Biopterin metabolism

PKU) phenylalanine hydroxylase. In care cases, defect of biopterin metabolism (Fig. 40-3 reaction 1) children. Avoidable with early institution of diet therapy. Prognosis less favorable in PKU secondary to defect of biopterin metabolism Carbidopa... 

Kuster T, Matasovic A, Niederwieser A (1984) Application of gas chromatography-mass spectrometry to the study of biopterin metabolism in man. Detection of biolumazine and 2 -de-oxysepialumazine. J Chromatogr 290 303-310... 

Bonafe L, Thony B, Leimbacher W, Kierat L, Blau N (2001) Diagnosis of Dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin Chem 47 477-485... 

Because LCEC had its initial impact in neurochemical analysis, it is not, surprising that many of the early enzyme-linked electrochemical methods are of neurologically important enzymes. Many of the enzymes involved in catecholamine metabolism have been determined by electrochemical means. Phenylalanine hydroxylase activity has been determined by el trochemicaUy monitoring the conversion of tetrahydro-biopterin to dihydrobiopterin Another monooxygenase, tyrosine hydroxylase, has been determined by detecting the DOPA produced by the enzymatic reaction Formation of DOPA has also been monitored electrochemically to determine the activity of L-aromatic amino acid decarboxylase Other enzymes involved in catecholamine metabolism which have been determined electrochemically include dopamine-p-hydroxylase phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase . Electrochemical detection of DOPA has also been used to determine the activity of y-glutamyltranspeptidase The cytochrome P-450 enzyme system has been studied by observing the conversion of benzene to phenol and subsequently to hydroquinone and catechol... 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway 673... 

FIGURE 40-2 The phenylalanine hydroxylase (PAH) pathway. Phenylketonuria usually is caused by a congenital deficiency of PAH (reaction 1), but it also can result from defects in the metabolism of biopterin, which is a cofactor for the hydroxylase. Enzymes (1) Phenylalanine hydroxylase (2) Dihydropteridine reductase (3) GTP cyclohydrolase (4) 6-pyruvoyltetrahydrobiopterin synthase. BH4, tetrahydrobiopterin DEDT, o-erythro-dihydroneopterin triphosphate QH2, dihydrobiopterin. 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway. The electron donor for phenylalanine hydroxylase is tetrahydrobiopterin (BH4), which transfers electrons to molecular oxygen to form tyrosine and dihydrobiopterin (QH2 Fig. 40-2 reaction 2). BH4 is regenerated from QH2 in an NADH-dependent reaction that is catalyzed by dihydropteridine reductase (DHPR), which is widely distributed. In the brain, this... 

Phenylketonuria is due to an inborn error of phenylalanine metabolism. Typically, it is due to a deficiency of phenylalanine hydroxylase. Atypically, it can be caused by a deficiency of dihydrobiopterin reductase and a resultant inability to synthesize biopterin. All these conditions cause an accumulation of phenylalanine, which can be transaminated to phenylpyruvic acid. 

In addition to the established vitamins, a number of organic compounds have clear metabolic functions they can be synthesized in the body, but it is possible that under some circumstances (as in premature infants and patients maintained on long-term total parenteral nutrition) endogenous synthesis may not be adequate to meet requirements. These compounds include biopterin (Section 10.4), carnitine (Section 14.1), choline (Section 14.2), creatine (Section 14.3), inositol (Section 14.4), molybdopterin (Section 10.5), taurine (Section 14.5), and ubiquinone (Section 14.6). 

Fates of tyrosine. Tyrosine can be degraded by oxidative processes to ace-toacetate and fumarate which enter the energy generating pathways of the citric acid cycle to produce ATP as indicated in Figure 38-2. Tyrosine can be further metabolized to produce various neurotransmitters such as dopamine, epinephrine, and norepinephrine. Hydroxylation of tyrosine by tyrosine hydroxylase produces dihydroxyphenylalanine (DORA). This enzyme, like phenylalanine hydroxylase, requires molecular oxygen and telrahydrobiopterin. As is the case for phenylalanine hydroxylase, the tyrosine hydroxylase reaction is sensitive to perturbations in dihydropteridine reductase or the biopterin synthesis pathway, anyone of which could lead to interruption of tyrosine hydroxylation, an increase in tyrosine levels, and an increase in transamination of tyrosine to form its cognate a-keto acid, para-hydroxyphenylpyruvate, which also would appear in urine as a contributor to phenylketonuria. 

Several studies have shown altered catecholamine metabolism in uremia and have suggested that the unconjugated pteridines may play a role in the causation of some of the neurological symptoms (C21, D8). Dhondt and Vahille have reported an increase of the pteridines neopterin and biopterin in the serum of maintenance dialysis patients (D12). They did not, however, describe an accumulation of xanthopterin, perhaps because this compound, unlike the blue-fluoresc-ing pteridines (excitation maxima = 360 10 nm), has its maximum excitation at 390 nm. 

The increase in serum xanthopterin levels may be directly related to renal failure, because the kidney maintains pteridine concentrations within narrow limits (L4, PI, Z5). However, xanthopterin is one of the end products of biopterin and neopterin metabolism, which are elevated in uremia (D12, R9). Thus an increase in their catabolism could be a source of increased xanthopterin production. 

The interaction between lead and tetrahydrobiopterin metabolism has also received some attention, and serum biopterin derivative levels have been positively correlated with blood lead levels in human patients (Leeming and Blair, 1980 Blair et al., 1982). 

Metabolomics of the urine from an 8-year-old patient with epilepsy and an 11-year-old patient with malignant lymphoma who was being treated with methotrexate, both of whom were receiving parenteral nutrition, showed identical metabolic profiles to that of phenylketonuria [61 ]. Neopterin concentrations were markedly raised and in one case the biopterin concentration was also above normal. The metabolic profiles were normal when they were not receiving parenteral nutrition. 

H]-Biopterin (97), required for metabolism studies, was synthesised by reaction of the phenylhydrazone of 5-deoxy-[5- H]-L-arabinose (see chapter 12) with 2,5,6-triaminopyrimidin-4-one. The same reaction applied to the semicarbazones of pentoses proceeded regiospecifically to yield D-anapterin (98) and L-primapterin (99), which have the polyhydroxyalkyl substituent in a different position on the pteridinone ring. Condensation of 2-methylthio-4,5,6-triamino-pyrimidine with pentose phenylhydrazones yielded triqrclic adducts such as the crystalline product (100) obtained from D-arabinose . 

Fig. 16.10 Inter-relationship of biopterin synthesis and the normal metabolism of l-phenylalanine and the L-phenylalanine hydroxylase system in man.

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