3LQS

Complex Structure of D-Amino Acid Aminotransferase and 4-amino-4,5-dihydro-thiophenecarboxylic acid (ADTA)

Summary for 3LQS

• Entry DOI: 10.2210/pdb3lqs/pdb
• Related: 3DAA
• Descriptor: D-alanine aminotransferase, 4-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]THIOPHENE-2-CARBOXYLIC ACID, ACETIC ACID, ... (4 entities in total)
• Functional Keywords: plp aminotransferase, mechanism-based inhibitor, stereo-specificity, r-adta, aminotransferase, pyridoxal phosphate, transferase
• Biological source: Bacillus sp.
• Total number of polymer chains: 2
• Total formula weight: 64929.88

Authors

Lepore, B.W.,Liu, D.,Peng, Y.,Fu, M.,Yasuda, C.,Manning, J.M.,Silverman, R.B.,Ringe, D. (deposition date: 2010-02-10, release date: 2010-03-16, Last modification date: 2024-02-21)

Primary citation

Lepore, B.W.,Liu, D.,Peng, Y.,Fu, M.,Yasuda, C.,Manning, J.M.,Silverman, R.B.,Ringe, D.
Chiral discrimination among aminotransferases: inactivation by 4-amino-4,5-dihydrothiophenecarboxylic acid.
Biochemistry, 49:3138-3147, 2010

PubMed Abstract: Mechanism-based inhibitors such as cycloserine and gabaculine can inactivate aminotransferases via reactions of the compounds with the pyridoxal phosphate cofactor forming an irreversible adduct. The reaction is chirally specific in that any one enzyme usually only recognizes one enantiomer of the inactivator. For instance, l-aspartate aminotransferase (l-AspAT) is inactivated by 4-amino-4,5-dihydro-2-thiophenecarboxylic acid (ADTA), however, only by the S-isomer. We have now shown that d-amino acid aminotransferase (d-a-AT) is irreversibly inactivated by the R-isomer of the same compound. The X-ray crystal structure (PDB code: 3LQS ) of the inactivated enzyme shows that in the product the enzyme no longer makes a Schiff base linkage to the pyridoxal 5'-phosphate (PLP) cofactor, and instead the compound has formed a derivative of the cofactor. The adduct is similar to that formed between d-cycloserine and d-a-AT or alanine racemase (Ala-Rac) in that the thiophene ring of R-ADTA is intact and seems to be aromatic. The plane of the ring is rotated by nearly 90 degrees with respect to the plane of the pyridine ring of the cofactor, in comparison with the enzyme inactivated by cycloserine. Based on the structure of the product, the mechanism of inactivation most probably involves a transamination followed by aromatization to form an aromatic thiophene ring.

PubMed: 20192272
DOI: 10.1021/bi902052x

Experimental method

X-RAY DIFFRACTION (1.9 Å)