d-Amino acids in the brain: the biochemistry of brain serine racemase

MINIREVIEW

D-Amino acids in the brain: the biochemistry of brainserine racemaseFlorian Baumgart and Ignacio Rodrı́guez-Crespo

Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Ciencias Quı́micas, Universidad Complutense de Madrid, Spain

The initial purification of brain mammalian serine

racemase was performed by Wolosker, Snyder and

coworkers using 60 brains obtained from rats [1]. This

seminal work permitted the isolation of a homo-

geneous protein preparation that displayed the ability

to isomerize l-serine into its enantiomeric d-serine

counterpart. In addition, the authors established the

molecular mass of the enzyme, its pH and temperature

dependence, the presence of bound pyridoxal-5¢ phos-

phate (PLP) and the exquisite activity regulation

exerted by reagents that react with free SH groups,

such as oxidized glutathione. The subsequent mole-

cular cloning of mouse brain serine racemase, as well

as the comparison with PLP-containing racemases

from other organisms, led to the identification of K56

as the lysine residue that formed the Schiff base with

the PLP moiety [2]. The first recombinant expression

and purification experiment was performed by Wolos-

ker and coworkers using HEK293 cells transfected with

a serine racemase–glutathione S-transferase plasmid [3].

Keywords

AMPA receptor; astrocytes; ATP; calcium

activation; D-serine; gliotransmitters; GRIP;

NMDA receptor; PDZ interaction; serine

racemase

Correspondence

I. Rodrı́guez-Crespo, Departamento de

Bioquı́mica y Biologı́a Molecular, Facultad de

Ciencias Quı́micas, Universidad

Complutense, Ciudad Universitaria, 28040

Madrid, Spain

Fax: +34 91 394 4159

Tel: +34 91394 4137

E-mail: [email protected]

(Received 30 January 2008, revised 3 April

2008, accepted 4 April 2008)

doi:10.1111/j.1742-4658.2008.06517.x

It has been recently established that in various brain regions d-serine, the

product of serine racemase, occupies the so-called ‘glycine site’ within

N-methyl d-aspartate receptors. Mammalian brain serine racemase is a

pyridoxal-5¢ phosphate-containing enzyme that catalyzes the racemization

of l-serine to d-serine. It has also been shown to catalyze the a,b-elimina-

tion of water from l-serine or d-serine to form pyruvate and ammonia.

Serine racemase is included within the group of type II-fold pyridoxal-5¢phosphate enzymes, together with many other racemases and dehydratases.

Serine racemase was first purified from rat brain homogenates and later

recombinantly expressed in mammalian and insect cells as well as in

Escherichia coli. It has been shown that serine racemase is activated by

divalent cations like calcium, magnesium and manganese, as well as by

nucleotides like ATP, ADP or GTP. In turn, serine racemase is also

strongly inhibited by reagents that react with free sulfhydryl groups such

as glutathione. Several yeast two-hybrid screens for interaction partners

identified the proteins glutamate receptor interacting protein, protein inter-

acting with C kinase 1 and Golga3 to bind to serine racemase, having

different effects on its catalytic activity or stability. In addition, it has also

been proposed that serine racemase is regulated by phosphorylation. Thus,

d-serine production in the brain is tightly regulated by various factors

pointing at its physiologic importance. In this minireview, we will focus on

the regulation of brain serine racemase and d-serine synthesis by the

factors mentioned above.

Abbreviations

[Ca2+]cyt, cytosolic calcium concentration; AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; AMPAR, AMPA receptor; GluR2,

glutamate receptor subunit 2; Golga3, Golgin subfamily A member 3; GRIP, glutamate receptor interacting protein; GSNO, S-nitroso-

glutathione; NO, nitric oxide; PDZ, PSD95 ⁄ disc large ⁄ ZO-1; PICK1, protein interacting with C kinase 1; PKC, protein kinase C;

PLP, pyridoxal-5¢ phosphate.

3538 FEBS Journal 275 (2008) 3538–3545 ª 2008 The Authors Journal compilation ª 2008 FEBS

The purified enzyme was extremely efficient in terms of

the elimination reaction, using l-serine-O-sulfate as a

substrate and producing pyruvate plus ammonia.

