Human serine racemase

Key residues/active site motifs and their relation to enzyme function

Danielle L. Graham, Matthew L. Beio, David L. Nelson, David B Berkowitz

Research output: Contribution to journalReview article

Abstract

Serine racemase (SR) is the first racemase enzyme to be identified in human biology and converts L-serine to D-serine, an important neuronal signaling molecule that serves as a co-agonist of the NMDA (N-methyl-D-aspartate) receptor. This overview describes key molecular features of the enzyme, focusing on the side chains and binding motifs that control PLP (pyridoxal phosphate) cofactor binding as well as activity modulation through the binding of both divalent cations and ATP, the latter showing allosteric modulation. Discussed are catalytically important residues in the active site including K56 and S84-the si- and re-face bases, respectively,-and R135, a residue that appears to play a critical role in the binding of both negatively charged alternative substrates and inhibitors. The interesting bifurcated mechanism followed by this enzyme whereby substrate L-serine can be channeled either into D-serine (racemization pathway) or into pyruvate (β-elimination pathway) is discussed extensively, as are studies that focus on a key loop region (the so-called "triple serine loop"), the modification of which can be used to invert the normal in vitro preference of this enzyme for the latter pathway over the former. The possible cross-talk between the PLP enzymes hSR and hCBS (human cystathionine β-synthase) is discussed, as the former produces D-serine and the latter produces H 2 S, both of which stimulate the NMDAR and both of which have been implicated in neuronal infarction pursuant to ischemic stroke. Efforts to gain a more complete mechanistic understanding of these PLP enzymes are expected to provide valuable insights for the development of specific small molecule modulators of these enzymes as tools to study their roles in neuronal signaling and in modulation of NMDAR function.

Original languageEnglish (US)
Article number8
JournalFrontiers in Molecular Biosciences
Volume6
Issue numberMAR
DOIs
StatePublished - Jan 1 2019

Fingerprint

Catalytic Domain
Serine
Enzymes
Pyridoxal Phosphate
Modulation
Cystathionine
Racemases and Epimerases
Molecules
Divalent Cations
Substrates
serine racemase
N-Methyl-D-Aspartate Receptors
Pyruvic Acid
Infarction
Modulators
Adenosine Triphosphate
Stroke

Keywords

  • Allosteric activation/regulation
  • ATP
  • D-serine
  • Elimination
  • Mechanism
  • Pyridoxal phosphate (PLP)
  • Racemization
  • Serine racemase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

Human serine racemase : Key residues/active site motifs and their relation to enzyme function. / Graham, Danielle L.; Beio, Matthew L.; Nelson, David L.; Berkowitz, David B.

In: Frontiers in Molecular Biosciences, Vol. 6, No. MAR, 8, 01.01.2019.

Research output: Contribution to journalReview article

@article{52ced57a1cf24d0e92bb6b92aaaa8279,
title = "Human serine racemase: Key residues/active site motifs and their relation to enzyme function",
abstract = "Serine racemase (SR) is the first racemase enzyme to be identified in human biology and converts L-serine to D-serine, an important neuronal signaling molecule that serves as a co-agonist of the NMDA (N-methyl-D-aspartate) receptor. This overview describes key molecular features of the enzyme, focusing on the side chains and binding motifs that control PLP (pyridoxal phosphate) cofactor binding as well as activity modulation through the binding of both divalent cations and ATP, the latter showing allosteric modulation. Discussed are catalytically important residues in the active site including K56 and S84-the si- and re-face bases, respectively,-and R135, a residue that appears to play a critical role in the binding of both negatively charged alternative substrates and inhibitors. The interesting bifurcated mechanism followed by this enzyme whereby substrate L-serine can be channeled either into D-serine (racemization pathway) or into pyruvate (β-elimination pathway) is discussed extensively, as are studies that focus on a key loop region (the so-called {"}triple serine loop{"}), the modification of which can be used to invert the normal in vitro preference of this enzyme for the latter pathway over the former. The possible cross-talk between the PLP enzymes hSR and hCBS (human cystathionine β-synthase) is discussed, as the former produces D-serine and the latter produces H 2 S, both of which stimulate the NMDAR and both of which have been implicated in neuronal infarction pursuant to ischemic stroke. Efforts to gain a more complete mechanistic understanding of these PLP enzymes are expected to provide valuable insights for the development of specific small molecule modulators of these enzymes as tools to study their roles in neuronal signaling and in modulation of NMDAR function.",
keywords = "Allosteric activation/regulation, ATP, D-serine, Elimination, Mechanism, Pyridoxal phosphate (PLP), Racemization, Serine racemase",
author = "Graham, {Danielle L.} and Beio, {Matthew L.} and Nelson, {David L.} and Berkowitz, {David B}",
year = "2019",
month = "1",
day = "1",
doi = "10.3389/fmolb.2019.00008",
language = "English (US)",
volume = "6",
journal = "Frontiers in Molecular Biosciences",
issn = "2296-889X",
publisher = "Frontiers Media S. A.",
number = "MAR",

