 |
PDBsum entry 5equ
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Divergent non-Heme iron enzymes in the nogalamycin biosynthetic pathway.
|
|
|
Authors
|
|
V.Siitonen,
B.Selvaraj,
L.Niiranen,
Y.Lindqvist,
G.Schneider,
M.Metsä-Ketelä.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2016,
113,
5251-5256.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Nogalamycin, an aromatic polyketide displaying high cytotoxicity, has a unique
structure, with one of the carbohydrate units covalently attached to the
aglycone via an additional carbon-carbon bond. The underlying chemistry, which
implies a particularly challenging reaction requiring activation of an aliphatic
carbon atom, has remained enigmatic. Here, we show that the unusual C5''-C2
carbocyclization is catalyzed by the non-heme iron α-ketoglutarate
(α-KG)-dependent SnoK in the biosynthesis of the anthracycline nogalamycin. The
data are consistent with a mechanistic proposal whereby the Fe(IV) = O center
abstracts the H5'' atom from the amino sugar of the substrate, with subsequent
attack of the aromatic C2 carbon on the radical center. We further show that, in
the same metabolic pathway, the homologous SnoN (38% sequence identity)
catalyzes an epimerization step at the adjacent C4'' carbon, most likely via a
radical mechanism involving the Fe(IV) = O center. SnoK and SnoN have
surprisingly similar active site architectures considering the markedly
different chemistries catalyzed by the enzymes. Structural studies reveal that
the differences are achieved by minor changes in the alignment of the substrates
in front of the reactive ferryl-oxo species. Our findings significantly expand
the repertoire of reactions reported for this important protein family and
provide an illustrative example of enzyme evolution.
|
|
|
|
|
|
|