However, this purified enzyme failed to catalyze the

elimination when l-serine was used as a substrate. A

major breakthrough was the observation that both

divalent cations and nucleotides were actually cofac-

tors of serine racemase [4]. Both the racemase and

eliminase reactions of recombinant serine racemase

expressed in mammalian cells when l-serine was used

as a substrate were activated to similar levels in the

presence of divalent cations such as calcium and mag-

nesium [4]. This activation by divalent cations was also

observed when serine racemase was recombinantly

expressed and purified from Escherichia coli [5] or

when it was purified from mouse brain [6]. When

recombinant serine racemase produced in mammalian

cells was used, in terms of d-serine synthesis (racemase

activity) both magnesium and ATP independently acti-

vated the enzyme and their effect was additive. Even

in the presence of the chelating agent EDTA, ATP

was still able to increase serine racemase activity [4]. In

the absence of added ATP, mammalian cells expressing

serine racemase became activated, in terms of pyruvate

production, at about 100 lm magnesium. However, in

the presence of the nucleotide, the amount of magne-

sium needed for half activation was close to 10 lm [4].

Similar data were obtained when the enzyme purified

from bacteria was used: in the absence of added ATP,

calcium activated the racemase activity of the enzyme

at a half-maximal concentration (EC50) of about

26 lm, although using changes in tryptophan fluores-

cence a binding constant for calcium to serine race-

mase was narrowed down to about 6 lm [5]. The

physiological activation of brain serine racemase by

divalent cations is described in detail below.

Very recently, no fewer than six PLP-containing

enzymes having broad sequence homology with human

brain serine racemase have been cloned and recombi-

nantly expressed. Three recombinant plant serine race-

mases have recently been characterized: those of

Arabidopsis thaliana, Hordeum vulgare (barley) and

Oryza sativa (rice) [7,8]. An aspartate racemase that has

a very high homology with brain serine racemase has

recently been cloned and characterized from a bivalve

mollusk [9]. The so-called serine racemase from Saccha-

romyces cerevisiae has been recombinantly expressed in

E. coli and characterized, and its properties seem to

indicate that it is a paralog rather than an ortholog of

mammalian serine racemases [10]. Likewise, the serine

racemase from the hyperthermophylum Pyrobacu-

lum islandicum was both purified and recombinantly

expressed, and the isolated enzymes were characterized

[11]. Finally, the coordinates of the 3D structure of ser-

ine racemase from Schizosaccharomyces pombe, another

enzyme that displays high homology with mammalian

serine racemase, have been recently deposited (Protein

Data Bank code 1WTC). Sequence comparison allowed

us to rationalize the dependence of each of these

enzymes on divalent cations and nucleotides, and on

their binding to other interacting proteins.

Regulation of serine racemase bydivalent cations and nucleotides

The sequence comparison of human brain serine race-

mase with selected homologous proteins is depicted in

Fig. 1. We recently used the coordinates obtained from

the crystal structure of the Mg2+-bound S. pombe

serine racemase and the Ca2+-bound Thermus thermo-

philus threonine deaminase to identify the equivalent

positions within mammalian serine racemase that

would bind the divalent cation [12]. We were able to

predict that the metal is hexavalently coordinated and

that the cation-binding site is formed by two carboxyl-

ate-containing residues, a main-chain carbonyl oxygen

and three well-ordered water molecules. The positions

involved in the interaction with the divalent cation are

marked in orange in Fig. 1. In human serine racemase,

the residues predicted to be directly involved in cal-

cium binding are Glu210, Asp216 and Ala214. Consis-

tent with this prediction, these three residues, which

are conserved in plant and yeast serine racemases,

would be responsible for the Ca2+ ⁄Mg2+ racemase

activation observed for these enzymes [7,8,10]. Con-

versely, the absence of these residues in the bivalve

and Pyrobaculum serine racemases is in agreement with

the absence of increased racemization of these enzymes

induced by Ca2+or Mg2+ [9,11].

The enzyme activation by nucleotides is somehow

more puzzling. For instance, the activation of the

homologous protein E. coli Thr dehydratase by AMP

was observed as early as 1949 [13]. However, in this

bacterial enzyme the nucleotide exerted an allosteric

role, promoting protein oligomerization and activating

the enzyme [14]. In the absence of AMP, the Km of

E. coli Thr deaminase for Thr was 70 mm and it

decreased to 5 mm in the presence of the nucleotide

[15]. The residues participating in the binding of nucle-

otides (shown in red in Fig. 1) could also be predicted

because the crystal structure of the S. pombe serine

racemase has the nucleotide AMPpcp bound [12].

