Acetoacetate from phenylalanine

Homogcntisate oxidase plays a part in the metabolic sequence which forms fumarate and acetoacetate from phenylalanine (123, 204,223,239.433,577,656,825, and especially the comprehensive review of aromatic amino acid metabolism by Dalgliesh (182)),... 

Phenylalanine is converted to tyrosine by a hydroxylation reaction. Tyrosine, pro-dnced from phenylalanine or obtained from the diet, is oxidized, nltimately forming acetoacetate and fnmarate. The oxidative steps required to reach this point are, surprisingly, not energy-generating. The conversion of fnmarate to malate, followed by the action of malic enzyme, allows the carbons to be used for gluconeogenesis. The conversion of phenylalanine to tyrosine and the production of acetoacetate are considered further in section IV of this chapter. 

Approximately the same dilution of activity was found for both the and the labels, indicating that the acetoacetic acid is derived as a 4-carbon atom unit from phenylalanine. 

The origins of the skeletal fragments of 6.19), 6.20), and 6.21) not accounted for by lysine (and A -piperideine) are as follows. The C3 side-chain in A -methylpelletierine 6.19) has its origins in acetate plausibly via acetoacetate [9]. The side-chain of sedamine 6.21), on the other hand, derives from phenylalanine, probably by way of its deamination product, cinnamic acid [10, 11]. Benzoylacetic acid, a normal in vivo transformation product of cinnamic acid, may also reasonably be included in the pathway to this alkaloid, as it is in, e.g., the biosynthesis of lobeline 6.34) and of phenanthroindolizidine alkaloids (see Section 6.2.2). The pyridine ring of anabasine 6.20) arises from nicotinic acid [14] by way presumably of 6.5) (cf nicotine. Section 6.2.2). The acid precursors (see Scheme 6.6) for 6.19), 6.20) and 6.21), have in common an electron-donating functionality (Scheme 6.7) which may react with A -piperideine 6.18), possibly with concommitant decarboxylation, to give the alkaloids (cf fatty acid biosynthesis. Section 1.1.2). 

The biosynthesis starts from the amino acid ornithine which is converted into the pyrrolidine system by the two paths sketched above. The 3 C or 4 C chain must now be built on. The starting material fdr this is, in both cases, acetate. It is probable that two units of acetate first form acetoacetate which can then be linked with the pyrrolidine ring to give variant 2 of the tropane skeleton. Variant 2 can then be converted to cocaine. However, decarboxylation of variant 2 gives variant 1 of the tropane skeleton which can then be transformed into hyoscyamine or scopolamine. For this tropic acid, which is derived from phenylalanine, is necessary (Fig. 125). 

Tyrosine—whether formed from phenylalanine or arising directly from ingested proteins— has various pathways available. Quantitatively, the most important is the degradation to acetoacetate -t- fumarate the melanins, the dark hair and skin pigments, also come from tyrosine, as do the hormones epinephrine (Chapt. VIII-5, XX-5) and thyroxine (cf. Chapt. XX-4). 

Tyrosine, obtained from the diet or by hydroxylation of phenylalanine, is converted to homogentisate, whose aromatic ring is opened and cleaved, forming fumarate and acetoacetate (Figure 7-12). 

Tyrosine is either used for the biosynthesis of proteins, thyroxine, epinephrine, or melanin, or catabo-lized to yield fumaryl acetoacetate. The biosynthesis of proteins and thyroxine is discussed elsewhere this discussion is restricted to epinephrine and melanin synthesis and tyrosine catabolism. Dopa 3,4-dihydroxy-phenylalanine is an intermediate common to epinephrine and melanin. To yield epinephrine, dopa is first decarboxylated by an enzyme called dopa decarboxylase. This enzyme is present in several mammalian tissues, including the adrenal medulla, where the reaction yields hydroxytryptamine chloride. From this... 

Tyrosine, a nonessential AA, is created from the hydroxylation of phenylalanine. Catecholamine neurotransmitters such as dopamine, epinephrine, and norepinephrine are produced from it, and it is also a precursor of the hormones thyroxine and triiodothyronine. Fumarate, a TCA cycle intermediate, and acetoacetate are formed in the catabohsm of tyrosine, making it both glucogenic and ketogenic. Performance-related stress during intense military operations has been shown to be attenuated or reversed by exogenous tyrosine, apparently by increasing norepinephrine levels in the brain. ... 

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