Introduction

D-amino acids are being recognized as molecules with function [1-3]. The shibboleth of these stereoisomers being present only in invertebrates has been dispelled. D-serine is a well-studied stereoisomer that functions as a co agonist at the glycine site of the NMDA receptor and associated function [4,5]. NMDA receptor hypofunction has documented significance in schizophrenia. Our unpublished work has shown that D-serine may have additional metabolic roles [6]. We identified endogenous D-cysteine in the developing mammalian brain where it regulates neural progenitor cell proliferation via AKT signaling. D-cysteine is racemized from L-cysteine by serine racemase (SR), the same enzyme that racemizes D-serine from L-serine [7]. The purpose of this mini-review is to showcase a novel stereoisomer D-cysteine, highlight roles for D-serine in neuronal metabolism and raise questions aimed at understanding their function in mammals.

Serine Racemace

Amino acid racemases are enzymes that interconvert L and D stereoisomers. Racemases are comprised of two families, Pyridoxal Phosphate (PLP) cofactor dependent and PLP independent. Well known among the PLP dependent family is serine racemase (E.C 5.1.1.18). SR synthesizes D-serine from L-serine and vice versa in presence of PLP, Mg2+ and DTT. SR is a bifunctional enzyme as it also converts L-serine and D-serine to produce ammonia and pyruvate [8,9].

A recent GWAS study identified SR as a risk factor gene in schizophrenia [10,11]. SR deficient mouse (SR-/-) show decreased NMDAR signaling, altered D-serine metabolism, glutamatergic neurotransmission and elevated anxiety behavior [12]. Our work shows that SR is an effecient cysteine racemase [13]. The importance of SR in neurobiology and psychiatry has been underscored by the seminal works of Solomon Snyder, Joe Coyle, Herman Wolosker and other laboratories [1,14-19].

Cysteine is the fastest racemizing amino acid and its omission in the literature made us curious [20,21]. Using a bioluminescent luciferase assay, chiral chromatography and SR-/- mice, we recently identified endogenous D-cysteine in mammalian brain and pancreas [7]. D-cysteine is enriched in the embryonic mouse brain (E9.5) at a concentration of 4.5 mM and decreases with development to approximately 50 µM. D-cysteine is also enriched in adult human brain (white matter) and in the cerebrospinal fluid at a concentration of approximately 40 µM.

Our work shows that D-cysteine is synthesized by SR and has a different temporal expression profile in the brain compared to D-serine. D-cysteine inhibits neural progenitor cell proliferation and signals via AKT, activating its downstream targets Foxo1, Foxo3a and GSK-3b. This inhibition is not shared by D-serine or L-cysteine.

The temporal distribution profile of mammalian D-cysteine suggests that it may play roles in neural development with possible implications in autism spectrum and schizophrenia [2]. D-Serine. D-serine is also synthesized by SR and serves as a co agonist at the glycine modulatory site of the NMDAR [4].

D-serine is well characterized among the identified D-stereoisomers, highlighting its role in psychiatry [1,4,5,11]. For an in depth review on D serine, the reader is directed to a few excellent references [3,5,11]. Our (unpublished) work on serine metabolism implicates D-serine in adult Sub Ventricular Zone (SVZ) neurogenesis, its actions mediated by alterations in fatty acid metabolism [6].

Lack of D-serine and possibly L-serine in the adult SVZ induces a quiescent state in isolated mouse Neural Stem Cells (NSCs), resulting from local alterations in fatty acid metabolism. Such metabolic alteration leads to loss of membrane lipid microenvironment in NSCs leading to their quiescence [22].

Dysregulation of adult neurogenesis and loss of olfactory behaviour in schizophrenia and mental health disorders now appears to be beyond an epiphenomenon [23,24]. Elucidating the role of D-serine and L-serine in the context of neuronal and astrocytic metabolism may uncover interesting aspects with implications in disorders of adult neurogenesis like Alzheimer’s disease and schizophrenia [25,26].

An explication

A few questions arise from such explication; What is the function of these stereoisomers synthesized by SR? Does SR play different roles during development and in adult?

Dysregulation of adult neurogenesis and loss of olfactory behaviour in schizophrenia and mental health disorders now appears to be beyond an epiphenomenon [23,24]. Elucidating the role of D-serine and L-serine in the context of neuronal and astrocytic metabolism may uncover interesting aspects with implications in disorders of adult neurogenesis like Alzheimer’s disease and schizophrenia [25,26].

If so, what is its expression profile? Is there a redundancy in function of these two stereoisomers, or do they serve specific functions?

What is the purpose of the distinct temporal disposition between D-serine and D-cysteine in the brain? These are a few among the many questions that may be relevant in understanding these two stereoisomers (separated by one atom) in an increasingly complex cellular environment.

Acknowledgement

I acknowledge my mentor Prof. Solomon Snyder (Sol) at the Dept. of Neuroscience, Johns Hopkins School of Medicine, in whose laboratory my work identified endogenous D-cysteine. This silent discovery was the result of brainstorming sessions with Sol, during which I got a glimpse into his legendary mind and a plethora of ideas about these novel molecules.

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