these results could raise speculations that l-β-EHAsn might have unexplored important biological roles. It has been demonstrated that l-β-EHAsn also inhibits serine racemase with Ki values (40 μM) similar to its concentration in urine (50 μM). Given that serine racemase is the enzyme involved in the synthesis of d-ser, and l-β-EHAsn is also a substrate for DSD, further investigations could verify if this amino acid would be involved in the metabolic regulation of pathways involving d-ser.


2021 ◽  
Author(s):  
Fabio Kendi Tamaki

The analysis of the urine contents can be informative of physiological homeostasis, and it has been speculated that the levels of urinary D-serine (D-ser) could inform about neurological and renal disorders. By analysing the levels of urinary D-ser using a D-ser dehydratase (DSD) enzyme, Ito et al. have described abundant levels of L-β-EHAsn, a non-proteogenic amino acid which is also a newly described substrate for DSD. The data presented supports the endogenous production L-β-EHAsn, with its concentration significantly correlating with the concentration of creatinine in urine. Taken together, these results could raise speculations that L-β-EHAsn might have unexplored important biological roles. It has been demonstrated that L-β-EHAsn also inhibits serine racemase with Ki values (40 μM) similar to its concentration in urine (50 μM). Given that serine racemase is the enzyme involved in the synthesis of D-ser, and L-β-EHAsn is also a substrate for DSD, further investigations could verify if this amino acid would be involved in the metabolic regulation of pathways involving D-ser.


2021 ◽  
Author(s):  
Xiaqing Yuan ◽  
Shanshan Diao ◽  
Shujun Chen ◽  
Jiajie Lu ◽  
Haitao Shen ◽  
...  

Abstract D-Serine is thought to be involved in N-methyl-D-aspartate (NMDA)-type glutamate receptor-mediated neurotoxicity and plays a pathophysiologic role in stroke. D-Serine is synthesized by serine racemase (SR), which directly converts L-serine into D-serine. The deletion of SR has been reported to protect against cerebral ischemia damage. Additionally, SR catalytic activity is physiologically regulated by its binding to stargazin. However, whether the stargazin-SR interaction affects the level of stroke damage remains elusive. We showed that cerebral ischemia increased the interaction of stargazin and SR and decreased the levels of D-serine. Disrupting the stargazin-SR interaction by knocking down stargazin aggravated cerebral ischemic insults. We found that cerebral ischemia decreased the phosphorylation of stargazin at the Thr-321 residue, which was phosphorylated by cAMP-dependent protein kinase A (PKA). Treatment with the PKA inhibitor H89 blocked stargazin T321 phosphorylation, augmented the stargazin-SR interaction, decreased D-serine levels, and alleviated focal cerebral ischemic damage in rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). Thus, the stargazin-SR interaction is a promising strategy in the treatment of stroke.


2021 ◽  
Vol 12 ◽  
Author(s):  
Magdalena Orzylowski ◽  
Esther Fujiwara ◽  
Darrell D. Mousseau ◽  
Glen B. Baker

Dementia, of which Alzheimer's disease (AD) is the most common form, is characterized by progressive cognitive deterioration, including profound memory loss, which affects functioning in many aspects of life. Although cognitive deterioration is relatively common in aging and aging is a risk factor for AD, the condition is not necessarily a part of the aging process. The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-Serine is necessary for activation of the NMDAR and in maintenance of long-term potentiation (LTP) and is involved in brain development, neuronal connectivity, synaptic plasticity and regulation of learning and memory. In this paper, we review evidence, from both preclinical and human studies, on the involvement of D-serine (and the enzymes involved in its metabolism) in regulation of cognition. Potential mechanisms of action of D-serine are discussed in the context of normal aging and in dementia, as is the potential for using D-serine as a potential biomarker and/or therapeutic agent in dementia. Although there is some controversy in the literature, it has been proposed that in normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.


2021 ◽  
Author(s):  
Tian A. Qiu ◽  
Harvey M. Andersen ◽  
Nissa J. Larson ◽  
Nathan E. Schroeder ◽  
Jonathan V. Sweedler

Free D-serine (D-Ser) is a potent co-agonist of the N-methyl-D-aspartate receptor (NMDAR) in glutamate neurotransmission and regulates NMDAR functions in the nervous system. Serine racemases convert L-serine to D-Ser and are believed to be the major source of D-Ser in animals. In Caenorhabditis elegans, a knockout of the serine racemase serr-1 results in behavioral changes, but the level of D-Ser is unaffected. By growing C. elegans on peptone-free nematode growth medium (PF-NGM), we delineated the sources of D-Ser, both exogenous from peptone in culturing media and endogenous from the serine racemase serr-1, and a potential serine/aspartate racemase candidate, Y51H7C.9, identified by sequence similarity network analysis. We also discovered a new serine dehydratase (aka serine ammonia-lyase), K01C8.1, in C. elegans. We identified the serr-1 knockout and PF-NGM culturing conditions as two independent factors that impact C. elegans locomotion behavior after off-food, both short-term and long-term, and no interactions were found between the two factors.


