 |
|
Title
|
|
The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters.
|
|
|
Authors
|
|
G.Auerbach,
A.Herrmann,
M.Gütlich,
M.Fischer,
U.Jacob,
A.Bacher,
R.Huber.
|
|
|
Ref.
|
|
EMBO J, 1997,
16,
7219-7230.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Sepiapterin reductase catalyses the last steps in the biosynthesis of
tetrahydrobiopterin, the essential co-factor of aromatic amino acid hydroxylases
and nitric oxide synthases. We have determined the crystal structure of mouse
sepiapterin reductase by multiple isomorphous replacement at a resolution of
1.25 A in its ternary complex with oxaloacetate and NADP. The homodimeric
structure reveals a single-domain alpha/beta-fold with a central four-helix
bundle connecting two seven-stranded parallel beta-sheets, each sandwiched
between two arrays of three helices. Ternary complexes with the substrate
sepiapterin or the product tetrahydrobiopterin were studied. Each subunit
contains a specific aspartate anchor (Asp258) for pterin-substrates, which
positions the substrate side chain C1'-carbonyl group near Tyr171 OH and NADP
C4'N. The catalytic mechanism of SR appears to consist of a NADPH-dependent
proton transfer from Tyr171 to the substrate C1' and C2' carbonyl functions
accompanied by stereospecific side chain isomerization. Complex structures with
the inhibitor N-acetyl serotonin show the indoleamine bound such that both
reductase and isomerase activity for pterins is inhibited, but reaction with a
variety of carbonyl compounds is possible. The complex structure with N-acetyl
serotonin suggests the possibility for a highly specific feedback regulatory
mechanism between the formation of indoleamines and pteridines in vivo.
|
|
|
|