Biopterin synthesis

Figure 19-3. De novo biopterin synthesis and recycling. Tetrahydrobiopterin can be synthesized de novo from GTP or resynthesized from the pterin 4a-carbinolamine.

The pterins include the redox cofactors biopterin and molybdopterin, as well as various insect pigments. Folic acid is a conjugated pterin, in which the pteridine ring is linked to p-aminobenzoyl-poly-y-glutamate it is this linkage that renders folate a dietary essential, because it is the ability to condense p-aminobenzoate to a pteridine, rather than to synthesize the pteridine nucleus itself, which has been lost by higher animals. Biopterin (Section 10.4) and molybdopterin (Section 10.5) are coenzymes in mixed-function oxidases they are not vitamins, but can be synthesized in the body. Rare genetic defects of biopterin synthesis render it a dietary essential for affected individuals. 

Patients with a variety of cancers and some viral diseases excrete relatively large amounts of neopterin, formed by dephosphorylation and oxidation of dihydroneopterin triphosphate, an intermediate in biopterin synthesis. This reflects the induction of GTP cyclohydrolase by interferon-y and tumor necrosis factor-a in response to the increased requirement for tetrahydrobiopterin for nitric oxide synthesis (Section 10.4.2). It is thus a marker of ceU-mediated immune reactions and permits monitoring of disease progression (Werner et al., 1993,1998 Berdowska and Zwirska-Korczala, 2001). 

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. 

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

A strategy has been described for the synthesis of 2-ethyIthio-6-(3-hydroxy-1,2-0-isopropylidenepropyl)pteridin-4(3//)-one 90 which can be used as a useful intermediate for the conversion of neopterin to biopterin. Diaminopyrimidinone 86 reacts with D-arabinose phenylhydrazone 87, the obtained diastereomeric mixture 88 is converted into its isopropylidene derivative 89 which under oxidation conditions yields 90 <00H(53)1551>. 

With carefully selected aliphatic precursors, the synthesis of single stereoisomers of side-chain-substituted pteridines has been achieved (Schemes 20-22). The synthesis of L-biopterin 106 requires 5-deoxy-L-arabinose 102 as a key intermediate preparable from the expensive sugars L-rhamnose and L-arabinose. Alternatively, the readily... 

Synthesis of NO Arginine, 02, and NADPH are substrates for cytosolic NO synthase (Figure 13.9). Flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), heme, and tetrahydro- biopterin are coenzymes for the enzyme, and NO and citrulline are products of the reaction. Three NO synthases have been identified. Two are constitutive (synthesized at a constant rate regardless of physiologic demand), Ca2+-calmodulin-dependent enzymes. They are found primarily in endothelium (eNOS), and neural tissue... 

A much more expensive route to (11) has been described which involves periodate cleavage of L-neopterin [33]. An analogous but synthetically uninteresting synthesis involves photolysis of either biopterin or neopterin in a phosphate buffer at pH 10 in the absence of oxygen. Subsequent introduction of oxygen results in oxidation of the intermediate 5,8-dihydropterin-6-car-boxaldehyde to give (11) in unspecified yield [34]. 

Various attempts to synthesize biopterin independent of naturally occurring sugars have been carried out (Scheme 11). L-Tartalic acid and (S)-lactic acid were converted to 5-deoxy-L-arabinose (62) and its derivative (67), respectively [76-78]. However, these procedures required multiple steps and cannot be replaced by the procedure using L-rahmnose (65). The stereoselective process of biopterin 7-carboxylic acid (68) starting from E-2-butenoic acid, which is a bulk industrial chemical, looked attractive because the process is thoroughly independent of natural chiral resources, however, it is not applicable to the synthesis of biopterin (30) [79]. 

The application of Gabriel-Coleman synthesis to the synthesis of biopterin (30) is reliable, however, it has a serious problem in that the condensation of the pyrimidine precursor with asymmetrically substituted sugar derivatives is sometimes less regioselective or even nonregioselective. For example,... 

PCD deficient patients excrete 7-biopterin (137), called primaterin, in their urine [152-154], which had not been observed in normal mammals. The mechanism of the 7-substituted pterin synthesis from 6-substitute has been proposed [155,156] (Scheme 33). When 95 is rapidly dehydrated to 45 via PCD, the dihydroxypropyl side chain of 95 is retained at its 6-position. However, in the absence of PCD activity, the rate of conversion of unstable 95 is slow. Therefore, its pyrazine ring is opened to give 98, and recyclization of 98 to the 7-substituted pterin derivative proceeds via spiro intermediate 138 [89,156]. 

A novel regio- and stereoselective synthesis of biopterin and various 6-substituted pteridines... 

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). 

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