the tryptophan ( trp ) degradation pathways can be divided into four pathways as follows : serotonin , kynurenine , glutarate , and niacin pathways ( fig .
many biologically important compounds such as serotonin , melatonin , kynurenine , kynurenic acid ( ka ) , quinolinic acid ( qa ) , and niacin are synthesized from trp . of these pathways , we are interested in the conversion pathway of trp to niacin .
this is because a deficiency of trp and a metabolic disorder of trp is pellagra , which is cured by administration of niacin .
we have previously reported that the conversion percentage of niacin from trp is around 2% in molar ratio , the rate - limiting enzyme is quinolinic acid phosphoribosyltransferase ( qprt ) , and this pathway mainly exists in the liver , while nonhepatic tissues are not associated with this conversion pathway.120 however , our recent findings21,22 have revealed that the latter is incorrect . the urine total amount of nicotinamide ( nam ) and its catabolites , such as n - methylnicotinamide ( mna ) , n - methyl-2-pyridone-5-carboxamide ( 2-py ) , and n - methyl-4-pyridone-3-carboxamide ( 4-py ) , reflects the formation of niacin - active compounds .
we investigated the relationships between the urine total amount of nam and its catabolites and other urine trp catabolites such as anthranilic acid , ka , xanthurenic acid ( xa ) , 3-hydroxyanthranilic acid ( 3-ha ) , and qa.120,23 we found a significant correlation between the urine total amount of nam and its catabolites and urine qa .
next , we examined the enzyme that controls the formation of niacin from trp in the liver.25,1012,15,16,18,19,23 the relationship between tryptophan 2,3-dioxygenase ( tdo ) and urine nam and its catabolites was not significant .
the relationship between 3-hydroxyanthranilic acid 3,4-dioxygenase ( 3-hado ) and urine total amount of nam and its catabolites was significant ( p = 0.040 ) .
the relationship between qprt and urine nam and its catabolites was not significant . from these results
, we concluded that the enzyme that governs the biosynthesis of nam from trp is 3-hado .
more than 90% of the trp intake is said to be metabolized by the trp - kynurenine - glutarate pathway ( fig .
1 ) in the liver.21,24,25 2-amino-3-carboxymuconate-6-semialde - hyde ( acms ) is a very unstable compound ; therefore , it non - enzymatically cyclizes to form qa .
qa then enters the nicotinamide adenine dinucleotide ( nad ) pathway . the nad metabolism in the liver
qa is converted to nicotinic acid mononucleotide ( namn ) , nicotinic acid adenine dinucleotide ( naad ) , and then to nad .
also , in the liver , nam is converted to nicotinamide mononucleotide ( nmn ) and nad .
when excessive nam is present in the body , it is catabolized to form mna , 2-py , and 4-py , which are eliminated into the urine .
the activity of kynurenine 3-monooxygenase and kynureninase in nonhepatic tissues is weak compared with that of the liver enzymes .
therefore , some parts of kynurenine and 3-hydroxykynurenine ( 3-hk ) are converted to side intermediates such as ka and xa .
furthermore , 3-ha is an end product , because 3-hado does not exist in nonhepatic tissues.21 namely , trp is not a precursor of nad in nonhepatic tissues . te nad biosynthetic pathway in nonhepatic tissues
is shown in figure 4 . in nonhepatic tissues , nam is only a precursor of nad .
nam generated from trp in the liver is transported to nonhepatic tissues via the blood .
thus , surplus nam in nonhepatic tissues returns back to the liver where it is catabolized .
the organ correlation with trp metabolism in wild - type ( wt ) mice is summarized in figure 5 .
the first enzyme in liver trp degradation is tdo . a small amount of trp is also degraded in nonhepatic tissues . in this case , the first enzyme is ido .
we investigated the distribution of the enzymes involved in the trp  niacin metabolism.21,26,27 we found that 3-hado was only in the liver , and not in nonhepatic tissues.21 therefore , 3-ha is an end product of the trp degradation pathway in nonhepatic tissues .
also , a certain amount of 3-ha is taken up by the liver , and 3-ha is used as a niacin precursor . in nonhepatic tissues , nad is synthesized only from nam .
the upper metabolites in the trp  niacin pathway such as 3-ha , ka , and xa are detected in the urine .
the lower metabolites in the trp  niacin pathway such as qa , mna , 2-py , and 4-py are detected in the urine .
the urine total amount of nicotinamide ( nam ) and its catabolites , such as n - methylnicotinamide ( mna ) , n - methyl-2-pyridone-5-carboxamide ( 2-py ) , and n - methyl-4-pyridone-3-carboxamide ( 4-py ) , reflects the formation of niacin - active compounds .
we investigated the relationships between the urine total amount of nam and its catabolites and other urine trp catabolites such as anthranilic acid , ka , xanthurenic acid ( xa ) , 3-hydroxyanthranilic acid ( 3-ha ) , and qa.120,23 we found a significant correlation between the urine total amount of nam and its catabolites and urine qa .
next , we examined the enzyme that controls the formation of niacin from trp in the liver.25,1012,15,16,18,19,23 the relationship between tryptophan 2,3-dioxygenase ( tdo ) and urine nam and its catabolites was not significant .
the relationship between 3-hydroxyanthranilic acid 3,4-dioxygenase ( 3-hado ) and urine total amount of nam and its catabolites was significant ( p = 0.040 ) .
the relationship between qprt and urine nam and its catabolites was not significant . from these results
, we concluded that the enzyme that governs the biosynthesis of nam from trp is 3-hado .
more than 90% of the trp intake is said to be metabolized by the trp - kynurenine - glutarate pathway ( fig .
