Vitamin deficiency, tryptophan metabolism

Diagram 19. Relation of vitamins to tryptophan metabolism. Deficiencies of... 

It has been shown by the author that examination of the products excreted after administration of tryptophan to vitamin-deficient animals can give valuable information on the function of that vitamin in tryptophan metabolism (142, 171, 173). When tryptophan is given to the riboflavin-deficient rat there is a large excretion of those substances which lie to the left of line BB in diagram 19 (142, 582). This clearly indicates that this is the step at which riboflavin functions, and this is strongly supported by the fact that riboflavin deficiency can reduce up to ten-fold the conversion of tryptophan to quinolinic acid, whereas similar conversion of hydroxykynurenine is unaffected (385). On the other hand, the excretory pattern... 

Nicotinate and nicotinamide, together referred to as niacin, are required for biosynthesis of the coenzymes nicotinamide adenine dinucleotide (NAD"") and nicotinamide adenine dinucleotide phosphate (NADP" ). These both serve in energy and nutrient metabolism as carriers of hydride ions (see pp. 32, 104). The animal organism is able to convert tryptophan into nicotinate, but only with a poor yield. Vitamin deficiency therefore only occurs when nicotinate, nicotinamide, and tryptophan are all simultaneously are lacking in the diet. It manifests in the form of skin damage (pellagra), digestive disturbances, and depression. 

Metabolic loading tests and the determination of enzyme saturation with cofactor measure the ability of an individual to meet his or her idiosyncratic requirements from a given intake, and, therefore, give a nearly absolute indication of nutritional status, without the need to refer to population reference ranges. A number of factors other than vitamin intake or adequacy can affect responses to metabolic loading tests. This is a particular problem with the tryptophan load test for vitamin Be nutritional status (Section 9.5.4) a number of drugs can have metabolic effects that resemble those seen in vitamin deficiency or depletion, whether or not they cause functional deficiency. 

Estrogens cause abnormalities of tryptophan metabolism that resemble those seen in vitamin Be deficiency, and the vitamin is widely used to treat the side effects of estrogen administration and estrogen-associated symptoms of the premenstrual syndrome, although there is litde evidence of its efficacy. High doses of the vitamin, of the order of 100 times requirements, cause peripheral sensory neuropathy. 

In 1942 it was shown that the urine of pyridoxine-deficient rats contained large amounts of xanthurenic acid (L2). This was the starting point for studies on the interrelationship among vitamin Be, tryptophan, and protein metabolism. 

Increased excretion of xanthurenic acid was found (H7) in 13 cases of infantile spasm as compared with a control group of healthy infants, before and ter tryptophan loadings. This finding is interpreted as a sign of relative vitamin Be deficiency in tissue concerned with tryptophan metabolism caused by an increased demand for pyridoxine as a co-enzyme in the brain tissue. In most cases the disturbed tryptophan metabolism should have no direct relation to the cerebral symptoms, as these were not relieved by parenteral administration of high doses of vitamin Be. 

By 1950 the outline of the main pathway for tryptophan metabolism was therefore established, and it was becoming apparent that the over-all conversion of tryptophan to nicotinic acid was markedly reduced in many B-vitamin deficiencies. Thus this occurred in pyridoxine deficiency (50, 387, 732, 784), riboflavin deficiency (387,455, 675), and thiamine deficiencj (455, 675) but not in pantothenate or folic acid deficiencies (455). 

Xanthurenic acid excretion can be caused in the rabbit by a idtamin-E as well as vitamin-Be-deficiency (200). This is more likely to loe due to vitamin interaction than to a direct effect of vitamin E on tryptophan metabolism. 

If the dietary levels of niacin and tryptophan are insufficient, the condition known as pellagra results. The symptoms of pellagra are dermatitis, diarrhea, dementia, and, finally, death. In addition, abnormal metabolism of tryptophan occurs in a vitamin B6 deficiency. Kynurenine intermediates in tryptophan degradation cannot be cleaved because kynureninase requires PLP derived from vitamin B6. Consequently, these intermediates enter a minor pathway for tryptophan metabolism that produces xanthurenic acid, which is excreted in the urine. 

