Histidine purine synthesis

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. 

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. 

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. ... 

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

PRPP is the activated intermediate in the synthesis of phosphoribosylamine in the de novo pathway of purine formation of purine nucleotides from free bases by the salvage pathway of orotidylate in the formation of pyrimidines of nicotinate ribonucleotide of phosphoribosyl ATP in the pathway leading to histidine and of phosphoribosylanthranilate in the pathway leading to tryptophan. 

Once inside the cell, folates participate in a number of interconnected metabolic pathways involving (1) thymidine and purine biosynthesis necessary for DNA synthesis, (2) methionine synthesis via homocysteine remethylation, (3) methylation reactions involving S-adenosylmethionine (AdoMet), (4) serine and glycine interconversion, and (5) metabolism of histidine and formate (see Figure 8). Via these pathways. 

Serum/giyeine metaboUsm Histidine catabolism Thymidylate synthesis Melhibnine synthesis Purine isyhthesis... 

One-carbon methyl donors for tetrahydrofolate and SAM Glycine, serine, histidine, methionine Most cells, but highest in liver Choline, phosphatidylcholine, purine and pyrimidine synthesis, inactivation of waste metabolites and xenobiotics through methylation. 

Histidine (His), like tryptophan, is an amino acid essential for protein synthesis. The biosynthetic pathway for histidine, which is closely linked to the biosynthesis of purine, has been identified in many organisms and thoroughly reviewed [302, 303]. 

The pathway of histidine biosynthesis, as it is now known, is shown in Fig. 3-1. The N-1 and C-2 of ATP, and the ribose-P w hich becomes bound to its N-1 position, provide the skeleton of histidine, while the phospho-ribosyl aminoimidazole carboxamide remnant is released. As is shown in Chapter 7, phosphoribosjd aminoimidazole carboxamide is an intermediate in the pathway of purine biosynthesis de novo, and so histidine synthesis not only provides a branch leading into this pathway, but actually makes a loop. 

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