Transcript The kynurenine pathway as a drug target

The kynurenine pathway as a drug
target
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 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
O2
N H 3+
N
H
O
O
O
NH
O
N H 3+
NH2
O
N H 3+
O HC
OH
O
O2
O 2C C O 2-
OH
O2
O
NADPH
NH2
acetate + succinate
O
+
O
N H 3+
The kynurenine pathway in humans
O2
O
O
O
NH3+
N
H
O
O
O
NH
O
O
NH2
NH3+
NH3+
OHC
O2, NADPH
O
O
HO
O
O2
O
O
O
NH2
HO
+
NH2
CO2-
CO2 + H2O + NH3
CO2-
N
liver
CO2NAD(P)+
N
niacin
O
O
O
O
NH3+
HO
O
NH2
NH3+
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 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 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?
Possibly the depletion of tryptophan prevents Tcell activation.
Other metabolites (kynurenines) may inhibit Tcell proliferation.
Maybe both effects are involved.
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
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
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.
The kynureninase family tree
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
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.
The structure of human kynureninase
Comparison of bacterial and human
kynureninase