HOW DOES NATURE FORM HOW DOES NATURE FORM GLYCOSIDIC BONDS? GLYCOSIDIC BONDS? An ab initio molecular dynamics investigation C R i An ab initio molecular dynamics investigation Carme Rovira Universitat de Barcelona – Parc Científic de Barcelona Parc Científic de Barcelona
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HOW DOES NATURE FORM GLYCOSIDIC BONDS? · How do glycosidic bonds form? The ggy p glycosidic bond is formed upon transfer of a sugar molecule from the donor (an activated sugar) to
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HOW DOES NATURE FORM HOW DOES NATURE FORM
GLYCOSIDIC BONDS?GLYCOSIDIC BONDS?An ab initio molecular dynamics investigation
C R i
An ab initio molecular dynamics investigation
Carme RoviraUniversitat de Barcelona –Parc Científic de BarcelonaParc Científic de Barcelona
Carbohydrates
50% of our dailycalorie intake comes from carbohydrates
http://en wikipedia org/
Carbohydrates are our “biological fuel “,
http://en.wikipedia.org/
as well as the primary form of storageand energy consumption in organisms
D i h i h i i hi h b h d i li dDeciphering mechanisms in which carbohydrates are implicatedis of enormous interest for the search of new therapeutic agents.
IntroductionGlicosidic bond
OOH
OOH
OH
OHO
O
HO
O
O
HO OH
OH
OH
O
HO
OO
glucose glucose glucose glucose
HOO
HO
glycosidic bond: C O bond between two sugar unitsC-O bond between two sugar units
How do glycosidic bonds form?
Most glycosidic bonds are synthesized in nature from sugars that
are activated by a cofactor
Enzyme (glycoside transferase)
How do glycosidic bonds form?
The glycosidic bond is formed upon transfer of a sugar molecule from g y p gthe donor (an activated sugar) to an acceptor molecule (typically another sugar)
Enzyme (glycoside transferase)
Two modes of enzyme operation
Retention or inversion of the configuration of the anomeric carbon
t i i GTretaining GT
The molecular mechanism of retaining GTs is very controversial
Palcic, Curr. Opin. Chem. Biol. 2011; Lee et al. Nat. Chem. Biol. 2011Lairson et al. Annu. Rev. Biochem. 2008
Retention of the configuration of the anomeric carbon
• Metadynamics (Laio and Parrinello, PNAS 99, 12562-66, 2002)
(to model the chemical reaction)
Enzyme studied: trehalose-6-phosphate synthase
O
OHOPO 2-
OHO
HO
OH
OHOOH OH
OO
O
PO-
O
O
+O
OH OH
NP
O-
O
O
+HOHO
HO
OHO
OH
OHOPO3
OH
HOHO
OHO
OH
O OPO32-
OH
PO-
O
OO
N
HN
O
O
PO-
O
Oenzyme
O
UDP-glucose(donor)
glucose-6P(acceptor)
N
HN
O
O
OO
trehalose-6P UDP
O
Enzyme Trehalose is a natural disaccharidey Trehalose is a natural disaccharideused as food ingredient for itssweet flavor and preservativepropertiesproperties
Enzyme·substrate complex
St t t bl d l l d i• Structure stable under molecular dynamics• Good agreement with binary complexes structures
(Enzyme + UDP-Glc and Enzyme + UDP + Glc-6P)(Enzyme + UDP-Glc and Enzyme + UDP + Glc-6P)
Discussions with:Antoni Planas (Universitat Ramon Llull Barcelona)Antoni Planas (Universitat Ramon Llull, Barcelona)Seung Lee, Ben Davis (University of Oxford, UK)