PDBsum entry 3fvu

Lyase, transferase

PDB id: 3fvu

Contents

Protein chains

419 a.a. *

Ligands

IAC ×2

GOL ×5

Metals

_NA ×2

Waters ×590

* Residue conservation analysis

PDB id:

3fvu

Name:

Lyase, transferase

Title:

Crystal structure of human kynurenine aminotransferase i in complex with indole-3-acetic acid

Structure:

Kynurenine--oxoglutarate transaminase 1. Chain: a, b. Synonym: kynurenine--oxoglutarate transaminase i, kynurenine aminotransferase i, kati, glutamine--phenylpyruvate transaminase, glutamine transaminase k, gtk, cysteine-s-conjugate beta-lyase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ccbl1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

1.55Å R-factor: 0.186 R-free: 0.210

Authors:

Q.Han,H.Robinson,T.Cai,D.A.Tagle,J.Li

Key ref:

Q.Han et al. (2009). Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K. J Med Chem, 52, 2786-2793. PubMed id: 19338303

Date:

16-Jan-09 Release date: 19-May-09

Protein chains

Q16773  (KAT1_HUMAN) -  Kynurenine--oxoglutarate transaminase 1 from Homo sapiens

Seq: 422 a.a.

Struc: 419 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: E.C.2.6.1.64 - glutamine--phenylpyruvate transaminase.
• Reaction: 3-phenylpyruvate + L-glutamine = 2-oxoglutaramate + L-phenylalanine

3-phenylpyruvate + L-glutamine = 2-oxoglutaramate + L-phenylalanine (Bound ligand (Het Group name = IAC) matches with 78.57% similarity)

• Cofactor: Pyridoxal 5'-phosphate
• Enzyme class 2: E.C.2.6.1.7 - kynurenine--oxoglutarate transaminase.

Pathway:

• Reaction: L-kynurenine + 2-oxoglutarate = kynurenate + L-glutamate + H2O

L-kynurenine + 2-oxoglutarate = kynurenate + L-glutamate (Bound ligand (Het Group name = IAC) matches with 68.75% similarity) + H2O

• Cofactor: Pyridoxal 5'-phosphate
• Enzyme class 3: E.C.4.4.1.13 - cysteine-S-conjugate beta-lyase.
• Reaction: an S-substituted L-cysteine + H2O = a thiol + pyruvate + NH4⁺

S-substituted L-cysteine + H2O = thiol + pyruvate + NH4(+) (Bound ligand (Het Group name = GOL) matches with 71.43% similarity)

• Cofactor: Pyridoxal 5'-phosphate

Pyridoxal 5'-phosphate (Bound ligand (Het Group name = IAC) matches with 45.00% similarity)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 52:2786-2793 (2009)

PubMed id: 19338303

Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K.

Q.Han, H.Robinson, T.Cai, D.A.Tagle, J.Li.

ABSTRACT

Human kynurenine aminotransferase I (hKAT I) catalyzes the formation of kynurenic acid, a neuroactive compound. Here, we report three high-resolution crystal structures (1.50-1.55 A) of hKAT I that are in complex with glycerol and each of two inhibitors of hKAT I: indole-3-acetic acid (IAC) and Tris. Because Tris is able to occupy the substrate binding position, we speculate that this may be the basis for hKAT I inhibition. Furthermore, the hKAT/IAC complex structure reveals that the binding moieties of the inhibitor are its indole ring and a carboxyl group. Six chemicals with both binding moieties were tested for their ability to inhibit hKAT I activity; 3-indolepropionic acid and DL-indole-3-lactic acid demonstrated the highest level of inhibition, and as they cannot be considered as substrates of the enzyme, these two inhibitors are promising candidates for future study. Perhaps even more significantly, we report the discovery of two different ligands located simultaneously in the hKAT I active center for the first time.