Cleavage of the 5-amino substituent of pyrimidine cofactors by phenylalanine hydroxylase.

Sw, Bailey; Je, Ayling

doi:10.1016/s0021-9258(19)43899-4

Cited by 23 publications

(13 citation statements)

References 19 publications

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“…(Intriguingly, the 90% uncoupling with BDP makes it the the most-coupled cofactor for o -methylphenylalanine hydroxylation. TP, DMPH 4 , and BH 4 all give >99% uncoupled turnover as had been suggested (Figure ).…”

Section: Transformations Of Alternate Cofactorssupporting

confidence: 70%

“…Rapid decomposition of BDP follows its anaerobic oxidation by I 2 to the quinonoid form (Figure ), which liberates TP and benzaldehyde (≤0.5% benzylamine). Air oxidation of BDP, while much slower, gives the same products …”

Section: Transformations Of Alternate Cofactorsmentioning

confidence: 88%

“…However, this determination does not take into account the further oxidation of NADH by the pyrimidine product. When this is done, 2.5 TP and 1.4 BDP (1.7 BDP in Lazarus et al ) are oxidized for every tyrosine formed, the same degree of coupling as their respective cyclic analogues PH 4 and 6PhPH 4 . , The triaminopyrimidine cofactors are irreversibly modified as a result of turnover, the subject of the following section.…”

Section: Cofactor Requirements1 Biopterin Analogues and Pyrimidinesmentioning

confidence: 99%

“…By using BDP with PAH, every tyrosine produced is the result of oxidation of 1.4 equiv of BDP, which forms 1.4 divicine and 1.0 benzylamine. The remainder of the cleaved BDP substituent (0.4 per tyrosine) is found as benzaldehyde, the exclusive decomposition product of nonenzymatic oxidation (and possibly of uncoupled BDP oxidation by PAH/O 2 ) …”

Section: Transformations Of Alternate Cofactorsmentioning

confidence: 99%

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Pterin-Dependent Amino Acid Hydroxylases

1996

Chem. Rev.

314

385

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Section: Transformations Of Alternate Cofactorssupporting

confidence: 70%

Section: Transformations Of Alternate Cofactorsmentioning

confidence: 88%

Section: Cofactor Requirements1 Biopterin Analogues and Pyrimidinesmentioning

confidence: 99%

Section: Transformations Of Alternate Cofactorsmentioning

confidence: 99%

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Pterin-Dependent Amino Acid Hydroxylases

1996

Chem. Rev.

314

385

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“…The utilization of 2,5,6-triamino-4(3//)-pyrimidinone, or its 5-iY-benzyl or 5-iV-methyl derivative, by phenylalanine hydroxylase results not only in tyrosine formation but also in the cleavage of the cofactor into quinoid divicine plus ammonia, benzylamine, or methylamine, respectively (Bailey & Ayling, 1980b). Whether this is the result of Hamilton's proposed mechanism or of preferential loss of the amine from a carbinolamine subsequent to substrate hydroxylation is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Pyrimidodiazepine, a ring-strained cofactor for phenylalanine hydroxylase

Pike¹,

Hora²,

Bailey³

et al. 1986

Biochemistry

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Homologues of 6-methyl-7,8-dihydropterin (6-Me-7,8-PH2) and 6-methyl-5,6,7,8-tetrahydropterin (6-Me-PH4), expanded in the pyrazine ring, were synthesized to determine the effect of increased strain on the chemical and enzymatic properties of the pyrimidodiazepine series. 2-Amino-4-keto-6-methyl-7,8-dihydro-3H,9H-pyrimido[4,5-b] [1,4]diazepine (6-Me-7,8-PDH2) was found to be more unstable in neutral solution than 6-Me-7,8-PH2. Its decomposition appears to proceed by hydrolytic ring opening of the 5,6-imine bond, followed by autooxidation. 6-Me-7,8-PDH2 can be reduced, either chemically or by dihydrofolate reductase (Km = 0.16 mM), to the 5,6,7,8-tetrahydro form (6-Me-PDH4). This can be oxidized with halogen to quinoid dihydropyrimidodiazepine (quinoid 6-Me-PDH2), which is a substrate for dihydropteridine reductase (Km = 33 microM). Whereas quinoid 6-methyldihydropterin was found to tautomerize to 6-Me-7,8-PH2 in 95% yield in 0.1 M tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl), pH 7.4, quinoid 6-Me-PDH2 gives only 53% 6-Me-7,8-PDH2, the remainder decomposing via an initial opening of the diazepine ring. Additional evidence for the extra strain in the pyrimidodiazepine system is the cyclization of quinoid 6-N-(2'-aminopropyl)divicine to quinoid 6-Me-PH2 in 57% yield in 0.1 M Tris-HCl, pH 7.4. By comparison, no quinoid 6-Me-PDH2 is formed from the homologue quinoid 6-N-(3'-aminobutyl)divicine. A small (2%) yield of 6-Me-PDH4 is found if the unstable C4a-carbinolamine intermediate is trapped by enzymatic dehydration and reduction. Although phenylalanine hydroxylase utilizes 6-Me-PDH4 (Km = 0.15 mM), the maximum velocity of tyrosine production is 20 times slower than that with 6-Me-PH4, indicating that a ring opening reaction is not a rate-limiting step in the hydroxylase pathway. Further, the maximum velocities of 2,5,6-triamino-4(3H)-pyrimidinone, 2,6-diamino-5-(methylamino)-4(3H)-pyrimidinone, and 2,6-diamino-5-(benzylamino)-4(3H)-pyrimidinone span a 35-fold range. These cofactors would theoretically form the same oxide of quinoid divicine if oxygen activation involves a carbonyl oxide intermediate. Thus, the limiting step is also not transfer of oxygen from this hypothetical intermediate to the phenylalanine substrate.

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The Phenylalanine Hydroxylating System

Kaufman

1993

Advances in Enzymology - And Related Areas of Molecular Biology

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Cleavage of the 5-amino substituent of pyrimidine cofactors by phenylalanine hydroxylase.

Cited by 23 publications

References 19 publications

Pterin-Dependent Amino Acid Hydroxylases

Pterin-Dependent Amino Acid Hydroxylases

Pyrimidodiazepine, a ring-strained cofactor for phenylalanine hydroxylase

The Phenylalanine Hydroxylating System

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