Pterin-dependent phenylalanine

Figure 13.21 Mononuclear non-haem iron enzymes from each of the five families in structures which are poised for attack by 02. (a) The extradiol-cleaving catechol dioxygenase, 2,3-dihydroxy-biphenyl 1,2-dioxygenase (b) the Rieske dioxygenase, naphthalene 1,2-dioxygenase (c) isopenicillin N-synthase (d) the ot-ketoglutarate dependent enzyme clavaminate synthase and (e) the pterin-dependent phenylalanine hydroxylase. (From Koehntop et al., 2005. With kind permission of Springer Science and Business Media.)...

In bacterial (Chromobacterium violaceum) pterin-dependent phenylalanine hydroxylase, a cupric ion is in a tetragonal coordination environment with several nitrogen donors [54]. Dopamine p-mo nooxygenase takes part in the biosynthetic pathway for the production of epinephrine from tyrosine [55] ... 

The aromatic amino add hydroxylases (AAHs) are a family of pterin-dependent enzymes comprising phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH, with two gene products TPH1 and TPH2). The AAHs perform the hydroxylation of aromatic amino adds and play an important role in mammalian metabolism and in the biosynthesis of... 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

The important metaboUsm of the neurotransmitters norepinephrine, epinephrine, dopa, and serotonin involves pterin-dependent monooxygenases. The direct biocatalytic hydroxylation of the aromatic amino acids phenylalanine, tyrosine, and tryptophane requires tetrahydrobiopterin and Fe as the cofactors [60]. The cleavage of unsaturated glyceryl ethers by glyceryl ether monooxygenase also requires tetrahydrobioterin as the cofactor [61]. 

The pterin-dependent oxygenases, typified by the aryl amino acid hydroxylases, are a small family of closely related enzymes, which are essential to mammalian physiology. This class of metalloenzymes employs tetrahydrobiopterin (BH4) as a two-electron donating cofactor for the activation of O2. Members of this class include phenylalanine (PheH), tyrosine (TyrH) and tryptophan (TrpH) hydroxylases, which effect regiospecific aromatic hydroxylations of the namesake amino acids. 

Tetrahydrobiopterin (BPH4) is the natural cofactor required for the mammalian aromatic amino acid monooxygenases phenylalanine, tyrosine and tryptophan hydroxylase [4,89]. During the course of the reaction catalyzed by these enzymes, a molecule of oxygen is cleaved in order to hydroxylate the respective amino acid substrate. The remaining atom of oxygen is reduced to water at the expense of the cofactor, which is oxidized to the quinonoid form. Despite the many studies on the pterin-dependent hydroxylases, their precise mechanism of action is not well understood. This discussion will focus on mammalian phenylalanine hydroxylase (PAH), which has been favored for investigation due to its relative stability and ease of... 

Soluble MMO Pterine-dependent hydroxylases (Phenylalanine, Tyrosine, Tryptophan) Isopenicillin N synthase... 

Another subgroup of the 2His-lcarboxylate family is dependent on a reduced pterin cofactor (5). They catalyze hydrox-ylations at the aromatic positions of amino acids in phenylalanine catabolism and hormone biosynthesis (Fig. 2). Unlike the a-KG-dependent enzymes, the pterin co-substrate does not ligate to the iron directly. In the reaction cycle, the pterin cosubstrate supplies two electrons for the heteiolysis of O2 to give a yet to be characterized iron-oxygen hydroxylating species. 

Fig. 20.2 Pterin-cofactor-dependence of phenylalanine hydroxylase. Tetrahydrobiopterin, synthesized from guanosine triphosphate, donates the electron required to convert molecular oxygen to H O and hydroxylate the ring of phenylalanine to produce tyrosine. The resulting dihydrobiopterin is recycled by conversion to tetrahydrobiopterin using NADPH. (From McGUvery RW. Biochemistry A Functional Approach, 2nd edn. WB Saunders, Philadelphia, 1979)...

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