Phenylalanine degradation

Tetrahydrobiopterin, another cofactor of amino acid catabolism, is similar to the pterin moiety of tetrahydrofolate, but it is not involved in one-carbon transfers instead it participates in oxidation reactions. We consider its mode of action when we discuss phenylalanine degradation (see Fig. 18-24). 

C N Sarkissian, Z Shao, F Blain, R Peevers, H S Su, R Heft, T M S Chang, T S Scriver (1999) A different approach to tteatment of phenylketonuria Phenylalanine degradation with recombinant phenylalanine ammonia lyase, Proc Natl Acad Sci USA 96(5) 2339—2344... 

Another genetic disease that results from a deficiency of an enzyme in the pathway for phenylalanine degradation is al-captonuria, which is caused by lack of homogentisate dioxygenase. The only ill effect of this enzyme deficiency is black urine. The urine of those afflicted with alcaptonuria turns black because the homogentisate they excrete immediately oxidizes in the air. 

Taking into account the pathway for phenylalanine degradation, answer the following... 

Phenylalanine hydroxylase [39] catalyzes the first step of phenylalanine degradation in mammals. Phenylalanine is converted into tyrosine (Scheme XI.9). The enzyme has one tightly bound, non-heme iron atom per subunit. Tyrosine hydroxylase catalyzes [40] the hydroxylation of tyrosine to produce dihydroxy-phenylalanine (DOPA), the first step in the biosynthesis of catechol-amine neurotransmitters (Scheme XI.9). This enzyme also contains one ferrous iron atom per subunit. These two enzymes, together with tryptophane hydroxylase (Scheme XI.9) [41], constitute a family of tetrahydropterin-dependent aromatic acid hydroxylases (monooxygenases) [42], Other dioxygenases catalyze the hydroxylation ofarenes [43],... 

PAH catalyzes the first step of phenylalanine degradation, and the reaction converts the essential amino acid phenylalanine to tyrosine. Rat liver PAH (RLPAH) has been extensively studied. Recently bacterial PAH from Chromobacterium violaceum (CVPAH) has also been studied. Because the hydroxylation is irreversible and the enzyme activity is very high in most animal liver, regulation is required. Phenylalanine and the reaction cofactor, BPH4, are regulators as well as substrates. Phenylalanine is an activator and converts the enzyme from an essentially inactive, Ei, to an active form, Ea, by binding... 

PKU is an inherited disorder of amino acid metabohsm, with an incidence of 1 in 11000 Uve births in the UK, and thus is relatively common. It is caused by a deficiency of the enzyme phenylhydroxylase, which is the first step of phenylalanine degradation (and also the route for synthesis of tyrosine, melanin, dopamine, etc). If unrecognized, and untreated, the absence of the enzyme phenylalanine in the blood, which in turn causes damage to the developing brain in babies and young children. Clinical features of untreated PKU indue mental retardation, seizures, hyperactivity, and hypopigmentation of the eyes and hair. 

An alkaline pH (- pH 11) is desirable in order to achieve high conversion rates increase solubility of L-phenylalanine inhibit enzymes catalysing degradation of L-phenylalanine and formation of byproducts reduce inhibition of the reaction by the keto form of phenylpyruvic arid. 

Arias-Barrau E, ER Olivera, JM Lnengo, C Eemandez, B Galan, JL Garcia, E Dfaz, B Minambres (2004) The homogentisate pathway a central catabolic pathway involved in the degradation of L-phenylalanine, L-tyrosine, and 3-hydroxyphenylacetate in Pseudomonas putida J Bacterial 186 5062-5077. 

Akagi T, Higashi M, Kaneko T et al (2006) Hydrolytic and enzymatic degradation of nanoparticles based on amphiphilic poly(y-glutamic acidj-gra/t-L-phenylalanine copolymer. Biomacromolecules 7 297-303... 

Valine, leucine, and isoleucine biosynthesis Lysine biosynthesis Lysine degradation Arginine and proline metabolism Histidine metabolism Tyrosine metabolism Phenylalanine metabolism Tryptophan metabolism Phenylalanine, tyrosine, and tryptophan biosynthesis Urea cycle and metabolism of amino groups... 

The majority of cases of cystic fibrosis result from deletion of phenylalanine at position 508 (AF508), which interferes with proper protein folding and the posttranslational processing of oligosaccharide side chains. The abnormal chloride channel protein (CFTR) is degraded by the cytosolic proteasome complex rather than being translocated to the cell membrane. Other functional defects in CFTR protein that teaches the cell membrane may also contribute to the pathogenesis of cystic fibrosis. 

Aromatic acids include tyrosine and phenylalanine these are not metabolised by muscle so increased levels in muscle are consistent with increased rate of protein degradation. 

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