Interestingly, most of the nucleotide-binding sites are

conserved in all the enzymes. However, although mam-

malian serine racemase is strongly activated by nucleo-

tides [4,6,12] this is not the case in their plant

F. Baumgart and I. Rodrı́guez-Crespo Biochemistry of brain serine racemase

FEBS Journal 275 (2008) 3538–3545 ª 2008 The Authors Journal compilation ª 2008 FEBS 3539

Fig. 1. Sequence alignment of human serine racemase (gi:11345492), Arabidopsis thaliana serine racemase (gi:84458483), Hordeum vulgare

(barley) serine racemase (gi:148356707), Bivalve (Scapharca broughtonii) aspartate racemase (gi:86439930), Saccharomyces cerevisiae

homolog of serine racemase (gi:151941446), Schizosaccharomyces pombe serine racemase (gi:71041740) and Pyrobaculum islandicum ser-

ine racemase (gi:83582728). Based on the crystal structure of S. pombe serine racemase, green arrows depict b-strands and yellow barrels

depict a-helices. The modelling has previously been described in detail by Baumgart et al. [12]. The residues involved in calcium binding are

shown in orange and those involved in nucleotide binding are shown in red. Residues involved in the binding to the PLP moiety are shown

in blue, whereas those involved in protein–protein interaction are shown in green. The first four amino acids of the barley serine racemase

and the final 88 amino acids of the Pyrobaculum serine racemase are omitted for clarity. Alignment was performed using the CLUSTAL

software.

Biochemistry of brain serine racemase F. Baumgart and I. Rodrı́guez-Crespo


orthologs [7,8]. In fact, both the bivalve and Pyrobacu-

lum serine racemases are actually inhibited by ATP,

although the former is activated slightly in the pres-

ence of AMP [9,11].

The question hence remains regarding the exact role

of the nucleotide in brain mammalian serine racemase

catalysis because a PLP-dependent racemization does

not require ATP-driven energy. An allosteric role may

provide an explanation. In fact, homology modeling

indicates that the nucleotide is positioned in the mono-

mer ⁄monomer interface [12 and Fig. 2]. In contrast to

the case of E. coli Thr dehydratase mentioned above,

we were unable to observe changes in the oligomeriza-

tion state of recombinant mouse serine racemase in the

presence and absence of added ATP [12]. In fact, all

the recombinant versions of serine racemase mentioned

above are either homodimers [7–9] or homotrimers [11]

in the absence of the nucleotide. Consequently, it is

unlikely that ATP might be regulating the quaternary

structure of serine racemase. In this regard, as noted by

Wolosker and coworkers [4] ATP is not hydrolyzed

during catalysis, because both ADP and a nonhydro-

lyzable analog of ATP are able to activate the enzyme

to a similar extent. Furthermore, in the cytosol the

ATP concentrations are in the 3–6 mm range, an obser-

vation suggesting that serine racemase is always satu-

rated with enough nucleotide to exert its racemase

activity because 100 lm ATP is more than enough to

result in full activity [4,6].

Perhaps it is even more important to know if serine

racemase is activated by Ca2+ or Mg2+ in vivo. In

principle, if the Mg2+ concentration in the cellular

cytosol is indeed 600 lm [4,16], the brain serine race-

mase would always be ‘on’. However, when type II

astrocytes were loaded with radioactive d-serine, its

release would be induced by l-glutamate and kainate,

agents known to increase intracellular calcium concen-

trations [17]. Subsequently, we observed the increased

release of d-serine by primary astrocytes when gluta-

mate, kainate or the calcium ionophore A23187 was

added to the cellular medium [5]. Likewise, C6 glioma

cells increased their secretion of d-serine when

incubated with a-amino-3-hydroxy-5-methylisoxazole-

4-propionic acid (AMPA) [18]. A more direct demon-

stration has been recently performed by Mothet and

coworkers when they showed that d-serine release is

directly related to the increase of cytosolic calcium

concentration ([Ca2+]cyt) [19]. These authors showed

that the removal of extracellular calcium, or the deple-

tion of thapsigargin-sensitive intracellular calcium

stores, abrogated the release of d-serine [19]. It is

conceivable that perhaps the increase of [Ca2+]cyt is

only involved in the secretion of d-serine previously

accumulated in secretion granules [19] although the

storage of d-serine in granules in glia has recently been

ruled out [18]. It is very likely that serine racemase at

various intracellular localizations might be challenged

with different calcium concentrations, hence regulating

its enzymatic activity. For instance, direct coupling of

serine racemase to the AMPA receptor (AMPAR) via

glutamate receptor interacting protein (GRIP) binding

might be one way to regulate its d-serine synthesizing

activity (see below).

