Tyrosine degradative pathway

HPPD catalyzes an early step in a tyrosine degradation pathway [12] that is widely distributed in nature [13] and thus, as in animals, treatment of plants with inhibitors causes significant accumulation of tyrosine [8, 14]. HPP derived from transamination of tyrosine, is converted into HGA via HPPD, HGA is oxidized via HGA oxidase to 4-maleylacetoacetate, which is further degraded via 4-maleylacetoacetate isomerase and 4-fumarylacetoacetate lyase to fumarate and acetoacetate. In microbes the pathway provides assimilable carbon from tyrosine... 

Fig. 4.1. Tyrosine degradation pathway. Metabolic markers are framed. Possible metabolic disorders are marked with boxes, 4.1, fumarylacetoacetase 4.2, tyrosine aminotransferase 4.3, 4-hydroxyphenylpyruvate dioxygenase 4.5, homogentisate dioxygenase. Inhibition by succinylacetone and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-l,3-cyclo-hexanedione) are indicated by crosses. 5-ALA, 5-aminolevulinate...

Fig. 4.2. Increased tyrosine concentration is caused by inborn or acquired deficiency of the first two enzymes of the tyrosine degradation pathway (the increased tyrosine concentration of tyrosinemia type I is caused by secondary deficiency of 4-hydroxyphenyl-pyruvate dioxygenase). Hypertyrosinemia in the newborn is in most instances not due to inborn errors of tyrosine metabolism, but rather to liver immaturity or other unspecific liver affections. However, whenever hypertyrosinemia is found, the pathognomonic sign of tyrosinemia type I should be excluded by a sufficiently sensitive analysis of suc-cinylacetone and related metabolites. Decreased activity of porphobilinogen synthase activity in RBC is a sensitive and easily performed marker for increased concentrations of succinylacetone, which may be used as a first line diagnostic test before positive identification of succinylacetone and related metabolites by GC-MS can be achieved. It should also be noted that increased excretion of phenolic tyrosine metabolites is always found in hypertyrosinemia and is of no differential diagnostic value...

Store it while it s here. Insulin binds to a specific receptor on the cell surface and exerts its metabolic effect by a signaling pathway that involves a receptor tyrosine kinase phosphorylation cascade. Note that insulin stimulates storage processes and at the same time inhibits degradative pathways. 

Figure 25-5 shows the principal catabolic pathways, as well as a few biosynthetic reactions, of phenylalanine and tyrosine in animals. Transamination to phenylpyruvate (reaction a) occurs readily, and the product may be oxidatively decarboxylated to phen-ylacetate. The latter may be excreted after conjugation with glycine (as in Knoop s experiments in which phenylacetate was excreted by dogs after conjugation with glycine, Box 10-A). Although it does exist, this degradative pathway for phenylalanine must be of limited importance in humans, for an excess of phenylalanine is toxic unless it can be oxidized to tyrosine (reaction b, Fig. 25-5). Formation of phenylpyruvate may have some function in animals. The enzyme phenylpyruvate tautomerase, which catalyzes interconversion of enol and oxo isomers of its substrate, is also an important immunoregulatory cytokine known as macrophage migration inhibitory factor.863...

Figure 23.29. Phenylalanine and Tyrosine Degradation. The pathway for the conversion of phenylalanine into acetoacetate and fumarate.

The amino acids L-phenylalanine and L-tyrosine are broken down via aromatic degradation pathways that are found in mammals and bacteria, to form organic acids that can be utilized for growth. These pathways are the only aromatic degradation pathways found in mammals, and are of some medical significance, since there are several inherited metabolic diseases (phenylketonuria, alkaptonuria, tyrosinemia) that are caused by mutations in enzymes in these pathways. 

Fig. 4. The domain organizations of some CUE and LIP domain-containing proteins. Yeast Der3p/Hrdlp and Cuelp are proteins of the endoplasmic reticulum degradation pathway. As human autocrine motility factor receptor (AMFR) contains the same domain organization of a conceptual Der3p/Hrdlp and Cuelp fusion, it is proposed that DerSp/Hrdlp and Cuelp interact physically (Pouting, 2000). The C. elegans sequence most similar to human Tollip contains a C-terminal extension containing an F-box domain and an incomplete LIP domain. Over 190 LIP domains occur in at least 172 C. elegans hypothetical proteins, but have not been observed in other species sequences the functions of this domain remain unknown. LIP domains frequently co-occur with F-box domains and in one case (C33F10.8) a protein tyrosine phosphatase-like (FTP) domain.

Two of the nonessential amino acids, tyrosine and cysteine, are derived from essential amino acids and may be considered to be breakdown products of them, as they are intermediates in the normal degradation pathway of these amino acids. Provided sufficient quantities of the two essential amino acids, phenylalanine and methionine, are available in the diet, then net synthesis of tyrosine and cysteine occur. 

In addition to this main degradation pathway of phenylalanine via tyrosine, there is an alternative reversiblepathway via phenylpyruvic acid, of which only the intermediates are known. In normal as well as in phenylketonuric individuals, phenylalanine and phenylpyruvic and phenyllactic acids are interconvertible. 

As is the case in decarboxylation reactions involving malic acid, histidine, and tyrosine, degrading arginine provides yeasts with additional energy resonrces. The net energy gain via the arginine pathway consists of a molecnle of ATP produced from carbamyl-P. 

Much of the earlier knowledge of the metabolic pathways of phenylalanine and tyrosine was obtained by the study of the defects in the hereditary diseases, alcaptonuria, albinism, phenylpyruvic oligophrenia, and tyrosinosis. Widespread interest in this subject dates from the publication of Garrod s Inborn Errors of Metabolism (2). The metabolic Uoeka at particular steps in the degradative pathways of phenylalanine and tyrosine for the disorders mentioned above are shown in Fig. 15. 

Homogentisicase, or homogentisic oxidase, is an enzyme that catalyzes a step in the principal pathway of tyrosine degradation. The enzyme is found in both microbes and mammals the bulk of the information available has come from studies with mammalian liver enzymes. 

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