Biosynthesis of histidine

Phosphoribosylpyrophosphate (PRPP) synthetase is one of the very few enzymes which transfer a pyrophosphoryl group from ATP in one step. When the synthesis is carried out in lsO-enriched water, lsO is incorporated into the PRPP, but not into AMP.91 The lsO in the PRPP arises from a pre-exchange between the H2180 and the ribose phosphate, and hence the results confirm that fission of the /5-P—O bond takes place. PRPP and ATP are starting materials in the biosynthesis of histidine, and Ai-(5 -phospho-D-ribosyl)adenosine triphosphate (29) is an intermediate. The... 

FIGURE 22-20 Biosynthesis of histidine in bacteria and plants. Atoms derived from PRPP and ATP are shaded red and blue, respectively. Two of the histidine nitrogens are derived from glutamine and glutamate (green). Note that the derivative of ATP remaining after step (AICAR) is an intermediate in purine biosynthesis (see Fig. 22-33, step ), so ATP is rapidly regenerated. 

Scheme 8 Biosynthesis of histidine (30) (P P03H2, PPP = P308H4, PPi = H3P207", Pi = H2P04")...

During the conversion of anthranilate to tryptophan, two additional carbon atoms must be incorporated to form the indole ring. These are derived from phosphoribosyl pyrophosphate (PRPP) which is formed from ribose 5-phosphate by transfer of a pyro-phospho group from ATP.60 61 The - OH group on the anomeric carbon of the ribose phosphate displaces AMP by attack on Pp of ATP (Eq. 25-5). In many organisms the enzyme that catalyzes this reaction is fused to subunit II of anthranilate synthase.62 PRPP is also the donor of phosphoribosyl groups for biosynthesis of histidine (Fig. 25-13) and of nucleotides (Figs. 

The biosynthesis of histidine. The 5-aminoimidazole-4-carboxamide ribotide formed during the course of histidine biosynthesis is also an intermediate in purine nucleotide biosynthesis. Therefore it can be readily regenerated to an ATP, thus replenishing the ATP consumed in the first step in the histidine biosynthetic pathway (see fig. 23.13). 

Assays that detect reverse mutation are most popular, largely because of the development of the Salmonella/micro-some assay by Bruce Ames and his co-workers.10 13 All five of the strains that sure currently recommended95 contain point mutations that prevent the biosynthesis of histidine. Unless histidine is provided in the growth medium, the bacteria cannot grow. However, if a new mutation occurs at the site of the original mutation and "reverses" its effect, growth without histidine can take place. 

See also Table 5.1, Genetic Code, Metabolism of Aromatic Amino Acids and Histidine, Biosynthesis of Histidine / Ames Test, Essential Amino Acids... 

See also Biosynthesis of Histidine / Ames Test, Aromatic Amino Acid Utilization... 

Figure 5.82 Biosynthesis of histidine. PRPP, 5-phosphoribosyl-a-l-pyrophosphate PRATP, AT-5 -phosphoribosyl-ATP PRAMP, M-S -phosphoribosyl-AMP 5 -ProFAR, yV -[(5. phosphoribosyl)-formimino]-5-aminoiinidazole-4-carboxamide-ribonucleotide 5 -PRFAR, A/ -[(5 -phosphoribulosyl)-formimino]-5-aminoimidazole-4-carboxainide-ribonuc leotide IMGP, imidazole glycerol-phosphate AICAR, 5 -phosphoribosyl-4-carboxamide-5-aminoimidazole lAP, imidazoleacetol-phosphate HOL-P, L-histidinol-phosphate HOL, L-histidinol HAL, L-histidinal.

Pilocarpine has been suggested to arise from condensation of an alcohol involved in the biosynthesis of histidine (as the phosphate) and acetoacetate (Fig. 37,2). A second path has also been suggested. There is little experimental evidence to establish either pathway (Maat and Beyerman, 1983). 

