 |
PDBsum entry 2rdw
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
2rdw
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Active site and loop 4 movements within human glycolate oxidase: implications for substrate specificity and drug design.
|
|
|
Authors
|
|
M.S.Murray,
R.P.Holmes,
W.T.Lowther.
|
|
|
Ref.
|
|
Biochemistry, 2008,
47,
2439-2449.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Human glycolate oxidase (GO) catalyzes the FMN-dependent oxidation of glycolate
to glyoxylate and glyoxylate to oxalate, a key metabolite in kidney stone
formation. We report herein the structures of recombinant GO complexed with
sulfate, glyoxylate, and an inhibitor,
4-carboxy-5-dodecylsulfanyl-1,2,3-triazole (CDST), determined by X-ray
crystallography. In contrast to most alpha-hydroxy acid oxidases including
spinach glycolate oxidase, a loop region, known as loop 4, is completely visible
when the GO active site contains a small ligand. The lack of electron density
for this loop in the GO-CDST complex, which mimics a large substrate, suggests
that a disordered to ordered transition may occur with the binding of
substrates. The conformational flexibility of Trp110 appears to be responsible
for enabling GO to react with alpha-hydroxy acids of various chain lengths.
Moreover, the movement of Trp110 disrupts a hydrogen-bonding network between
Trp110, Leu191, Tyr134, and Tyr208. This loss of interactions is the first
indication that active site movements are directly linked to changes in the
conformation of loop 4. The kinetic parameters for the oxidation of glycolate,
glyoxylate, and 2-hydroxy octanoate indicate that the oxidation of glycolate to
glyoxylate is the primary reaction catalyzed by GO, while the oxidation of
glyoxylate to oxalate is most likely not relevant under normal conditions.
However, drugs that exploit the unique structural features of GO may ultimately
prove to be useful for decreasing glycolate and glyoxylate levels in primary
hyperoxaluria type 1 patients who have the inability to convert peroxisomal
glyoxylate to glycine.
|
|
|
|
|
|
|
