Biochemistry of Amino Acids - A. Maister 1961

Intermediary Metabolism of Amino Acids
Histidine
Histidine Degradation

The breakdown of histidine in mammalian Liver was first investigated by György and Röthler [644] and Edlbacher [645, 646]. Initially, it was hypothesized that this reaction—leading to the Cleavage of the imidazole ring, The formation of ammonia, and the disappearance of $\alpha$-amino nitrogen (determined by the Van Slyke method)—is catalyzed by a single specific enzyme, histidase. It was found that the main product of histidine transformation, which remained unidentified in early studies, readily hydrolyzes to yield ammonia, glutamic acid, and formic acid. Various potential structures for this compound were discussed [647–650], but the pathway was only fully elucidated in more recent work.

As early as 1874, Jaffe [651] observed the appearance of urocanic acid in dog urine, yet for a long time this compound was regarded as a minor byproduct of Histidine METABOLISM. Meanwhile, The conversion of histidine into urocanic acid was observed in Bacteria [652, 653]; urocanic acid was also frequently detected in animal urine following histidine administration [651, 653–660]. Sera and coworkers [661, 662], as well as other authors [663–670], observed the conversion of histidine to urocanic acid in liver tissue preparations. Thus, it became evident that urocanic acid is a normal intermediate of histidine metabolism. In a series of experiments, the conversion of urocanic acid into glutamic acid derivatives was noted. For instance, Takeuchi [663] obtained optically inactive isoglutamine from urocanic acid; Sera and Aihara [662] and Oyamada [665] isolated compounds that proved to be formyl derivatives of isoglutamine. Recently, Tabor and Hayaishi [671] found that Cell-free extracts from Pseudomonas fluorescens catalyze the conversion of L-histidine to yield L-glutamic acid, formic acid, and two moles of ammonia. Using labeled histidine, it was established that the $\alpha$-amino group of glutamic acid is derived from the $\gamma$-nitrogen of the imidazole ring, whereas the $\alpha$-amino group and the 5-nitrogen atom of histidine serve as the sources of the liberated ammonia [633]. Experiments with C¹⁴-labeled histidine demonstrated that formic acid is formed from the carbon atom at position 2 of the imidazole ring [673]. The conversion of histidine to urocanic acid, established through various experiments [661–670, 673–678], is catalyzed by the enzyme histidine deaminase (histidase, deaminohistidase; p. 196). In contrast to the reaction catalyzed by aspartase, the histidase reaction is irreversible, which is consistent with the inability of urocanic acid to replace histidine in rat growth assays [630]. Histidine deaminase has been found in bacteria and animal liver [648, 661, 663, 668, 679–682]. Available data do not allow for a definitive Conclusion regarding The Nature of the Cofactors involved in the action of this enzyme, although studies have been published indicating the participation of sulfhydryl groups [673, 680, 683, 684], Folic acid [680], and Metal Ions [673, 681, 683].

Urocanic acid is a constituent of murexine (urocanoylcholine) found in the Tissues of Murex trunculus and other Mollusks. The physiological action of urocanoylcholine has been found to resemble that of nicotine and curare [672, 685].

Class="center">

Urocanic acid is found in sweat; it may play a role in protecting the Skin against the effects of ultraviolet radiation [686, 687].

A number of researchers have studied the degradation of urocanic acid by the enzyme Urocanase. The product of urocanase action has been obtained in crystalline form by several authors and identified variously as formyl-DL-isoglutamine [665, 668], formyl-L-glutamine [648], and $\alpha$-formamido-L-glutamic acid [650, 683, 688–690]. Further studies [691, 692] confirmed that this compound is $\alpha$-formamido-L-glutamic acid. It turned out that this compound does not undergo rapid transformation in the liver, but is fairly easily subjected to non-enzymatic cleavage, yielding glutamic acid and isoglutamine. Meanwhile, data have been obtained on the conversion of histidine to glutamic acid in liver preparations [674, 676]. Pseudomonas and certain other bacteria readily convert urocanic acid, histidine, and $\alpha$-formamidoglutamic acid into glutamic acid, formic acid, and ammonia; formyl-L-glutamic acid appears to be an intermediate in this transformation [683, 689, 693–695].

