Aminophosphonate inhibitors of dialkylglycine decarboxylase: Structural basis for slow binding inhibition

Wenshe Liu, Claude J. Rogers, Andrew J Fisher, Michael D. Toney

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The kinetics of inhibition of dialkylglycine decarboxylase by five aminophosphonate inhibitors are presented. Two of these [(R)-1-amino-1-methylpropanephosphonate and (S)-1-aminoethanephosphonate] are slow binding inhibitors. The inhibitors follow a mechanism in which a weak complex is rapidly formed, followed by slow isomerization to the tight complex. Here, the tight complexes are bound 10-fold more tightly than the weak, initial complexes. The slow onset inhibition occurs with t1/2 values of 1.3 and 0.55 min at saturating inhibitor concentrations for the AMPP and S-AEP inhibitors, respectively, while dissociation of these inhibitor complexes occurs with t1/2 values of 13 and 4.6 min, respectively. The X-ray structures of four of the inhibitors in complex with dialkylglycine decarboxylase have been determined to resolutions ranging from 2.6 to 2.0 Å, and refined to R-factors of 14.5-19.5%. These structures show variation in the active site structure with inhibitor side chain size and slow binding character. It is proposed that the slow binding behavior originates in an isomerization from an initial complex in which the PLP pyridine nitrogen-D243 OD2 distance is ∼2.9 Å to one in which it is ∼2.7 Å. The angles that the C-P bonds make with the p orbitals of the aldimine π system are correlated with the reactivities of the analogous amino acid substrates, suggesting a role for stereoelectronic effects in Schiff base reactivity.

Original languageEnglish (US)
Pages (from-to)12320-12328
Number of pages9
JournalBiochemistry
Volume41
Issue number41
DOIs
StatePublished - Oct 15 2002

Fingerprint

2,2-dialkylglycine decarboxylase
Isomerization
R388
Schiff Bases
Catalytic Domain
Nitrogen
X-Rays
Amino Acids
X rays
Kinetics
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Aminophosphonate inhibitors of dialkylglycine decarboxylase : Structural basis for slow binding inhibition. / Liu, Wenshe; Rogers, Claude J.; Fisher, Andrew J; Toney, Michael D.

In: Biochemistry, Vol. 41, No. 41, 15.10.2002, p. 12320-12328.

Research output: Contribution to journalArticle

Liu, Wenshe ; Rogers, Claude J. ; Fisher, Andrew J ; Toney, Michael D. / Aminophosphonate inhibitors of dialkylglycine decarboxylase : Structural basis for slow binding inhibition. In: Biochemistry. 2002 ; Vol. 41, No. 41. pp. 12320-12328.
@article{008312111baa4848a473d313880c3680,
title = "Aminophosphonate inhibitors of dialkylglycine decarboxylase: Structural basis for slow binding inhibition",
abstract = "The kinetics of inhibition of dialkylglycine decarboxylase by five aminophosphonate inhibitors are presented. Two of these [(R)-1-amino-1-methylpropanephosphonate and (S)-1-aminoethanephosphonate] are slow binding inhibitors. The inhibitors follow a mechanism in which a weak complex is rapidly formed, followed by slow isomerization to the tight complex. Here, the tight complexes are bound 10-fold more tightly than the weak, initial complexes. The slow onset inhibition occurs with t1/2 values of 1.3 and 0.55 min at saturating inhibitor concentrations for the AMPP and S-AEP inhibitors, respectively, while dissociation of these inhibitor complexes occurs with t1/2 values of 13 and 4.6 min, respectively. The X-ray structures of four of the inhibitors in complex with dialkylglycine decarboxylase have been determined to resolutions ranging from 2.6 to 2.0 {\AA}, and refined to R-factors of 14.5-19.5{\%}. These structures show variation in the active site structure with inhibitor side chain size and slow binding character. It is proposed that the slow binding behavior originates in an isomerization from an initial complex in which the PLP pyridine nitrogen-D243 OD2 distance is ∼2.9 {\AA} to one in which it is ∼2.7 {\AA}. The angles that the C-P bonds make with the p orbitals of the aldimine π system are correlated with the reactivities of the analogous amino acid substrates, suggesting a role for stereoelectronic effects in Schiff base reactivity.",
author = "Wenshe Liu and Rogers, {Claude J.} and Fisher, {Andrew J} and Toney, {Michael D.}",
year = "2002",
month = "10",
day = "15",
doi = "10.1021/bi026318g",
language = "English (US)",
volume = "41",
pages = "12320--12328",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "41",

