N-phosphonacetyl-L-isoasparagine a potent and specific inhibitor of Escherichia coli aspartate transcarbamoylase.
The synthesis of a new inhibitor, N-phosphonacetyl-L-isoasparagine (PALI), of Escherichia coli aspartate transcarbamoylase (ATCase) is reported, as well as structural studies of the enzyme.PALI complex. PALI was synthesized in 7 steps from beta-benzyl L-aspartate. The KD of PALI was 2 microM. Kinetics and small-angle X-ray scattering experiments showed that PALI can induce the cooperative transition of ATCase from the T to the R state. The X-ray structure of the enzyme.PALI complex showed 22 hydrogen-bonding interactions between the enzyme and PALI. The kinetic characterization and crystal structure of the ATCase.PALI complex also provides detailed information regarding the importance of the alpha-carboxylate for the binding of the substrate aspartate.
Eldo
Joby
J
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachussetts 02467-3808, USA.
Cardia
James P
JP
O'Day
Elizabeth M
EM
Xia
Jiarong
J
Tsuruta
Hiro
H
Kantrowitz
Evan R
ER
D001216:Asparagine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology*; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000737:chemistry
C514368:N-phoshponacetylisoasparagine; D063065:Organophosphonates; D001224:Aspartic Acid; D001216:Asparagine; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid