Metabolic functions hydroxylases

Uptake of Ca2+ from the intestine is stimulated by vitamin D.447 Vitamin D3 is converted to the 25-hydroxy derivative in the liver (equation 11) by a two component mixed-function hydroxylase.448 The metabolically active 1,25-dihydroxy form is synthesized by further hydroxylation in the kidney. This latter stage involves the renal 25-hydroxyvitamin D3- 1-hydroxylase in a reaction which is controlled by Ca2+, parathyroid hormone and phosphate. This renal hydroxylase contains a flavoprotein, an iron-sulfur protein (with an Fe2S2 cluster) and cytochrome P-450.447... 

Ascorbic acid functions as a relatively nonspecific, radical-trapping antioxidant and also reduces the tocopheroxyl radical formed by oxidation of vitamin E. It has a specific metabolic function as the redox coenzyme for dopamine /3-hydroxylase and peptidyl glycine hydroxylase, and it is required to maintain the iron of 2-oxoglutarate-dependent hydroxylases in the reduced state. 

The synthesis and metabolism of DA are very similar to that of NA, even when it functions as a NT in its own right. Although both phenylalanine and tyrosine are found in the brain it is tyrosine which is the starting point for NA and DA synthesis. It appears to be transported into the brain after synthesis from phenylalanine (phenylalanine hydroxylase) in the liver rather than from phenylalanine found in the brain. Despite the fact that the concentration of tyrosine in the brain is high (5 X 10 M) very little body tyrosine (1%) is used for the synthesis of DA and NA. 

There is no evidence of a general overactivity in DA function in schizophrenic patients. Plasma prolactin is not reduced, so the DA inhibitory control of its release is normal there is no recorded increase in DA turnover as CSF and plasma levels of its major metabolite HVA are normal and dyskinesias, which would reflect increased DA activity, are rare. PM studies have shown no consistent increases in DA brain levels, although some reports show an increase in the left amygdala, or in the activity of enzymes involved in its synthesis (tyrosine hydroxylase) or metabolism (MAO). For a review of the neurochemistry see Reynolds (1995). 

Phenylalanine hydroxylase (PH) which requires tetrahydrobiopterin (BH4) as a cofactor, is defective in cases of phenylketonuria (PKU). This is a rare (prevalence 1 / 15 000 in the United Kingdom) genetic condition characterized by fair complexion, learning difficulties and mental impairment. If PH is either not present in the hepatocytes or is unable to bind BH4 and is therefore non functional, phenylalanine accumulates within the cells. Enzymes in minor pathways which are normally not very active metabolize phenylalanine ultimately to phenylpyruvate (i.e. a phenylketone). To use the traffic flow analogy introduced in Chapter 1, the main road is blocked so vehicles are forced along side roads. Phenylpyruvate is excreted in the urine (phenyl-ketone-uria), where it may be detected but a confirmatory blood test is required for a reliable diagnosis of PKU to be made. 

An intriguing puzzle in NOS catalysis is the precise role of H4B. The traditional function of H4B is in aromatic amino acid metabolism where H4B directly participates in the hydroxylation reaction via a nonheme iron. However, the NOS pterin site has no similarity to the pterin site in the hydroxylases, nor does NOS have a nonheme iron to assist pterin in substrate hydroxylation as in the amino acid hydroxylases 111). NOS more closely resembles pterin-containing enz5unes that have a redox function 81). In particular, N3 and the 03 amino group form H-bonds with either GIu or Asp residues in a series of pterin enzymes 112-116) similar to NOS, except that NOS utilizes the heme propionate (Fig. 6). 

The liver is also the principal metabolic center for hydrophobic amino acids, and hence changes in plasma concentrations or metabolism of these molecules is a good measure of the functional capacity of the liver. Two of the commonly used aromatic amino acids are phenylalanine and tyrosine, which are primarily metabolized by cytosolic enzymes in the liver [1,114-117]. Hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase is very efficient by the liver first pass effect. In normal functioning liver, conversion of tyrosine to 4-hy-droxyphenylpyruvate by tyrosine transaminase and subsequent biotransformation to homogentisic acidby 4-hydroxyphenylpyruvic acid dioxygenase liberates CO2 from the C-1 position of the parent amino acid (Fig. 5) [1,118]. Thus, the C-1 position of phenylalanine or tyrosine is typically labeled with and the expired C02 is proportional to the metabolic activity of liver cytosolic enzymes, which corresponds to functional hepatic reserve. Oral or intravenous administration of the amino acids is possible [115]. This method is amenable to the continuous hepatic function measurement approach by monitoring changes in the spectral properties of tyrosine pre- and post-administration of the marker. 

Corticosteroids also affect adrenomeduUary function by increasing epinephrine production the mechanism is exertion of a stimulatory action on two of the enzymes that regulate catecholamine synthesis, tyrosine hydroxylase, the rate-Umiting enzyme, and phenyl-ethanolamine Af-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. Steroids also influence the metabolism of circulating catecholamines by inhibiting their uptake from the circulation by noimeuronal tissues (i.e., extraneuronal uptake see Chapter 9). This effect of corticoids may explain their permissive action in potentiating the hemodynamic effects of circulating catecholamines. 

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