Nitrosylation of serineine racemase

Only scant data are available on possible post-transla-

tional modifications of serine racemase in vivo. The

observation that both oxidized glutathione [1,5] and cys-

tamine [5] could inhibit serine racemase provided some

evidence that reactive cysteine residues should be pres-

ent that are essential for serine racemase function. When

we tested if the nitric oxide (•NO) donor DETA

NONOate [(z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)

amino]diazen-1-ium,2-diolate] could alter serine race-

mase activity, we obtained a negative result [5]. Quite

recently, reports of •NO as an inhibitor of serine race-

mase in a glioblastoma cell line added a new aspect to

d-serine-dependent modulation of the glutamatergic

synapse. The authors propose that NMDAR-mediated

calcium entry into postsynaptic neurons entails cal-

cium ⁄ calmodulin-dependent activation of neuronal

nitric oxide synthase and the consequent liberation of•NO. Serine racemase is subsequently nitrosylated and

inhibited, whereas d-amino oxidase, which is thought to

ACP

PLP

ACP

PLP

Ca2+

Ca2+

Fig. 2. Molecular model of human serine racemase, as described

by Baumgart et al. [12]. The calcium ions are depicted as yellow

spheres, the PLP moiety is shown in blue and the nucleotide analo-

gue phosphomethylphosphonic acid adenylate ester (AMP-PCP) is

shown in magenta. The molecular modelling was performed using

the crystal structures of the S. pombe serine racemase and the

E. coli Thr deaminase.



counteract serine racemase activity in vivo by degrada-

tion of d-serine, is upregulated by •NO [20,21]. Subse-

quent biochemical proof for this model was provided

[22], pinning down the residue that becomes modified

and proposing a structural model for the action of •NO.

Apparently, cysteine 113 (out of seven cysteine residues

in the mouse and human serine racemase sequence) can

become nitrosylated, both in the recombinant enzyme

and in transfected cells, using the •NO donor, S-nitroso-

glutathione (GSNO). A molecular model of mouse ser-

ine racemase, based on a yeast homolog, reveals that

residue 113 lies in proximity to the putative ATP-bind-

ing region of the enzyme. Nitrosylation would therefore

lead to impaired nucleotide binding and inactivation of

the enzyme. It is noteworthy that GSNO is known to

modify cysteines not only with •NO but also with gluta-

thione, leading to protein glutathionylation, another

post-translational modification occurring under condi-

tions of oxidative ⁄nitrosative stress. In fact, GSNO is

very frequently used in glutathionylating studies [23]. It

is thus conceivable that purified serine racemase

becomes modified by glutathione together with •NO.

Experiments with milder nitrosylating reagents that lack

a glutathione moiety would unambiguously demon-

strate if serine racemase is, in fact, modified by •NO.

