Enzyme Responses to Vitamin B6 Deficiency

Some pyridoxal phosphate-dependent enzymes are normally fully saturated with cofactor and show the same activity on assay in vitro whether additional pyridoxal phosphate is present in the incubation medium or not. Examples of this class of enzymes include liver cysteine sulfinate decarboxylase (which is involved in the synthesis of taurine from cysteine; Section 14.5.1) and the brain and liver glutamate and aspartate aminotransferases.

Other enzymes appear not to be fully saturated with cofactor and show increased activity in vitro when additional pyridoxal phosphate is present

Figure 9.4. Tryptophan load test for vitamin B6 status. Tryptophan dioxygenase, EC 1.13.11.11; formylkynurenine formamidase, EC 3.5.1.9; kynurenine hydroxylase, EC 1.14.13.9; kynureninase, EC 3.7.1.3; kynurenine oxoglutarate aminotransferase, EC 2.6.1.7; and kynurenine glyoxylate aminotransferase, 2.6.1.63. Relative molecular masses (Mr): tryptophan, 204.2; kynurenine, 208.2; 3-hydroxykynurenine, 223.2; kynurenic acid, 189.2; and xanthurenic acid, 205.2.

Figure 9.4. Tryptophan load test for vitamin B6 status. Tryptophan dioxygenase, EC 1.13.11.11; formylkynurenine formamidase, EC 3.5.1.9; kynurenine hydroxylase, EC 1.14.13.9; kynureninase, EC 3.7.1.3; kynurenine oxoglutarate aminotransferase, EC 2.6.1.7; and kynurenine glyoxylate aminotransferase, 2.6.1.63. Relative molecular masses (Mr): tryptophan, 204.2; kynurenine, 208.2; 3-hydroxykynurenine, 223.2; kynurenic acid, 189.2; and xanthurenic acid, 205.2.

in the incubation medium; examples of these enzymes include brain glutamate decarboxylase, liver kynureninase and cystathionase, and aspartate aminotransferase from red blood cells. The activities of these enzymes thus vary with vitamin B6 nutritional status. As discussed in Section 9.3.1.5, enzymes that undergo transamination, and hence mechanism-dependent inactivation, may show greater inactivation under conditions of vitamin B6 deficiency and an exaggerated response to the addition of pyridoxal phosphate. When the intake of vitamin B6 is increased to a relatively high level, these apoenzymes are activated in vivo, resulting in increased activity of enzymes that may well be rate controlling in metabolic pathways.

The rates of synthesis and catabolism of some pyridoxal phosphate-dependent enzymes are altered in deficiency. For example, within a few days of feeding a vitamin B6-free diet to animals, there is a fall in the activity of cysteine sulfinate decarboxylase in liver; after 2 weeks, the amount of the enzyme protein has fallen to extremely low levels. It is likely that these enzymes are sacrificed to release pyridoxal phosphate for other, more essential enzymes. Other enzymes show the opposite response - apparent induction of the apoenzyme in vitamin B6 deficiency, presumably in an attempt to trap as much of the available pyridoxal phosphate as possible. Sato and coworkers (1996) demonstrated increased catabolism of apocystathionase in vitamin B6 deficiency, but no decrease in the amount of immunoreactive protein in the liver, as a result of increased transcription.

Katunuma and coworkers (1971) described a protease in the rat that hy-drolyzes the apoenzymes of a number of pyridoxal phosphate-dependent enzymes; it has no effect on other proteins or the holoenzymes. Presumably, it attacks the conserved amino acid sequence around the active lysine residue to which the internal Schiff base is formed. The activity of the enzyme is increased some 10- to 20-fold in vitamin B6 deficiency, suggesting that its function is to degrade those enzymes that lose their coenzyme more readily, and so make more pyridoxal phosphate available for use by other enzymes. There is also evidence that some pyridoxal phosphate-dependent apoenzymes are modified to become incapable of activation by pyridoxal phosphate, although retaining immunological cross-reactivity with the normal form of the enzyme in vitamin B6 deficiency (Nagata and Okada, 1985).

As discussed in Section 9.3.3, pyridoxal phosphate is involved in the regulation of gene expression, terminating the responses to steroid hormones and inactivating some tissue-specific transcription factors. There is decreased synthesis of pancreatic digestive enzymes in vitamin B6 deficiency, although the synthesis of other pancreatic proteins is unaffected (Dubick et al., 1995).

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