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Structure–function relationships in human d-amino acid oxidase

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Abstract

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 d-amino acid oxidase and provide an extensive overview of the biochemical and structural properties of this flavoprotein and their functional significance. Furthermore, we discuss the mechanisms involved in modulating enzyme activity and stability with the aim to substantiate the pivotal role of d-amino acid oxidase in brain d-serine metabolism in physiological and pathological conditions and to highlight its great significance for novel drug design/development.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

BSN:

Bassoon protein

CP:

Choroid plexus

CPZ:

Chlorpromazine

CBIO:

6-Chlorobenzo[d]isoxazol-3-ol

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DAAO:

d-Amino acid oxidase

d-KYN:

d-Kynurenine

DOPA:

3,4-Dihydroxy-phenylalanine

ECFP:

Enhanced cyan fluorescent protein

EYFP:

Enhanced yellow fluorescent protein

FRET:

Fluorescence resonance energy transfer

hDAAO:

Human d-amino acid oxidase

KYNA:

Kynurenic acid

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate type glutamate receptor

pkDAAO:

Porcine kidney d-amino acid oxidase

PTS1:

Peroxisomal targeting signal 1

RMSD:

Root-mean-square deviation

SAP:

Structurally ambivalent peptide

SPR:

Surface plasmon resonance

SR:

Serine racemase

T m :

Melting temperature

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Acknowledgments

This work was supported by grants from Fondo di Ateneo per la Ricerca to L. Pollegioni, S. Sacchi and G. Molla. We are grateful for the support from Consorzio Interuniversitario per le Biotecnologie and Centro Grandi Attrezzature, Università degli studi dell’Insubria.

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  1. Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell’Insubria, via J.H. Dunant 3, 21100, Varese, Italy

    Silvia Sacchi, Laura Caldinelli, Pamela Cappelletti, Loredano Pollegioni & Gianluca Molla

  2. The Protein Factory, Centro Interuniversitario di Biotecnologie Proteiche, Politecnico di Milano, ICRM CNR Milano, Università degli Studi dell’Insubria, Varese, Italy

    Silvia Sacchi, Laura Caldinelli, Loredano Pollegioni & Gianluca Molla

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  1. Silvia Sacchi
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  2. Laura Caldinelli
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  3. Pamela Cappelletti
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  4. Loredano Pollegioni
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  5. Gianluca Molla
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Correspondence to Silvia Sacchi.

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Sacchi, S., Caldinelli, L., Cappelletti, P. et al. Structure–function relationships in human d-amino acid oxidase. Amino Acids 43, 1833–1850 (2012). https://doi.org/10.1007/s00726-012-1345-4

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