The kynurenine pathway as a drug target
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The kynurenine pathway as a drug target. Hayaishi and tryptophan metabolism. Osamu Hayaishi is the founder of biochemistry in Japan. After the 2 nd World War, he returned to Osaka University to take a position. Everything had been destroyed, so he had nothing to do research with.

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Hayaishi and tryptophan metabolism
Hayaishi and tryptophan metabolism

  • Osamu Hayaishi is the founder of biochemistry in Japan.

  • After the 2nd World War, he returned to Osaka University to take a position.

  • Everything had been destroyed, so he had nothing to do research with.

  • Professor Kotake gave him a bottle of tryptophan to do research.

  • He isolated a bacterium from the soil outside the lab that could grow on tryptophan.


Hayaishi and tryptophan metabolism1
Hayaishi and tryptophan metabolism

  • Hayaishi found that the bacterium, Pseudomonas fluorescens, used a pathway called the kynurenine pathway previously found in animals.

  • This pathway was found in rats to be related to a nutrional deficiency called pelagra.

  • The end products of the kynurenine pathway are different in animals and bacteria.

  • Bacteria completely metabolize tryptophan to CO2 and NH3.

  • Animals metabolize tryptophan to NAD(P).


The kynurenine pathway in pseudomonas fluorescens

O

O

O

O

2

O

O

O

N

H

+

O

N

H

+

N

H

+

O

3

3

N

H

3

N

H

N

2

H

O

H

C

O

H

O

O

H

O

O

O

C

-

O

2

2

2

O

+

C

O

-

NADPH

2

N

H

+

O

3

N

H

2

acetate + succinate

The kynurenine pathway in Pseudomonas fluorescens


The kynurenine pathway in humans

O

O

O

O

2

O

O

O

N

H

+

O

N

H

+

N

H

+

O

3

3

N

H

3

N

H

N

2

H

O

H

C

O

,

N

A

D

P

H

2

O

O

O

O

O

O

2

O

O

O

O

+

N

H

+

O

O

N

H

N

H

+

3

N

H

H

O

H

O

2

3

H

O

N

H

2

2

C

O

-

2

C

O

-

N

2

C

O

+

H

O

+

N

H

2

2

3

liver

C

O

-

2

N

A

D

(

P

)

+

N

niacin

The kynurenine pathway in humans


Where is the kynurenine pathway found in the body
Where is the kynurenine pathway found in the body?

  • Most tryptophan metabolism occurs in the liver.

  • However, Hayaishi found that it can occur in other tissues, such as lung, intestines, and placenta.

  • The first enzyme in the pathway is different in liver (TDO) and the other tissues (IDO).

  • Both enzymes contain a heme group like hemoglobin, so they bind O2 and are red in color.


Ido and the fetal maternal paradox
IDO and the fetal-maternal paradox

  • IDO is found in the placenta, in cells contacting the maternal blood.

  • The placenta is made of fetal cells, which are not the same as the mother.

  • Why doesn't the mother's immune system attack the fetus?

  • Andrew Mellor and David Munn at MCG showed that inhibition of IDO causes abortion in gravid mice.

  • Thus, IDO regulates the immune response to determine self and other.


Ido and cancer
IDO and cancer

  • IDO is also found in cancer cells.

  • Although cancer cells are different than normal cells, they are not attacked by the immune system.

  • An IDO inhibitor, 1-methyltryptophan, is now being investigated at MCG for anticancer activity

  • The D-isomer seems to be more active in vivo.


How do ido inhibitors affect the immune response
How do IDO inhibitors affect the immune response?

  • Possibly the depletion of tryptophan prevents T-cell activation.

  • Other metabolites (kynurenines) may inhibit T-cell proliferation.

  • Maybe both effects are involved.


Quinolinate and the central nervous system
Quinolinate and the central nervous system

  • Another metabolite of the kynurenine pathway is quinolinate.

  • Quinolinate is an excitatory neurotoxin due to binding at the NMDA receptor.

  • Glutamate is the natural ligand for the NMDA receptor.

  • Too much MSG can cause “Chinese restaurant syndrome” in some people.


Quinolinate and the central nervous system1
Quinolinate and the central nervous system

  • The kynurenine pathway is elevated by inflammation and infection.

  • Increased levels of quinolinate are found in serum of patients with HIV-related dementia.

  • Increased quinolinate has also been found in patients with Huntington's disease and Alzheimer's disease.

  • Compounds which block quinolinate formation could be used to treat these diseases.


Kynurenine pathway enzymes are drug targets
Kynurenine pathway enzymes are drug targets

  • Kynurenines and quinolinate are neurotoxic.

  • Reduction of these metabolites may be therapeutic for neurodegenerative diseases.

  • Inhibition of kynurenine monoxygenase and kynureninase will reduce kynurenines and quinolinate.



Kynureninase sequences
Kynureninase sequences

  • The amino acid sequence of the protein from bacteria to humans is only about 28% identical.

  • Chimpanzees and humans differ in only 1 amino acid out of 465, so we are 99.6% identical.

  • The human sequence is similar to dog (88.8%), rat (86.3%), mice (84.8%), chickens (72.5%), zebrafish (72.3%), and worms (51.5%), then fungi.

  • The similarity is related to the evolutionary distance between organisms.

  • These data provide a time-clock for evolution.

  • Other proteins give similar results.


Alleles of kynureninase
Alleles of kynureninase

  • Even individual humans show variation in protien sequences.

  • Several alleles of kynureninase have been found in humans.

  • K412E and R188Q have been found in Han Chinese, and are linked with hypertension.

  • T198A was found in a boy in Somalia, and he had high levels of excretion of kynurenic and xanthurenic acids.




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