}

TY - JOUR

T1 - Aminophosphonate inhibitors of dialkylglycine decarboxylase

T2 - Structural basis for slow binding inhibition

AU - Liu, Wenshe

AU - Rogers, Claude J.

AU - Fisher, Andrew J

AU - Toney, Michael D.

PY - 2002/10/15

Y1 - 2002/10/15

N2 - The kinetics of inhibition of dialkylglycine decarboxylase by five aminophosphonate inhibitors are presented. Two of these [(R)-1-amino-1-methylpropanephosphonate and (S)-1-aminoethanephosphonate] are slow binding inhibitors. The inhibitors follow a mechanism in which a weak complex is rapidly formed, followed by slow isomerization to the tight complex. Here, the tight complexes are bound 10-fold more tightly than the weak, initial complexes. The slow onset inhibition occurs with t1/2 values of 1.3 and 0.55 min at saturating inhibitor concentrations for the AMPP and S-AEP inhibitors, respectively, while dissociation of these inhibitor complexes occurs with t1/2 values of 13 and 4.6 min, respectively. The X-ray structures of four of the inhibitors in complex with dialkylglycine decarboxylase have been determined to resolutions ranging from 2.6 to 2.0 Å, and refined to R-factors of 14.5-19.5%. These structures show variation in the active site structure with inhibitor side chain size and slow binding character. It is proposed that the slow binding behavior originates in an isomerization from an initial complex in which the PLP pyridine nitrogen-D243 OD2 distance is ∼2.9 Å to one in which it is ∼2.7 Å. The angles that the C-P bonds make with the p orbitals of the aldimine π system are correlated with the reactivities of the analogous amino acid substrates, suggesting a role for stereoelectronic effects in Schiff base reactivity.

AB - The kinetics of inhibition of dialkylglycine decarboxylase by five aminophosphonate inhibitors are presented. Two of these [(R)-1-amino-1-methylpropanephosphonate and (S)-1-aminoethanephosphonate] are slow binding inhibitors. The inhibitors follow a mechanism in which a weak complex is rapidly formed, followed by slow isomerization to the tight complex. Here, the tight complexes are bound 10-fold more tightly than the weak, initial complexes. The slow onset inhibition occurs with t1/2 values of 1.3 and 0.55 min at saturating inhibitor concentrations for the AMPP and S-AEP inhibitors, respectively, while dissociation of these inhibitor complexes occurs with t1/2 values of 13 and 4.6 min, respectively. The X-ray structures of four of the inhibitors in complex with dialkylglycine decarboxylase have been determined to resolutions ranging from 2.6 to 2.0 Å, and refined to R-factors of 14.5-19.5%. These structures show variation in the active site structure with inhibitor side chain size and slow binding character. It is proposed that the slow binding behavior originates in an isomerization from an initial complex in which the PLP pyridine nitrogen-D243 OD2 distance is ∼2.9 Å to one in which it is ∼2.7 Å. The angles that the C-P bonds make with the p orbitals of the aldimine π system are correlated with the reactivities of the analogous amino acid substrates, suggesting a role for stereoelectronic effects in Schiff base reactivity.

UR - http://www.scopus.com/inward/record.url?scp=0037108173&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037108173&partnerID=8YFLogxK

U2 - 10.1021/bi026318g

DO - 10.1021/bi026318g

M3 - Article

C2 - 12369820

AN - SCOPUS:0037108173

VL - 41

SP - 12320

EP - 12328

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 41

ER -