Serine racemase

Last updated
SRR
Crystal structure of serine racemase 3hmk.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SRR , ILV1, ISO1, serine racemase
External IDs OMIM: 606477 MGI: 1351636 HomoloGene: 22775 GeneCards: SRR
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001304803
NM_021947

NM_001163311
NM_013761
NM_001362742
NM_001362743
NM_001362744

Contents

RefSeq (protein)

NP_001291732
NP_068766

NP_001156783
NP_038789
NP_001349671
NP_001349672
NP_001349673

Location (UCSC) Chr 17: 2.3 – 2.33 Mb Chr 11: 74.8 – 74.82 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Serine racemase (SR, EC 5.1.1.18) is the first racemase enzyme in human biology to be identified. This enzyme converts L-serine to its enantiomer form, D-serine. D-serine acts as a neuronal signaling molecule by activating NMDA receptors in the brain.

Since NMDA receptors Dysfunction has been suggested as one of the promising hypotheses for the pathophysiology of schizophrenia, it has been shown that underexpression of this enzyme is an indicator, especially for the paranoid subtype. [5] Treatment of schizophrenia with D-serine has been shown to play some role in ameliorating some symptoms. [6]

In humans, the serine racemase protein is encoded by the SRR gene. [7] Serine racemase may have evolved from L-thre-hydroxyaspartate (L-THA) eliminase and served as the precursor to aspartate racemase. [8]

Mammalian serine racemase is a pyridoxal 5'-phosphate dependent enzyme that catalyzes both the racemization of L-serine to D-serine and also the elimination of water from L-serine, generating pyruvate and ammonia through the β-elimination of L-serine. [9] This makes serine a known bifurcating enzyme. The β-elimination pathway is thought to serve as a bleed valve that allows local stores of L-serine to be diverted away from D-serine as a means of muting the D-serine signaling pathway. The canonical tetraglycine loop that serves as a PLP phosphate binding pocket includes the active residues being F55, K56, G185, G186, G187, G188, and S313. [10]

PLP in serine racemase PLPwithresidues.png
PLP in serine racemase

The enzyme is physiologically stimulated by divalent cations (e.g., magnesium) and is allosterically activated by the magnesium/ATP complex, associated with a conformational change upon nucleotide binding that depends upon interactions with Q89. The canonical coordination sphere of the divalent cation interaction site includes the active residues E210 and D216 within 2.1 angstroms of the ion. [11]

Divalent cation (Mn) in serine racemase Mnwithresidues.png
Divalent cation (Mn) in serine racemase

Related Research Articles

Serine is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

<span class="mw-page-title-main">Protein tyrosine phosphatase</span> Class of enzymes

Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:

<span class="mw-page-title-main">Cycloserine</span> Tuberculosis medication

Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. It is given by mouth.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">Cathepsin C</span> Human protease (enzyme)

Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the CTSC gene.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">TPH2</span> Protein-coding gene in the species Homo sapiens

Tryptophan hydroxylase 2 (TPH2) is an isozyme of tryptophan hydroxylase found in vertebrates. In humans, TPH2 is primarily expressed in the serotonergic neurons of the brain, with the highest expression in the raphe nucleus of the midbrain. Until the discovery of TPH2 in 2003, serotonin levels in the central nervous system were believed to be regulated by serotonin synthesis in peripheral tissues, in which tryptophan hydroxylase is the dominant form.

In enzymology, an aspartate racemase is an enzyme that catalyzes the following chemical reaction:

<span class="mw-page-title-main">Serine C-palmitoyltransferase</span>

In enzymology, a serine C-palmitoyltransferase (EC 2.3.1.50) is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">KLK6</span> Protein-coding gene in the species Homo sapiens

Kallikrein-6 is a protein that in humans is encoded by the KLK6 gene. Kallikrein-6 is also referred to as neurosin, protease M, hK6, or zyme. It is a 223 amino acid sequence, derived from its 244 original form, which contains a 16 residue presignal and 5 residue activation peptide.

<span class="mw-page-title-main">PSPH</span> Enzyme found in humans

Phosphoserine phosphatase is an enzyme that in humans is encoded by the PSPH gene.

<span class="mw-page-title-main">ZDHHC8</span> Protein-coding gene in the species Homo sapiens

ZDHHC8 is a putative palmitoyltransferase enzyme containing a DHHC domain that in humans is encoded by the ZDHHC8 gene.