Author(s):  
Shekib Ahmad Jami ◽  
Scott Cameron ◽  
Jonathan M Wong ◽  
Emily R Daly ◽  
A. Kimberly McAllister ◽  
...  

There is substantial evidence that both NMDA receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. While models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR co-agonist d-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically-driven neuronal excitability without changes in intrinsic excitability. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading to disrupted feedback inhibition and impaired neuronal synchrony.


2021 ◽  
Vol 8 ◽  
Author(s):  
Silvia Sacchi ◽  
Valentina Rabattoni ◽  
Matteo Miceli ◽  
Loredano Pollegioni

In the central nervous system, the flavoprotein D-amino acid oxidase is responsible for catabolizing D-serine, the main endogenous coagonist of N-methyl-D-aspartate receptor. Dysregulation of D-serine brain levels in humans has been associated with neurodegenerative and psychiatric disorders. This D-amino acid is synthesized by the enzyme serine racemase, starting from the corresponding L-enantiomer, and degraded by both serine racemase (via an elimination reaction) and the flavoenzyme D-amino acid oxidase. To shed light on the role of human D-amino acid oxidase (hDAAO) in D-serine metabolism, the structural/functional relationships of this enzyme have been investigated in depth and several strategies aimed at controlling the enzymatic activity have been identified. Here, we focused on the effect of post-translational modifications: by using a combination of structural analyses, biochemical methods, and cellular studies, we investigated whether hDAAO is subjected to nitrosylation, sulfhydration, and phosphorylation. hDAAO is S-nitrosylated and this negatively affects its activity. In contrast, the hydrogen sulfide donor NaHS seems to alter the enzyme conformation, stabilizing a species with higher affinity for the flavin adenine dinucleotide cofactor and thus positively affecting enzymatic activity. Moreover, hDAAO is phosphorylated in cerebellum; however, the protein kinase involved is still unknown. Taken together, these findings indicate that D-serine levels can be also modulated by post-translational modifications of hDAAO as also known for the D-serine synthetic enzyme serine racemase.


2021 ◽  
Vol 145 ◽  
pp. 104990
Author(s):  
Oluwarotimi O. Folorunso ◽  
Theresa L. Harvey ◽  
Stephanie E. Brown ◽  
Cristina Cruz ◽  
Ellie Shahbo ◽  
...  

2021 ◽  
Vol 41 (4) ◽  
Author(s):  
Tomokazu Ito ◽  
Mayuka Tono ◽  
Yasuyuki Kitaura ◽  
Hisashi Hemmi ◽  
Tohru Yoshimura

Abstract In the present study, we identified l-erythro-β-hydroxyasparagine (l-β-EHAsn) found abundantly in human urine, as a novel substrate of Zn2+-dependent d-serine dehydratase (DSD). l-β-EHAsn is an atypical amino acid present in large amounts in urine but rarely detected in serum or most organs/tissues examined. Quantitative analyses of urinary l-β-EHAsn in young healthy volunteers revealed significant correlation between urinary l-β-EHAsn concentration and creatinine level. Further, for in-depth analyses of l-β-EHAsn, we developed a simple three-step synthetic method using trans-epoxysuccinic acid as the starting substance. In addition, our research revealed a strong inhibitory effect of l-β-EHAsn on mammalian serine racemase, responsible for producing d-serine, a co-agonist of the N-methyl-d-aspartate (NMDA) receptor involved in glutamatergic neurotransmission.


2021 ◽  
Author(s):  
Chloe R. Koulouris ◽  
Sian E. Gardiner ◽  
Tessa K. Harris ◽  
Karen T. Elvers ◽  
S. Mark Roe ◽  
...  

ABSTRACTHuman serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a ‘closed’ hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the ATP a-phosphate. In contrast, in ‘open’ hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84. The ability to regulate SR activity by flipping Tyr121 from the core of the small domain to the dimer interface appears to have evolved in animals with a CNS. Multiple X-ray crystallographic enzymefragment structures show that Tyr121 is flipped out of its pocket, suggesting that this pocket is druggable.


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