1 ) in the liver.21,24,25 2-amino-3-carboxymuconate-6-semialde - hyde ( acms ) is a very unstable compound ; therefore , it non - enzymatically cyclizes to form qa .
qa then enters the nicotinamide adenine dinucleotide ( nad ) pathway . the nad metabolism in the liver
qa is converted to nicotinic acid mononucleotide ( namn ) , nicotinic acid adenine dinucleotide ( naad ) , and then to nad .
also , in the liver , nam is converted to nicotinamide mononucleotide ( nmn ) and nad . when excessive nam is present in the body , it is catabolized to form mna , 2-py , and 4-py , which are eliminated into the urine .
the activity of kynurenine 3-monooxygenase and kynureninase in nonhepatic tissues is weak compared with that of the liver enzymes .
therefore , some parts of kynurenine and 3-hydroxykynurenine ( 3-hk ) are converted to side intermediates such as ka and xa .
furthermore , 3-ha is an end product , because 3-hado does not exist in nonhepatic tissues.21 namely , trp is not a precursor of nad in nonhepatic tissues . te nad biosynthetic pathway in nonhepatic tissues
is shown in figure 4 . in nonhepatic tissues , nam is only a precursor of nad .
nam generated from trp in the liver is transported to nonhepatic tissues via the blood .
thus , surplus nam in nonhepatic tissues returns back to the liver where it is catabolized .
the organ correlation with trp metabolism in wild - type ( wt ) mice is summarized in figure 5 .
a small amount of trp is also degraded in nonhepatic tissues . in this case , the first enzyme is ido .
niacin metabolism.21,26,27 we found that 3-hado was only in the liver , and not in nonhepatic tissues.21 therefore , 3-ha is an end product of the trp degradation pathway in nonhepatic tissues .
also , a certain amount of 3-ha is taken up by the liver , and 3-ha is used as a niacin precursor . in nonhepatic tissues , nad is synthesized only from nam .
the upper metabolites in the trp  niacin pathway such as 3-ha , ka , and xa are detected in the urine .
the lower metabolites in the trp  niacin pathway such as qa , mna , 2-py , and 4-py are detected in the urine .
we found that mice can biosynthesize the necessary amount of niacin from trp by catalysis of ido ( exists in non - hepatic tissues ) even in the absence of tdo ( mainly exists in the liver).21 a retardation of body weight gain was not observed in tryptophan 2,3-dioxygenase knockout ( tdo - ko ) mice .
namely , we found that the necessary amount of nam was synthesized from trp by ido , which exists in nonhepatic tissues .
in nonhepatic tissues , 3-hado does not exist.21 consequently , 3-ha is sent out to the blood stream and some of it is then taken and metabolized into nam in the liver , which is then distributed to nonhepatic tissues by the blood stream .
we obtained interesting findings in the experiment with tdo - ko mice ( table 1 ) .
the urinary excretion amounts of the upper intermediates of the trp  niacin pathway such as kynurenine , ka , xa , and 3-ha were higher in the tdo - ko mice than in the wt mice . on the other hand ,
the amounts of the lower intermediates such as qa , nam , mna , 2-py , and 4-py were lower in the tdo - ko mice than in the wt mice .
these findings indicate that the urinary excretion amounts of the upper metabolites reflect the conversion ability of trp to 3-ha in nonhepatic tissues , but do not reflect that ability in the liver .
the conversion ability of nam from trp was very low in tdo - ko mice , because tdo was absent .
table 2 shows the relative niacin conversion activity from exogenous trp , kynurenine , 3-hk , and 3-ha.2830 each compound was orally fed to niacin - deficient animals .
these findings indicate that liver cells can incorporate trp and 3-ha , but can not incorporate kynurenine and 3-hk . from these findings
, we summarized the trp to nam metabolism in tdo - ko mice ( fig .
3-hado does not exist in nonhepatic tissues.21 hence , 3-ha in non - hepatic tissues , which is synthesized from trp by ido , is sent out to the blood stream , and some of the 3-ha is then taken up by the liver , where the 3-ha is metabolized into nam . the synthesized nam is distributed to nonhepatic tissues via the blood stream , and then , the nam is converted to nad .
we found that mice can biosynthesize the necessary amount of niacin from trp by catalysis of ido ( exists in non - hepatic tissues ) even in the absence of tdo ( mainly exists in the liver).21 a retardation of body weight gain was not observed in tryptophan 2,3-dioxygenase knockout ( tdo - ko ) mice .
namely , we found that the necessary amount of nam was synthesized from trp by ido , which exists in nonhepatic tissues .
