Histidine purines

The amino acid histidine has important functions in the active centres of several enzymes. Its biosynthesis involves intermediates which are possibly related to a precursor molecule (purine base) of a ribozyme. 

Bioinorganic chemists have been attracted by the complex formations of NHC because the imidazolin-2-ylidene motif is encountered frequently in living organisms. The imidazole moiety is part of the purin bases in both DNA and RNA as well as the amino acid histidine which appears in proteins and enzymes and is in many cases considered to play a decisive role within the catalytically active center. The possible formation of NHC complexes under physiological conditions or in vivo has been addressed by investigation of A-confused caffeine 73 or purine 74 complexes. 

In connection with histidine, the work of Windaus and Knoop on the formation of methylimidazole from glucose must be mentioned on account of the possible synthesis in the animal body of both histidine and purine bases. 

Many of the simple heterocycles occur naturally within human biochemistry. For example, the amino acids proline, histidine, and tryptophan contain, respectively, a pyrrolidine, an imidazole, and an indole ring. The nucleic acids contain purine and pyrimidine rings. Vitamins are heterocyclic compounds vitamin Bg (8.8) is a substituted pyridine vitamin Bj (8.9) contains a pyrimidine ring. Simple heterocycles are therefore important to human biochemistry and thus to drug design. 

It plays a vital role in various intracellular reactions e.g. conversion of serine to glycine, synthesis of thymidylate, synthesis of purines, histidine metabolism etc. Due to folic acid deficiency these reactions are affected. 

Discussing the biosynthetic pathways for amino acids and nucleotides together is a sound approach, not only because both classes of molecules contain nitrogen (which arises from common biological sources) but because the two sets of pathways are extensively intertwined, with several key intermediates in common. Certain amino acids or parts of amino acids are incorporated into the structure of purines and pyrimidines, and in one case part of a purine ring is incorporated into an amino acid (histidine). The two sets of pathways also share... 

Histidine Biosynthesis Uses Precursors of Purine Biosynthesis... 

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. 

Among the essential amino acids, the aromatic amino acids (phenylalanine, tyrosine, and tryptophan) form by a pathway in which chorismate occupies a key branch point. Phosphoribosyl pyrophosphate is a precursor of tryptophan and histidine. The pathway to histidine is interconnected with the purine synthetic pathway Tyrosine can also be formed by hydroxylation of phenylalanine (and thus is considered conditionally essential). The pathways for the other essential amino acids are complex. 

Phosphoribosyl pyrophosphate (PRPP) is important in both, and in these pathways the structure of ribose is retained in the product nucleotide, in contrast to its fate in the tryptophan and histidine biosynthetic pathways discussed earlier. An amino acid is an important precursor in each type of pathway glycine for purines and aspartate for pyrimidines. Glutamine again is the most important source of amino groups—in five different steps in the de novo pathways. Aspartate is also used as the source of an amino group in the purine pathways, in two steps. 

Tetrahydrofolate receives one-carbon fragments from donors such as serine, glycine, and histidine and transfers them to intermediates in the synthesis of amino acids, purines, and thymine—a pyrimidine found in DNA. ... 

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). 

In contrast to our understanding of the pathways by which the purines, pyrimidines and histidine are formed, we know much less about the formation of other equally important... 

There are several classes of alkaloids. Among these are purines such as xanthine and caffeine, ter-penes (Chapter 22), polyketides (Chapter 21), and alkaloids derived from amino acids. The basic amino acids ornithine, arginine, histidine, and lysine as well as the aromatic amino acids, anthranilate, and nicoti-nate are some of the starting materials.199 201 Robinson202 203 in 1917 recognized that many alkaloids are derived directly from aromatic amino acids. He proposed that alkaloids arise from Mannich reactions (Eq. 25-12) in which an amine and an aldehyde (probably through a Schiff base) react with a nucleophilic carbon such as that of an enolate anion. Many of the... 

In Fig. 20, B, R, B2, and R2 are the positions of the base and ribose components of the dinucleotide or independent pyrimidine and purine nucleotides, respectively. The phosphate position pi can be occupied by the 3, 5"-diester (5" refers to the 5 position of R2 in a diester) or the 3 - and 5 -nucleotides, respectively. In the protein crystal a sulfate ion occupied this position in variable degree depending on the pH. Histidine 119 can be in any one of four or more positions depending on various factors. The second base might be in position B2 when it is a pyrimidine. The phosphate of a cyclic substrate or pentacovalent intermediate may be at p,. The position labeled H20 is the position of an isolated peak on the electron density map which is interpreted to be a water molecule, Wi, present in the protein and in the complexes. 

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