 |
PDBsum entry 2rhc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
2rhc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Inhibition kinetics and emodin cocrystal structure of a type ii polyketide ketoreductase.
|
|
|
Authors
|
|
T.P.Korman,
Y.H.Tan,
J.Wong,
R.Luo,
S.C.Tsai.
|
|
|
Ref.
|
|
Biochemistry, 2008,
47,
1837-1847.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Type II polyketides are a class of natural products that include
pharmaceutically important aromatic compounds such as the antibiotic
tetracycline and antitumor compound doxorubicin. The type II polyketide synthase
(PKS) is a complex consisting of 5-10 standalone domains homologous to fatty
acid synthase (FAS). Polyketide ketoreductase (KR) provides regio- and
stereochemical diversity during the reduction. How the type II polyketide KR
specifically reduces only the C9 carbonyl group is not well understood. The
cocrystal structures of actinorhodin polyketide ketoreductase (actKR) bound with
NADPH or NADP+ and the inhibitor emodin were solved with the wild type and P94L
mutant of actKR, revealing the first observation of a bent p-quinone in an
enzyme active site. Molecular dynamics simulation help explain the origin of the
bent geometry. Extensive screening for in vitro substrates shows that unlike FAS
KR, the actKR prefers bicyclic substrates. Inhibition kinetics indicate that
actKR follows an ordered Bi Bi mechanism. Together with docking simulations that
identified a potential phosphopantetheine binding groove, the structural and
functional studies reveal that the C9 specificity is a result of active site
geometry and substrate ring constraints. The results lay the foundation for the
design of novel aromatic polyketide natural products with different reduction
patterns.
|
|
|
|
|
|
|