These assessments of Bg nutrition in OCA-users by methods odier than studying tryptophan metabolism do indicate that at least some of the women who excrete abnormal quantities of tryptophan metabolites in urine have a degree of true deficiency in vitamin Bg. However, the possibility that contraceptive steroids may affect binding of B compounds to blood proteins, or to proteins in erythrocyte proteins remains to be explored. 

R16. Rose, D. P., Strong, R., Adams, P. W., and Harding, P. E., Experimental vitamin Ba deficiency and the effect of oestrogen-containing oral contraceptives on tryptophan metabolism and vitamin Ba requirements. Clin. Sci. 42, 465-477 (1972). 

Niacin is not strictly a vitamin, as it can be synthesized in the body from the essential amino acid tryptophan. Indeed, it is only when tryptophan metabolism is deranged that dietary preformed niacin becomes important. Nevertheless, niacin was discovered as a nutrient during studies of the deficiency disease pellagra, which was a major public health problem in the southern USA throughout the first half of the twentieth century, and continued to be a problem in parts of India and sub-Saharan Africa until the 1990s. 

The metabolism of methionine, shown in Figure 11.22, includes two pyridoxal phosphate-dependent steps cystathionine synthetase and cystathionase. Cystathionase activity falls markedly in vitamin deficiency, and as a result there is an increase in the urinary excretion of homocysteine and cystathionine, both after a loading dose of methionine and under basal conditions. However, as discussed below, homocysteine metabolism is affected more by folate status than by vitamin status, and, like the tryptophan load test, the methionine load test is probably not reliable as an index of... 

A member of the water-soluble B group of vitamins. It can be obtained from thediet orit can be synthesized endogenouslyfrom nicotinic acid, which is itself derived from tryptophan. Nicotinamide is a constituent of the coenzymes NAD and N ADP which have widespread roles in intermediary metabolism. Deficiency of the vitamins causes pellagra. Patients with Hart-nup s disease can develop a pellagra type condition probably due to insufficient endogenous synthesis of the vitamin from tryptophan. 

Metabolism of Tryptophan. The catabolism of tryptophan is interesting since it leads to the biosynthesis of a vitamin, nicotinamide. It appears contradictory to state that a vitamin is formed by an organism, but nicotinamide deficiency can indeed be demonstrated only with the concurrent deficiency of vitamin Be. Tryptophan largely replaces the vitamin even in man. 

Severe deficiency disease has only been reported in a single outbreak in infants fed overheated formula. However, a significant proportion of people in developed countries have marginal vitamin Bg status, and this may be associated with enhanced responsiveness to steroid hormone action and may be a factor in the development of hormone-dependent cancer of the breast, uterus, and prostate. A number of drugs have antivitamin activity, and prolonged use may lead to secondary development of pellagra, as a result of impaired tryptophan metabolism. 

The oxidative pathway of tryptophan metabolism is shown in Figure 3. Kynureninase is a pyridoxal phosphate-dependent enzyme, and in deficiency its activity is lower than that of tryptophan dioxygenase, so that there is an accumulation of hydroxy-kynurenine and kynurenine, resulting in greater metabolic flux through kynurenine transaminase and increased formation of kynurenic and xanthurenic acids. Kynureninase is exquisitely sensitive to vitamin Bg deficiency because it undergoes a slow inactivation as a result of catalysing the half-reaction of transamination instead of its normal reaction. The resultant enzyme with pyridoxamine phosphate at the catalytic site is catalytically inactive and can only be reactivated if there is an adequate concentration of pyridoxal phosphate to displace the pyridoxamine phosphate. 

A number of drugs that react with carbonyl compounds are capable of causing vitamin Bg deficiency on prolonged use. These include the antituberculosis drug isoniazid (iso-nicotinic acid hydrazide), penicillamine, and the anti-Parkinsonian drugs, benser-azide and carbidopa. In general, the main effect is impairment of tryptophan metabolism by inhibition of kynureninase, and hence the development of the niacin-deficiency disease, pellagra. The condition therefore responds to the administration of either vitamin Bg or niacin. 

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