}

TY - JOUR

T1 - Human serine racemase

T2 - Key residues/active site motifs and their relation to enzyme function

AU - Graham, Danielle L.

AU - Beio, Matthew L.

AU - Nelson, David L.

AU - Berkowitz, David B

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Serine racemase (SR) is the first racemase enzyme to be identified in human biology and converts L-serine to D-serine, an important neuronal signaling molecule that serves as a co-agonist of the NMDA (N-methyl-D-aspartate) receptor. This overview describes key molecular features of the enzyme, focusing on the side chains and binding motifs that control PLP (pyridoxal phosphate) cofactor binding as well as activity modulation through the binding of both divalent cations and ATP, the latter showing allosteric modulation. Discussed are catalytically important residues in the active site including K56 and S84-the si- and re-face bases, respectively,-and R135, a residue that appears to play a critical role in the binding of both negatively charged alternative substrates and inhibitors. The interesting bifurcated mechanism followed by this enzyme whereby substrate L-serine can be channeled either into D-serine (racemization pathway) or into pyruvate (β-elimination pathway) is discussed extensively, as are studies that focus on a key loop region (the so-called "triple serine loop"), the modification of which can be used to invert the normal in vitro preference of this enzyme for the latter pathway over the former. The possible cross-talk between the PLP enzymes hSR and hCBS (human cystathionine β-synthase) is discussed, as the former produces D-serine and the latter produces H 2 S, both of which stimulate the NMDAR and both of which have been implicated in neuronal infarction pursuant to ischemic stroke. Efforts to gain a more complete mechanistic understanding of these PLP enzymes are expected to provide valuable insights for the development of specific small molecule modulators of these enzymes as tools to study their roles in neuronal signaling and in modulation of NMDAR function.

AB - Serine racemase (SR) is the first racemase enzyme to be identified in human biology and converts L-serine to D-serine, an important neuronal signaling molecule that serves as a co-agonist of the NMDA (N-methyl-D-aspartate) receptor. This overview describes key molecular features of the enzyme, focusing on the side chains and binding motifs that control PLP (pyridoxal phosphate) cofactor binding as well as activity modulation through the binding of both divalent cations and ATP, the latter showing allosteric modulation. Discussed are catalytically important residues in the active site including K56 and S84-the si- and re-face bases, respectively,-and R135, a residue that appears to play a critical role in the binding of both negatively charged alternative substrates and inhibitors. The interesting bifurcated mechanism followed by this enzyme whereby substrate L-serine can be channeled either into D-serine (racemization pathway) or into pyruvate (β-elimination pathway) is discussed extensively, as are studies that focus on a key loop region (the so-called "triple serine loop"), the modification of which can be used to invert the normal in vitro preference of this enzyme for the latter pathway over the former. The possible cross-talk between the PLP enzymes hSR and hCBS (human cystathionine β-synthase) is discussed, as the former produces D-serine and the latter produces H 2 S, both of which stimulate the NMDAR and both of which have been implicated in neuronal infarction pursuant to ischemic stroke. Efforts to gain a more complete mechanistic understanding of these PLP enzymes are expected to provide valuable insights for the development of specific small molecule modulators of these enzymes as tools to study their roles in neuronal signaling and in modulation of NMDAR function.

KW - Allosteric activation/regulation

KW - ATP

KW - D-serine

KW - Elimination

KW - Mechanism

KW - Pyridoxal phosphate (PLP)

KW - Racemization

KW - Serine racemase

UR - http://www.scopus.com/inward/record.url?scp=85065448957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065448957&partnerID=8YFLogxK

U2 - 10.3389/fmolb.2019.00008

DO - 10.3389/fmolb.2019.00008

M3 - Review article

VL - 6

JO - Frontiers in Molecular Biosciences

JF - Frontiers in Molecular Biosciences

SN - 2296-889X

IS - MAR

M1 - 8

ER -