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