Acyl group specificity at the active site of tetrahydrodipicolinate N-succinyltransferase

Todd W. Beaman, Kurt W. Vogel, Dale G. Drueckhammer, John S. Blanchard, Steven L. Roderick

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Tetrahydrodipicolinate N-succinyltransferase (DapD) catalyzes the succinyl-CoA-dependent acylation of L-2-amino-6-oxopimelate to 2-N-succinyl-6-oxopimelate as part of the succinylase branch of the mesodiaminopimelate/lysine biosynthetic pathway of bacteria, blue-green algae, and plants. This pathway provides meso-diaminopimelate as a building block for cell wall peptidoglycan in most bacteria, and is regarded as a target pathway for antibacterial agents. We have solved the X-ray crystal structures of DapD in ternary complexes with pimelate/succinyl-CoA and L-2-aminopimelate with the nonreactive cofactor analog, succinamide-CoA. These structures define the binding conformation of the cofactor succinyl group and its interactions with the enzyme and place its thioester carbonyl carbon in close proximity to the nucleophilic 2-amino group of the acceptor, in support of a direct attack ternary complex mechanism. The acyl group specificity differences between homologous tetrahydrodipicolinate N-acetyl- and N-succinyltransferases can be rationalized with reference to at least three amino acids that interact with or give accessible active site volume to the cofactor succinyl group. These residues account at least in part for the substrate specificity that commits metabolic intermediates to either the succinylase or acetylase branches of the meso-diaminopimelate/lysine biosynthetic pathway.

Original languageEnglish (US)
Pages (from-to)974-979
Number of pages6
JournalProtein Science
Volume11
Issue number4
DOIs
StatePublished - 2002

Fingerprint

Biosynthetic Pathways
Lysine
Catalytic Domain
Viridiplantae
Acetylesterase
Bacteria
Acylation
Peptidoglycan
Cyanobacteria
Coenzyme A
Substrate Specificity
Cell Wall
Conformations
Carbon
Crystal structure
Cells
X-Rays
Anti-Bacterial Agents
Amino Acids
X rays

Keywords

  • Acetyltransferase
  • Coenzyme A
  • Lysine
  • Protein structure
  • Succinyltransferase
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry

Cite this

Acyl group specificity at the active site of tetrahydrodipicolinate N-succinyltransferase. / Beaman, Todd W.; Vogel, Kurt W.; Drueckhammer, Dale G.; Blanchard, John S.; Roderick, Steven L.

In: Protein Science, Vol. 11, No. 4, 2002, p. 974-979.

Research output: Contribution to journalArticle

Beaman, Todd W. ; Vogel, Kurt W. ; Drueckhammer, Dale G. ; Blanchard, John S. ; Roderick, Steven L. / Acyl group specificity at the active site of tetrahydrodipicolinate N-succinyltransferase. In: Protein Science. 2002 ; Vol. 11, No. 4. pp. 974-979.
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AB - Tetrahydrodipicolinate N-succinyltransferase (DapD) catalyzes the succinyl-CoA-dependent acylation of L-2-amino-6-oxopimelate to 2-N-succinyl-6-oxopimelate as part of the succinylase branch of the mesodiaminopimelate/lysine biosynthetic pathway of bacteria, blue-green algae, and plants. This pathway provides meso-diaminopimelate as a building block for cell wall peptidoglycan in most bacteria, and is regarded as a target pathway for antibacterial agents. We have solved the X-ray crystal structures of DapD in ternary complexes with pimelate/succinyl-CoA and L-2-aminopimelate with the nonreactive cofactor analog, succinamide-CoA. These structures define the binding conformation of the cofactor succinyl group and its interactions with the enzyme and place its thioester carbonyl carbon in close proximity to the nucleophilic 2-amino group of the acceptor, in support of a direct attack ternary complex mechanism. The acyl group specificity differences between homologous tetrahydrodipicolinate N-acetyl- and N-succinyltransferases can be rationalized with reference to at least three amino acids that interact with or give accessible active site volume to the cofactor succinyl group. These residues account at least in part for the substrate specificity that commits metabolic intermediates to either the succinylase or acetylase branches of the meso-diaminopimelate/lysine biosynthetic pathway.

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