Cocrystal structures of diaminopimelate decarboxylase: Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor

Soumya S. Ray; Jeffrey B. Bonanno; K. R. Rajashankar; Mariana G. Pinho; Guoshun He; Herminia De Lencastre; Alexander Tomasz; Stephen K. Burley

doi:10.1016/S0969-2126(02)00880-8

Cocrystal structures of diaminopimelate decarboxylase: Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor

Soumya S. Ray, Jeffrey B. Bonanno, K. R. Rajashankar, Mariana G. Pinho, Guoshun He, Herminia De Lencastre, Alexander Tomasz, Stephen K. Burley

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 Å and 2.0 Å, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in β-lactam antibiotic resistance in Staphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic "molecular rulers" that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (K_i) for azelaic acid (89 μM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such as Staphylococcus aureus, are discussed.

Original language	English (US)
Pages (from-to)	1499-1508
Number of pages	10
Journal	Structure
Volume	10
Issue number	11
DOIs	https://doi.org/10.1016/S0969-2126(02)00880-8
State	Published - Nov 1 2002
Externally published	Yes

All Science Journal Classification (ASJC) codes

Structural Biology
Molecular Biology

Keywords

Antibiotic resistance
Diaminopimalate decarboxylase
Lysine biosynthesis
Structural genomics
X-ray crystallography

Access to Document

10.1016/S0969-2126(02)00880-8

Cite this

@article{86c9ed18e9ea46dd93fd39932248e443,

title = "Cocrystal structures of diaminopimelate decarboxylase: Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor",

abstract = "Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 {\AA} and 2.0 {\AA}, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in β-lactam antibiotic resistance in Staphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic {"}molecular rulers{"} that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (Ki) for azelaic acid (89 μM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such as Staphylococcus aureus, are discussed.",

keywords = "Antibiotic resistance, Diaminopimalate decarboxylase, Lysine biosynthesis, Structural genomics, X-ray crystallography",

author = "Ray, {Soumya S.} and Bonanno, {Jeffrey B.} and Rajashankar, {K. R.} and Pinho, {Mariana G.} and Guoshun He and {De Lencastre}, Herminia and Alexander Tomasz and Burley, {Stephen K.}",

note = "Funding Information: We are most grateful to Dr. M. Becker for access to Beamline X25 at the National Synchrotron Light Source, Dr. Kevin D' Amico at the Advanced Photon Source, and Dr. Dan Thiel at the MacCHESS facility (Cornell). We thank Ms. T. Niven for manuscript preparation and Dr. G.A. Petsko and members of the New York Structural Genomics Research Consortium (NYSGRC) for useful discussions. This work was supported by the National Institutes of Health (P50 GM62529 to S.K.B. and AI45738 to A.T.), The Rockefeller University (S.K.B.), and the Burroughs-Wellcome Fund (K.R.R.). S.K.B. is an Investigator in the Howard Hughes Medical Institute. Mj-DAPDC represents NYSGRC target T135.",

year = "2002",

month = nov,

day = "1",

doi = "10.1016/S0969-2126(02)00880-8",

language = "English (US)",

volume = "10",

pages = "1499--1508",

journal = "Structure with Folding & design",

issn = "0969-2126",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - Cocrystal structures of diaminopimelate decarboxylase

T2 - Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor

AU - Ray, Soumya S.

AU - Bonanno, Jeffrey B.

AU - Rajashankar, K. R.

AU - Pinho, Mariana G.

AU - He, Guoshun

AU - De Lencastre, Herminia

AU - Tomasz, Alexander

AU - Burley, Stephen K.

N1 - Funding Information: We are most grateful to Dr. M. Becker for access to Beamline X25 at the National Synchrotron Light Source, Dr. Kevin D' Amico at the Advanced Photon Source, and Dr. Dan Thiel at the MacCHESS facility (Cornell). We thank Ms. T. Niven for manuscript preparation and Dr. G.A. Petsko and members of the New York Structural Genomics Research Consortium (NYSGRC) for useful discussions. This work was supported by the National Institutes of Health (P50 GM62529 to S.K.B. and AI45738 to A.T.), The Rockefeller University (S.K.B.), and the Burroughs-Wellcome Fund (K.R.R.). S.K.B. is an Investigator in the Howard Hughes Medical Institute. Mj-DAPDC represents NYSGRC target T135.

PY - 2002/11/1

Y1 - 2002/11/1

N2 - Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 Å and 2.0 Å, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in β-lactam antibiotic resistance in Staphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic "molecular rulers" that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (Ki) for azelaic acid (89 μM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such as Staphylococcus aureus, are discussed.

AB - Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 Å and 2.0 Å, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in β-lactam antibiotic resistance in Staphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic "molecular rulers" that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (Ki) for azelaic acid (89 μM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such as Staphylococcus aureus, are discussed.

KW - Antibiotic resistance

KW - Diaminopimalate decarboxylase

KW - Lysine biosynthesis

KW - Structural genomics

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=0036848911&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036848911&partnerID=8YFLogxK

U2 - 10.1016/S0969-2126(02)00880-8

DO - 10.1016/S0969-2126(02)00880-8

M3 - Article

C2 - 12429091

AN - SCOPUS:0036848911

SN - 0969-2126

VL - 10

SP - 1499

EP - 1508

JO - Structure with Folding & design

JF - Structure with Folding & design

IS - 11

ER -

Cocrystal structures of diaminopimelate decarboxylase: Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor

Abstract

All Science Journal Classification (ASJC) codes

Keywords

Access to Document

Other files and links

Fingerprint

Cite this