in nonhepatic tissues , 3-hado does not exist.21 consequently , 3-ha is sent out to the blood stream and some of it is then taken and metabolized into nam in the liver , which is then distributed to nonhepatic tissues by the blood stream .
we obtained interesting findings in the experiment with tdo - ko mice ( table 1 ) .
the urinary excretion amounts of the upper intermediates of the trp  niacin pathway such as kynurenine , ka , xa , and 3-ha were higher in the tdo - ko mice than in the wt mice . on the other hand ,
the amounts of the lower intermediates such as qa , nam , mna , 2-py , and 4-py were lower in the tdo - ko mice than in the wt mice .
these findings indicate that the urinary excretion amounts of the upper metabolites reflect the conversion ability of trp to 3-ha in nonhepatic tissues , but do not reflect that ability in the liver .
the conversion ability of nam from trp was very low in tdo - ko mice , because tdo was absent .
table 2 shows the relative niacin conversion activity from exogenous trp , kynurenine , 3-hk , and 3-ha.2830 each compound was orally fed to niacin - deficient animals .
these findings indicate that liver cells can incorporate trp and 3-ha , but can not incorporate kynurenine and 3-hk . from these findings
, we summarized the trp to nam metabolism in tdo - ko mice ( fig .
3-hado does not exist in nonhepatic tissues.21 hence , 3-ha in non - hepatic tissues , which is synthesized from trp by ido , is sent out to the blood stream , and some of the 3-ha is then taken up by the liver , where the 3-ha is metabolized into nam . the synthesized nam is distributed to nonhepatic tissues via the blood stream , and then , the nam is converted to nad .
true niacin - deficient animals can not be created using nutritional techniques , because the vitamin niacin can be synthesized from trp.22 we wanted to establish a truly niacin - deficient model animal using a protocol that does not involve manipulating the dietary trp .
we generated mice that do not have the qprt gene.21 the body weight of qprt - ko mice decreased when they were fed a diet without preformed niacin ; however , it did not decrease when they were fed a diet with preformed niacin .
qprt activity was not affected by the kind of diet , ie , with or without preformed niacin .
its activity was 1.0 mol / hour / g of liver in wt mice , 0.5 mol / hour / g of liver in hetero type mice , and 0 mol / hour / g of liver in qprt - ko mice .
the excretion amount percentage of qa was around 6% of the intake of dietary trp .
the urine qa was almost the same between the groups of wt and hetero mice .
this was unexpected , because we thought that qprt is the rate - limiting enzyme of the conversion pathway of trp to nam .
the trp to nam conversion percentages in wt and hetero mice were 1.4% and 1.2% , respectively .
this finding also indicates that qprt is not the limiting enzyme in the trp to nam conversion .
the degradation pathway of trp in qprt - ko mice , which does not have qprt , is shown in figure 7 .
therefore , the vitamin niacin is an essential nutrient for qprt - ko mice . in conclusion , these findings21,22 show that the limiting factors in the conversion of trp to niacin are based on the amounts of 3-ha and the conversion ability of 3-hado in the liver .
the formation of qa is catalyzed by 3-hado , whose activity is much higher than that of other enzymes involved in the trp degradation pathway . thus , generally speaking
nevertheless , our findings suggest that the limiting step may be the conversion reaction of 3-ha to qa .
the supply of 3-ha from nonhepatic tissues to the liver may have an important role .
we thought that the supply of 3-ha was significantly smaller in nonhepatic tissues than in the liver , but it turned out to be much higher than expected .
thus , ido in nonhepatic tissues plays an important role in the supply of 3-ha .
further studies on organ  organ relationships are required to elucidate the entire trp metabolism .
 the aim of this article is to report the organ - specific correlation with tryptophan ( trp ) metabolism obtained by analyses of tryptophan 2,3-dioxygenase knockout ( tdo - ko ) and quinolinic acid phosphoribosyltransferase knockout ( qprt - ko ) mice models . 
 we found that tdo - ko mice could biosynthesize the necessary amount of nicotinamide ( nam ) from trp , resulting in the production of key intermediate , 3-hydroxyanthranilic acid . 
 upstream metabolites , such as kynurenic acid and xanthurenic acid , in the urine were originated from nonhepatic tissues , and not from the liver . in qprt - ko mice , 
 the trp to quinolinic acid conversion ratio was 6% ; this value was higher than expected . 
 furthermore , we found that qprt activity in hetero mice was half of that in wild - type ( wt ) mice . 
 urine quinolinic acid levels remain unchanged in both hetero and wt mice , and the conversion ratio of trp to nam was also unaffected . 
 collectively , these findings show that qprt was not the rate - limiting enzyme in the conversion . in conclusion , 
 the limiting factors in the conversion of trp to nam are the substrate amounts of 3-hydroxyanthranilic acid and activity of 3-hydroxyanthranilic acid 3,4-dioxygenase in the liver . 
Introduction
An enzyme that governs the biosynthesis of niacin from Trp
Organ correlation with Trp metabolism in wild-type mice
TDO-KO Mice
The necessary amount of niacin can be synthesized only by IDO
Side-intermediates of the Trpniacin pathway originate from nonhepatic tissues
QPRT-KO Mice
Future Directions