Serine racemase-interacting proteins:GRIP, PICK1 and Golga3

The carboxy-terminal end of both mouse and human

serine racemase display a -Val-serine-Val-COOH

sequence, a motif reminiscent of the type II consensus

sequence for binding to PSD95 ⁄disc large ⁄ ZO-1

(PDZ) domains [24]. PDZ domains are among the

most ubiquitous protein–protein interaction motifs in

metazoan genomes and are especially important in the

nervous system for the assembly of synaptic complexes

and scaffolding [25,26]. After performing a yeast two-

hybrid screen of serine racemase against a rat hippo-

campus and cortex cDNA library, the hepta-PDZ

protein GRIP was identified as a binding partner of

serine racemase [18]. Out of the seven consecutive

PDZ modules found in GRIP, serine racemase was

found to bind specifically to the PDZ6 domain by

means of its C-terminal PDZ-binding motif. Previ-

ously, GRIP had been described to interact with gluta-

mate receptors of the AMPA ⁄ kainate type [27], where

it is responsible for proper trafficking and assembly of

the receptor and accessory proteins. GRIP can bind to

the glutamate receptor subunit 2 (GluR2) subunit of

AMPA receptors via PDZ4 ⁄PDZ5, both PDZ domains

working in concert to establish binding [27,28]. The

finding of serine racemase interacting with the PDZ6

domain of GRIP and being activated was the first

report on cellular interaction partners of serine race-

mase and it raised several intriguing questions. It was

not clear whether GRIP directly activated serine race-

mase or if binding led to a translocation to the prox-

imity of AMPARs in vivo (Fig. 3). Furthermore, the

influence of the other PDZ domains of GRIP was not

investigated. Therefore, other proteins that become

associated with GRIP, using some of the other six

PDZ domains, might modulate the activity of serine

racemase. Conversely, d-serine might also change the

activity of some GRIP-associated proteins. When ser-

ine racemase ⁄GRIP interactions were first studied, it

was proposed that GRIP was released from AMPARs

when they became stimulated and phosphorylated [18],

which would lead to GRIP interacting with serine

racemase in the cytosol where it would bind to and

activate serine racemase. With our own results we were

able to confirm the interaction of GRIP with serine

racemase via PDZ6 [12]. However, we observed that

binding to PDZ6 alone was not sufficient for activa-

tion. Rather, the presence of the rest of the C-terminal

region of GRIP, that is the PDZ7 module and a link-

ing segment between PDZ6 and PDZ7, was required

for full activation of serine racemase, both in vitro and

in vivo. Although these results do not necessarily pre-

clude a translocation process to AMPARs mediated by

GRIP, they do show the direct activation of serine

racemase by GRIP as a result of the concerted inter-

action of several PDZ modules, independent of the

subcellular localization. This PDZ crosstalk, where an

isolated PDZ domain is insufficient to carry out a

specific function, has also been observed in other

examples, for instance in the requirement of both

PDZ4 and PDZ5 for GRIP binding to GluR2 [27,28].

Interestingly, the activating effect of GRIP on serine

racemase results mainly in a change in Vmax. More-

over, the response curve to calcium remains unchanged

upon binding to GRIP under the experimental condi-

tions applied, which indicates that GRIP binding and

regulation by calcium must be regarded as independent

regulation pathways. It has been proposed that serine

racemase activation by GRIP takes place in the cytosol

after AMPAR phosphorylation and concomitant dis-

sociation of GRIP [18]. However, because nothing is

known about the kinetics of this process, the forma-

tion of a ternary complex among the GluR2 subunit

of the AMPA receptor, GRIP and serine racemase

cannot be discounted. It would be plausible that GRIP

brings serine racemase in close proximity to the gluta-

mate-activated channel, where serine racemase might

be close to other calcium channels. Although the

AMPAR is not a calcium channel, it is conceivable



that in certain calcium microdomains serine racemase

could become exposed to temporarily high calcium

concentrations. To shut the system off, GluR2 could

become phosphorylated, in order to release GRIP and

serine racemase, abolishing the transient activation of

serine racemase by calcium (Fig. 3). Because GRIP

can bind to serine racemase, both in the presence and

absence of calcium, it is possible that some other

GRIP-interacting protein that also binds to PDZ6

might disrupt the serine racemase–GRIP interaction,

hence diminishing the activity of the former.

In a similar yeast two-hybrid screen using a human

hippocampal cDNA library, a different PDZ domain-

containing protein was found to interact with serine

racemase, also requiring the C-terminal binding motif

[30]. Protein interacting with C kinase 1 (PICK1) con-

tains one PDZ domain that is required for interacting

with protein kinase C (PKC) [30,31] or serine racemase.

It also contains a Bin ⁄ amphiphysin ⁄Rys domain,

important for the interaction with lipids, and a coiled-

coil domain. Furthermore, it has been shown recently

that the PDZ domain of PICK1 is also capable of inter-

acting with lipid membranes, a property crucial for the

clustering of AMPAR and synaptic plasticity [32].

There are no data available regarding the effect of the

binding of PICK1 on serine racemase activity. There-

fore, biochemical characterization of the role of the

interaction of serine racemase and PICK1 is needed to

judge the importance of these observations. Surely the

interaction of PICK1 with PKC leads to the temptation

to speculate on a possible phosphorylation of serine

racemase by PKC [33]. As yet, however, there are no

data available, either on the details of the interaction of

PICK1 with serine racemase, or on the phosphorylation

of serine racemase.

