Tetrahydropteridine

Tyrosine is the immediate precursor of catecholamines, and tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis. Tyrosine hydroxylase is found in both soluble and particle-bound forms only in tissues that synthesize catecholamines it functions as an oxidoreductase, with tetrahydropteridine as a cofactor, to convert L-tyrosine to L-dihydroxyphenylalanine (L-dopa). 

It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine jS-hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine S-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). 

Ishimitsu, S., Fujimoto, S. and Ohara, A. (1984). Studies on the hydroxylation of phenylalanine by 6,7-dimethyl-5,6,7,8-tetrahydropteridine. Chem. Pharm. Bull. 32, 752-765. 

PT Pertussis toxin PTCA Percutaneous transluminal coronary angioplasty PTCR Percutaneous transluminal coronary recanalization Pte-H Tetrahydropteridine PUFA Polyunsaturated fatty acid PUMP-1 Punctuated metalloproteinase also known as matrilysin... 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

Two asymmetric carbon atoms, the or carbon in the glutamic acid portion of the molecule and the C6 carbon in the tetrahydropteridine ring, allow four possible isomers. Since synthetic procedures would undoubtedly start with L-glutamic acid, the isomeric possibilities are reduced to the dL and 1L diastereomers. Of these, the biologically more active form is the 1L separation of the diastereomers is effected by solubility differences of the calcium salts.2... 

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. 

Ring opening of 97 as indicated gives the 9-(a-amino-Q -phenylmethyl) purine 98, which by a base-catalyzed elimination of benzylideneimine is converted into 6,8-diphenyl-2-methylthiopurine 99. This pteridine-purine transformation has a close resemblance to the enzyme-catalyzed ring contraction of tetrahydropteridine into xanthine-8-carboxylic acid (64MI1), in which reaction it was proved by radioactive labeling that it is exclusively C-7 that is expelled. 

This enzyme [EC 1.6.99.7] catalyzes the reaction of NAD(P)H with 6,7-dihydropteridine (that is, the quinoid form of dihydropteridine) to produce NAD(P)+ and 5,6,7,8-tetrahydropteridine. The enzyme is not identical with dihydrofolate reductase. 

This iron-dependent enzyme [EC 1.14.16.6], also known as L-mandelate 4-hydroxylase, catalyzes the reaction of (5)-2-hydroxy-2-phenylacetate with tetrahydropteridine and dioxygen to produce (5)-4-hydroxymandelate, dihy-dropteridine, and water. 

As a final example of regioselective control (Scheme 25), sulfonium ylides usually give nitrones when reacted with nitroso groups via oxaziridine intermediates. However, 7-aryl-2-dimethylamino-3,4,5,6-tetrahydropteridine-4,6-diones 120 were directly formed when nitrosopyrimidine 121 reacted with dimethylphenacylsulfonium bromides 122 instead of the isomeric 5-oxides <1996H(43)437>. It was also reported that the resulting pteridines were reduced to give 7,8-dihydro derivatives 123 with sodium dithionite (Table 7). 

ATP [L-tyrosine,tetrahydropteridine oxygen oxidoreductase (3-hydroxylat-ing)] 0-phosphotransferase... 

R-Tetrahydro-eryt6ro-biopterin dihydrochloride (BH4.2HCI, [ lR,25 -l,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridine 2HC1)... 

The electrochemically oxidized forms of certain tetrahydropteridines,18 o-hydroquinones,244 and aromatic diamines245 are very active NADH oxidants. 

Tetrahydropteridines are oxidized to quinonoid dihydropteridines, the structures of which are not yet established.357... 

Pteridine adds ammonia at low temperature to form 4-amino-3,4-dihydropteridine (246) which is transformed in a slower reaction into 6,7-diamino-5,6,7,8-tetrahydropteridine (247) (cf. similar adducts with water, 166 and 167). 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+02 B=tyrosine hydroxylase+ tetrahydropteridine+Fe+++02 C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+++02 E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

The pteridine ring system is composed of fused pyrazine and pyrimidine rings, either of which might be attacked by a complex metal hydride. The reaction of pteridine (145), 2,4-dichloropteridine (146), or 2,4-dimethoxypteridine (147) with lithium aluminum hydride was reported to occur with reduction of the pyrazine ring to give the 5,6,7,8-tetrahydropteridine (148-150, respectively).150... 

The product of the reaction of sodium or potassium borohydride with substituted pteridines is highly sensitive to the location of the substituent. Thus, Albert and Matsuura151 reported the formation of 2-oxo-l,2,3,4-tetrahydropteridine (152) from the reaction of potassium borohydride with pteridin-2-one (151). This appears to be the only example of attack of the pyrimidine ring of pteridines by complex metal hydrides. The same dihydropteridine (152) was formed by reduction of 151 with hydrosulfite ion, and the structure of the product of the latter reaction was elegantly proved using deuterium... 

Pteridine and 2-chloropteridine were aminated by liquid ammonia (—40 °C) and potassium permanganate into the corresponding 4-aminopter-idines (86JHC473). Under these conditions no amino-dechlorination at C-2 was found. The regiospecificity of adduct formation is temperature dependent. At — 33 °C the C-4 adducts, i.e., the 4-amino-3,4-dihydro-2-R-pteridines (R = H, Cl), were formed as identified by NMR spectroscopy (Scheme 31). However, at temperatures up to 25 °C addition of ammonia takes place at positions C-6 and C-7, yielding the 2 1 a-adducts 6,7-diamino-5,6,7,8-tetrahydropteridines. Attempts to oxidize the C-6/C-7 diadduct into a 6,7-diaminopteridine were not successful (Scheme 31). 

Pteridine also adds ammonia at low temperature to form 4-amino-3,4-dihydropteridine (42) which is transformed in a slower reaction into 6,7-diamino-5,6,7,8-tetrahydropteridine (43) (Scheme 5). 2-Chloropteridine (36) shows the same behavior, whereas 2-chloro-4-phenylpteridine (37) and 2-methylthiopteridine (38) lead directly to the corresponding 6,7-diamino-5,6,7,8-tetrahydro derivatives (43) (Scheme 5). The 4-amino-3,4-dihydropteridines can easily be oxidized to the 4-aminopteridines <75RTC45>. Covalent hydrations with various 6,7-bis-trifluoromethyl-pteridine derivatives were studied showing that 6,7-bis-trifluoromethylpteridine (40) itself and the cor-... 

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