<span class="mw-page-title-main">PPP3CC</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform (PP2BC) is an enzyme that in humans is encoded by the PPP3CC gene.

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

<span class="mw-page-title-main">UHMK1</span> Protein-coding gene in the species Homo sapiens

U2AF homology motif (UHM) kinase 1, also known as UHMK1, is a protein which in humans is encoded by the UHMK1 gene.

<span class="mw-page-title-main">Zinc finger protein 804A</span> Protein found in humans

Zinc finger protein 804A is a protein that in humans is encoded by the ZNF804A gene. The human gene maps to chromosome 2 q32.1 and consists of 4 exons that code for a protein of 1210 amino acids.

<span class="mw-page-title-main">CDPPB</span> Chemical compound

CDPPB is a drug used in scientific research which acts as a positive allosteric modulator selective for the metabotropic glutamate receptor subtype mGluR5. It has antipsychotic effects in animal models, and mGluR5 modulators are under investigation as potential drugs for the treatment of schizophrenia, as well as other applications.

<span class="mw-page-title-main">ABCA13</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family A member 13 also known as ABCA13 is a protein that in humans is encoded by the ABCA13 gene on chromosome 7. It belongs to the wide ATP-binding cassette family of proteins. The protein contains 5058 residues, and is currently the largest known protein of the ABC family.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000167720 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001323 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Morita, Yukitaka; Ujike, Hiroshi; Tanaka, Yuji; Otani, Kyohei; Kishimoto, Makiko; Morio, Akiko; Kotaka, Tatsuya; Okahisa, Yuko; Matsushita, Masayuki; Morikawa, Akiko; Hamase, Kenji (May 2007). "A Genetic Variant of the Serine Racemase Gene Is Associated with Schizophrenia". Biological Psychiatry. 61 (10): 1200–1203. doi:10.1016/j.biopsych.2006.07.025. PMID   17067558. S2CID   8142062.
  6. Fujii, K; Maeda, K; Hikida, T; Mustafa, A K; Balkissoon, R; Xia, J; Yamada, T; Ozeki, Y; Kawahara, R; Okawa, M; Huganir, R L (2006-02-01). "Serine racemase binds to PICK1: potential relevance to schizophrenia". Molecular Psychiatry. 11 (2): 150–157. doi:10.1038/sj.mp.4001776. ISSN   1359-4184. PMID   16314870. S2CID   23387084.
  7. De Miranda J, Santoro A, Engelender S, Wolosker H (Oct 2000). "Human serine racemase: moleular cloning, genomic organization and functional analysis". Gene. 256 (1–2): 183–8. doi:10.1016/S0378-1119(00)00356-5. PMID   11054547.
  8. Graham, Danielle L.; Beio, Matthew L.; Nelson, David L.; Berkowitz, David B. (2019-03-13). "Human Serine Racemase: Key Residues/Active Site Motifs and Their Relation to Enzyme Function". Frontiers in Molecular Biosciences. 6: 8. doi: 10.3389/fmolb.2019.00008 . ISSN   2296-889X. PMC   6424897 . PMID   30918891.
  9. De Miranda J, Panizzutti R, Foltyn VN, Wolosker H (Oct 2002). "Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14542–7. Bibcode:2002PNAS...9914542D. doi: 10.1073/pnas.222421299 . PMC   137919 . PMID   12393813.
  10. Graham, Danielle L.; Beio, Matthew L.; Nelson, David L.; Berkowitz, David B. (2019-03-13). "Human Serine Racemase: Key Residues/Active Site Motifs and Their Relation to Enzyme Function". Frontiers in Molecular Biosciences. 6: 8. doi: 10.3389/fmolb.2019.00008 . ISSN   2296-889X. PMC   6424897 . PMID   30918891.
  11. Graham, Danielle L.; Beio, Matthew L.; Nelson, David L.; Berkowitz, David B. (2019-03-13). "Human Serine Racemase: Key Residues/Active Site Motifs and Their Relation to Enzyme Function". Frontiers in Molecular Biosciences. 6: 8. doi: 10.3389/fmolb.2019.00008 . ISSN   2296-889X. PMC   6424897 . PMID   30918891.

Further reading