It has been suggested that folic acid participates in the histidine deaminase reaction [680, 696]. $\alpha$-Formamido-L-glutamic acid has been found in the urine of folic acid-deficient rats [678, 690, 697, 698], which also points to the involvement of folic acid in histidine metabolism. Further studies have shown that $\alpha$-formamido-L-glutamic acid can serve as a formyl donor for the formylation of tetrahydrofolic acid [1122]; a reaction catalyzed by liver preparations has been described in which a formimino group is transferred from $\alpha$-formamido-L-glutamic acid to tetrahydrofolic acid, yielding $N^{10}$-formiminotetrahydrofolic acid, which is subsequently converted into $N^{10}$-formyltetrahydrofolic acid.

The available data are consistent with The pathway of histidine conversion to glutamic acid presented below. This pathway was proposed by Suda and coworkers and by Tabor and Mehler for Pseudomonas and for the liver (up to the stage of formamido-L-glutamic acid formation). Other potential pathways for histidine degradation involve the conversion of a hypothetical intermediate, imidazolonepropionic acid, into hydantoinpropionic acid and subsequently into carbamylglutamic and glutamic acids. The formation of $\alpha$-formylisoglutamine from imidazolonepropionic acid or urocanic acid is also possible.

Magasanik and Bowser [699, 700] and Wachsman and Barker [701] found that formamide accumulates during histidine metabolism in certain microorganisms (Clostridium tetanomorphum and Aerobacter aerogenes). In these microorganisms, the breakdown of $\alpha$-formamido-L-glutamic acid presumably occurs via Hydrolysis to formamide.

Histidine can be catabolized not only via urocanic acid, but also through alternative pathways. For instance, Roche and co-workers [702, 703] observed the conversion of histidine into a series of imidazole derivatives—imidazolepyruvic acid, imidazoleacetic acid, and imidazolemethanol—in the hepatopancreas of mussels. Histidine can also be converted into carnosine (which is hydrolyzed by a specific peptidase [704]) and anserine (p. 70). Thiolhistidine is a constituent of ergothioneine (p. 55), which was first isolated from ergot [705] and subsequently found in erythrocytes and various animal tissues [706, 707]. Evidence suggests that the ergothioneine in animal tissues is derived from dietary ergothioneine. In rats, ergothioneine accumulates in erythrocytes even at very low dietary concentrations (1:100,000) [708, 709]. Ergothioneine has also been detected in culture filtrates of N. crassa, where it is evidently synthesized from histidine; however, thiolhistidine is likely not an intermediate in this process. The sulfur of ergothioneine can be provided by Methionine or Cysteine, while the methyl groups are supplied by methionine [1123].

The decarboxylation of histidine to form histamine (Table 20) is of great physiological significance; the latter is well known for its potent pharmacological activity [710]. Mast Cells contain large amounts of histamine and exhibit high histidine decarboxylase activity. In the body, histamine exists in a bound form, the exact nature of which remains to be elucidated [1124]. Histamine is oxidized by histaminase (diamine oxidase, p. 192) to yield imidazoleacetaldehyde. The conversion of imidazoleacetaldehyde into imidazoleacetic acid has been demonstrated in experiments utilizing xanthine oxidase, as well as aldehyde dehydrogenase and diphosphopyridine nucleotide [711]. The oxidation of histamine to imidazoleacetic acid has been observed in vivo in certain animal species [712–717].

Cells of a Pseudomonas strain adapted to imidazoleacetic acid were shown to convert this compound into formylaspartic acid via the following reaction [718]:

There is currently no Evidence indicating the occurrence of a similar reaction in animals. Following the administration of labeled imidazoleacetic acid to rats, The excretion of imidazoleacetic acid ribonucleoside was observed [719]. This product was also isolated after the injection of histamine into rats. Imidazoleacetic acid appears to be the primary metabolite of histamine in the rat.

Fig. 18. Summary scheme of histidine transformations.

It has been reported that histidine may act as a coenzyme in certain Reactions Catalyzed by intestinal carbohydrases and Other Enzymes [720]. The Discovery of the enzymatic Synthesis of N-acetylimidazole in extracts of Clostridium kluyveri has led to suggestions that the imidazole group of histidine participates in acyl-transfer reactions [1125].

N-1-methylhistidine and N-3-methylhistidine occur naturally (p. 62), but little is known about their metabolism. When these methylhistidines are administered to rats, chickens, rabbits, or frogs, the bulk of the administered compound is excreted unchanged [1126].