Project idea: fighting the bad guys

One Ring to rule them all, One Ring to find them,

One Ring Glucosepane to bring them all and in the darkness bind them ...
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Why do those guys look so ugly without helmets?

Because they have a
lot of crosslinks
between proteins
caused by
Advanced Glycation
Products ( AGEs ),
especially in collagen!

And collagen is 35%

of all protein mass in the body
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Is it only about skin?

No :(

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Some consequences:
Atherosclerosis;
Kidney disease;
Eye diseases (crosslinks are created in cristallin in the eye)
And, of course, bad skin!
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How glycation works

Protein glycation:

non-enzymatic process
protein side chains react with open-chain carbohydrates.
glycation products are critically involved in both healthy and disease

Draghici et al. Science2015

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Same in short
Advanced
Glycation
End-Products
(AGEs)

=
proteins Cross-linked
proteins
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Example of a Bullet Point Slide

Bullet Point 1
Bullet Point 2
Sub Bullet

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Glucosepane the Dark Lord of

The concentration is 10 to 1000
then any other cross-linking AGE
AGEs

Crosslinks 50% of collagen in people

with diabetes and 30% of collagen
in people older than 50 years

C18H32N6O6

One for the Dark Lord on his dark throne

In the Land of Mordor where the Shadows lie.
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Tutorial: How to become a Dark Lord of AGEs

for dummies D-glucose

Draghici et al. Science2015

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Several methods may prevent the formation of glucosepane in vivo,

but no method of removing or breaking

glucosepane cross-links has been found so far
Possible solutions:
- The design of drugs that
can react with the crosslinks
without breaking any essential
structures. (Alabebriums
effects are not enough in
humans)
- Finding or engineering
enzymes to break the crosslinks.

Where to get enough

glucosepane for testing?

So what to do and who is guilty?

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Take vitamins? Benfotiamine?

NH2
N

N
N

HO
P

OH

Decreases formation of AGEs up to 40%

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Pathway of B1
NH2

N
N

B1 is similar to Benfotiamine
butHO
not as good

OH

Other types of prevention:

-Dicarbonyl trap
Thiazolium salts
ECM turnover

Still scared?
Want to break
existing cross-links?
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How to fight glucosepane?

Concise total synthesis

of glucosepane
Science 16 October 2015:
Vol. 350 no. 6258 pp. 294-298
DOI: 10.1126/science.aac9655

So, now Aubrey can

send a lot of glucosepane

Gandalf's Aubrey
De Grey's advice
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How to detect cross-links breaking

emission A = excitation B

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Rings to fight with

EC Number: 3.5.2.7

EC Number: 3.5.2.5

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Elves Directed evolution for rescue

Key steps in the cycle of directed evolution.

1: original enzyme

M.S. Packer and D.R. Liu, 2015, Nature

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Directed evoluton continues ...

Ryan E. Cobb et
al. 2012,

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THANK YOU
For your attention!

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