Histidine imidazole ring biosynthesis

The imidazole ring of histidine (30) arises by a quite different route to that used for the formation of the imidazole ring in purine biosynthesis. The sources of the carbon and nitrogen atoms of histidine were established as a result of a series of labelling experiments with T4C and 15N substrates coupled with degradation of the labelled histidines. A summary of these results is given in Scheme 7 (59JBQ234)586). 

Histidine can be prepared from imidazole as in Scheme 117. It is a basic amino acid, the biosynthesis of which appears to involve adenosine 5 -phosphate, ribose phosphate and glutamine (which supplies a nitrogen for the imidazole ring) (Scheme 118). Histidine is one of the most important amino acids and has involvement in such biological processes as ester hydrolysis, acylation and (by virtue of its complexing power with iron) oxygen... 

Imidazole alkaloids alkaloids of sporadic occurrence, possessing the imidazole ring system. Tlieir most important representative is Pilocarpine (see). The biosynthesis of the I. a. is coupled to histidine metabolism. 

The role of purines in the biosynthesis of the imidazole ring of histidine has been investigated in baeteria. The use of labeled purine bases (guanine and adenine) followed by the chemical breakdown of newly formed histidine established that the and the C2 of the purine base were incorporated in the N3 and C2 of the imidazole ring of histidine. The N3 of the imidazole ring was shown to be derived from glutamine. On the basis of further studies on cell-free preparations, the biosynthetic pathway of the imidazole ring of histidine ean now be outlined. Ribose-1-phosphate reacts with ATP to yield phosphoribosyl pyrophospate and AMP PRPP reacts with ATP to form a new complex assumed to be phosphoribosyl ATP. Phosphoribosyl (PR) ATP is then converted to PR AMP by a specific... 

The amino acid L-histidine is the assumed building block in the biosynthesis of pilocarpine (27) and other imidazolic alkaloids due to the presence of glyoxaline ring [8, 23]. First attempts to clarify this pathway were proposed by Boit and Leete that considered the phosphate derivative of 2-oxo-3-(5-imidazofyl)-propanol, also known as imidazole pyruvic acid, as imidazole ring precursor (Scheme 25.1-Pathway 1) [8]. This initial biosynthesis proposal was improved detailing the lactone ring formation by aldol condensation. Another biosynthetic approach suggested condensation of 2-oxobutyric acid (lactone moiety) with urocanic acid (imidazole moiety) (Scheme 25.1- Pathway 2) [8, 39]. 

All three elimination reactions—E2, El, and ElcB—occur in biological pathways, but the ElcB mechanism is particularly common. The substrate is usually an alcohol, and the H atom removed is usually adjacent to a carbonyl group, just as in laboratory reactions. Thus, 3-hydroxy carbonyl compounds are frequently converted to conjugated unsaturated carbonyl compounds by elimination reactions. A typical example occurs during the biosynthesis of fats when a 3-hydroxybutyryl thioester is dehydrated to the corresponding unsaturated (crotonyl) thioester. The base in this reaction is the imidazole ring (Section 9.4) of a histidine amino acid in the enzyme, and loss of the hydroxyl group is assisted by simultaneous protonation. 

The pattern of histidine biosynthesis began to emerge when certain metabolites accumulated by histidineless mutants of Nevrospora crasaa and E. coli were isolated and identified. Other clues were an interrelationship between histidine and purine metabolism shown by a sparing effect by histidine of the purine requirement of Lactobacillua casei [276, 277). k little later it was established that the purines were the source of at least a portion of the carbons and nitrogen of the imidazole ring 277-f 9). 

Subsequently Moyed and Magasanik ( 88) obtained the synthesis of D-er ro-imidazoleglycerol phosphate ester in cell-free preparations from three enteric bacterial species. This compound is a precursor of histidine. Evidence was also obtained that the imidazoleglycerol phosphate was formed from ribose 5-phosphate, the amide nitrogen of glutamine, and the N-1 and C-2 portion of the adenine ring of ATP. The residue of the ATP appears as 5-amino-l-ribosyl-4-imidazolecarboxamide 5 -phosphate. The latter is a well-known intermediate in purine biosynthesis and can be reconverted to ATP. This provides a cyclic process for the i thesis of the imidazole ring of histidine. 

Since aminoribosylimidazolecarboxamide phosphate is not a known precursor for purine biosynthesis and various experimental results were obtained which indicated that this compound was not being utilized for purine formation by the bacterial preparations, Moyed and Magasanik were led to suspect that this compound was involved in the biosynthesis of the imidazole ring of histidine. This suggestion was supported by the finding of the accumulation of D-erj/ffiro-imidazoleglycerol phosphate ester as a product of these reactions. 

Formation of L-histidine is closely related to purine biosynthesis (D 10.4, Fig. 239). ATP is the actual precursor. It condenses with phosphoribosyl pyrophosphate at position 1 before the purine ring is splitted between the positions 1 and 6. An Amadori rearrangement in the two-prime-ribose unit yields the ribulose derivative l-(5 -phosphoribosyl)-4-carboxamido-5-iV-(N -5 -phospho-ribosyl)-formamidinoimidazole, which reacts with glutamine to D-erythro-imidazole glycerol phosphate (the precursor of histidine) and l-(5 -phospho-ribosyl)-4-carboxamido-5-aminoimidazole, which may be regenerated to ATP (D 10.4). 

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