Considering that the phosphorylation of Ser880 of

the GluR2 subunit of the AMPA receptor, positioned

at the carboxy-terminal end of the polypeptide chain,

disrupts its interaction with PDZ4 ⁄PDZ5 of GRIP, it

is tempting to speculate that phosphorylation of

Ser336 of human serine racemase or of Thr336

of mouse serine racemase might also break their inter-

action with PDZ6 of GRIP. This putative phosphory-

latable residue is located at position -3 of the human

(Ser–Val–Ser–Val-COOH) and mouse (Thr–Val–Ser–

Val-COOH) sequences, respectively, and both are

inserted within amino acid sequences of type II con-

sensus PDZ domain-interacting partners [24,26]. It has

been proposed that PKCa phosphorylates serine race-

mase, probably brought into its proximity by PICK1

binding [33]. This hypothesis would rationalize a novel

mode of regulation of d-serine synthesis through the

activation of nonphosphorylated serine racemase by

the multi-PDZ domain GRIP. We have been unable to

identify PKCa as a kinase that modifies purified

recombinant serine racemase (unpublished data)

although perhaps this might be the case in vivo. In

addition, both the rat and cow serine racemases are

GluR2AMPAR GluR2AMPAR

GluR2AMPAR GluR2AMPAR

L-Ser

D-Ser

C C

CCC

L-Ser

D-Ser

C CP

CP P

P

A B

C DL-Ser

D-Ser

L-Ser

D-Ser

Fig. 3. Proposed modes of interaction

among serine racemase, GRIP and the

AMPAR. (A) A trimeric complex is assumed.

(B) Phosphorylation of the GluR2 subunit of

the AMPAR at Ser880 dissociates GRIP

binding, which remains bound to serine

racemase. (C) Serine racemase is active in

the cytoplasm and does not interact with

GRIP, whereas the latter associates with

the GluR2 subunit. (D) The simultaneous

phosphorylation of the GluR2 subunit of the

AMPAR together with the phosphorylation

of serine racemase releases GRIP to the

cytoplasm in the absence of any dual inter-

action.



truncated in the carboxy-terminal end, hence lacking

GRIP-interacting sequences. Further experiments will

demonstrate if the activation of serine racemase by

GRIP and its binding to PICK1 is exclusively present

in certain mammals or if there is sequence splicing at

this region and both rat and cow do have longer

(as-yet unidentified) versions of serine racemase.

Consequently, at least four different modes of inter-

action can be envisaged among AMPAR, serine race-

mase and GRIP (Fig. 3). Although phosphorylation of

the GluR2 subunit of the AMPAR and the disruption

of its association with GRIP have been unambiguously

demonstrated, the putative carboxy-terminal phosphor-

ylation of serine racemase remains to be established. If

GRIP brings serine racemase towards the proximity of

the calcium channel, a theoretical modulation of the

synthesis of d-serine by calcium concentration can be

postulated, in accordance with recent data [18]. Using

a mouse brain lysate we observed a trimeric GluR2–

GRIP–serine racemase (data not shown) although we

do not know which mechanisms lead to the dissocia-

tion of serine racemase from GRIP. Nevertheless, in

the absence of the association with the AMPAR,

recombinant purified GRIP alone is able to increase

the activity of recombinant purified serine racemase

[12]. We have shown that certain GRIP amino acids,

present further down in the sequence than PDZ6, are

responsible for the majority of the observed activation

of serine racemase by GRIP [12].

In another study to identify binding partners of ser-

ine racemase using the yeast two-hybrid technology,

the Golgi-localized protein, Golgin subfamily A mem-

ber 3 (Golga3), was found to interact with serine race-

mase [34]. In this case, however, no PDZ interactions

with the C-terminal amino acid triplet of serine were

crucial for binding, but instead, the interaction was

established with its N-terminal 66 residues. Binding of

Golga3 increases d-serine synthesis. Intriguingly, this is

achieved through a decrease in ubiquitin ⁄proteasomal

degradation of serine racemase, rather than by modula-

tion of the catalytic rate. Serine racemase was shown to

have an average half-life of about 4.5 h. When Golga3

and serine racemase were cotransfected, both serine

racemase stability and d-serine synthesis increased con-

siderably. Thus, it is important to note that in addition

to the modulators mentioned beforehand which directly

influence the catalysis of serine racemase, indirect

effects such as protein stability or subcellular localiza-

tion should be taken into account when investigating

the precise regulation of serine racemase-dependent

d-serine levels at glutamatergic synapses.

In conclusion, brain serine racemase, a member of

the type II-fold PLP-dependent racemases ⁄dehydrata-

ses, shares several mechanistic properties with other

members of the same family, such as activation by

nucleotides or divalent cations, although its functional-

ity in the brain is also modulated through interaction

with specific glial or neuronal proteins.

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d-Amino acids in the brain: the biochemistry of brain serine racemase

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