Feedback inhibition of the first enzyme in the pathway keeps the pathway adjusted to the availabihty of external histidine. When sufficient exogenous histidine is present, feedback inhibition completely stops the biosynthesis of histidine. Inhibition of the first enzyme by ADP and AMP adjusts the pathway to the energy charge status of the cell. Together, these repression and inhibition controls provide a complex circuitry by which the rate of histidine biosynthesis is correlated with the cell s needs and potential. 

Studies on the biosynthesis of histidine in Salmonella by Ames and Hartman [214] established the simultaneous repression of several enzymes. In the series of reactions (at least 10 different steps) involved in the biosynthesis of the histidine molecule, the 5-carbon chain of phosphoribosyl pyrophosphate is converted to the 5-carbon chain of histidine. In Sal-... 

Scheme 12.26. The initial steps in the biosynthesis of histidine (His, H) correspond to a building up of the appropriate network and results in the degradation of an equivalent of ribose (as the 1,5-diphosphate) and adenosine triphosphate (ATP). EC numbers and some graphic materials provided in this scheme have been taken from appropriate links in a URL starting with http //www.chem.qmul.ac.uk/iubmb/enzyme/.

Phosphorylation at the carboxylate (ATP ADP) followed by reaction with aspartate (Asp,D) in the presence of phosphoribosylaminoimidazolesuccinocarbox-amide synthase (EC 6.S.2.6) produces the corresponding (S)-succinate derivative. This is followed by loss of fumarate (adenylosuccinate lyase, EC 4.S.2.2) to the corresponding amide (last seen in the biosynthesis of histidine (His, H) (Scheme 12.26). Then, as shown in Scheme 12.97, N-formylation (as in Scheme 12.87) on the C-5 amino group is effected with IO-CHO-H4 folate (EC 2.1.2.3) to yield the N-formyl derivative (5-formamido-l-(5 -phosphoribosyl) imidazole-4-carboxyamide). Loss of water accompanies cyclization (EC 3.5.2.10) to yield inosine 5 -phosphate (IMP). 

Evidence is slowly accumulating on the mechanism of the biosynthesis of histidine. It has been established that glutamate and formate are products of the catabolism of histidine (see the chapter. Carbon Catabolism of Amino Acids). This offered a clue to the possible approach to the problem, as it is conceivable that the reversal of at least some of the reactions of degradation may be involved in the synthesis. 

In addition two compounds which appear to be the phosphate esters of I and II have also been obtained. These results have led Ames and C 0-workers to postulate a scheme for the biosynthesis of histidine in which the phosphate esters of I, 11, and III were assumed to be the direct sequential intermediates of histidine from an unknown carbohydrate. The occurrence of a trihydroxypropyl side chain in the first compound in... 

This observation suggests that the urinary substance giving rise to the atypical indican test was not derived from dextrorotary intermediates arising in the biosynthesis of histidine. 

The herbicide Amitrole (455) has several documented effects on metabolism. In E. coli, histidine and adenine together reverse the inhibition of growth by Amitrole, whereas adenine alone, but not histidine alone, partially relieves the inhibition. In the yeast T. cremoris, histidine alone, but not adenine alone, completely reverses the inhibition.A metabolite, identified as a conjugate of alanine and Amitrole, has been shown to accumulate in the medium of E. coli cultured in the presence of Amitrole it apparently competes with histidine for incorporation into protein.Unlike Amitrole, this metabolite does not inhibit the conversion of imidazole glycerol phosphate (IGP) to imidazole acetol phosphate by IGP dehydratase in Salmonella the reaction is part of the biosynthesis of histidine. 

The presence of similar structural groups in their molecules led to much speculation and experimental work to demonstrate interrelations between histidine, arginine, creatine, the purines, and the pyrimidines. A relationship has been established in the biosynthesis of histidine and the purines in certain bacteria. This is discussed in Chapter 15. 

---