Histidine

Ligand

Histidine forms complexes with many metal ions. The imidazole sidechain of the histidine residue commonly serves as a ligand in metalloproteins. One example is the axial base attached to Fe in myoglobin and hemoglobin. Poly-histidine tags (of six or more consecutive H residues) are utilized for protein purification by binding to columns with nickel or cobalt, with micromolar affinity.^[12] Natural poly-histidine peptides, found in the venom of the viper Atheris squamigera have been shown to bind Zn(2+), Ni(2+) and Cu(2+) and affect the function of venom metalloproteases.^[13]

Biosynthesis

l-Histidine is an essential amino acid that is not synthesized de novo in humans.^[14] Humans and other animals must ingest histidine or histidine-containing proteins. The biosynthesis of histidine has been widely studied in prokaryotes such as E. coli. Histidine synthesis in E. coli involves eight gene products (His1, 2, 3, 4, 5, 6, 7, and 8) and it occurs in ten steps. This is possible because a single gene product has the ability to catalyze more than one reaction. For example, as shown in the pathway, His4 catalyzes 4 different steps in the pathway.^[15]

Histidine is synthesized from phosphoribosyl pyrophosphate (PRPP), which is made from ribose-5-phosphate by ribose-phosphate diphosphokinase in the pentose phosphate pathway. The first reaction of histidine biosynthesis is the condensation of PRPP and adenosine triphosphate (ATP) by the enzyme ATP-phosphoribosyl transferase. ATP-phosphoribosyl transferase is indicated by His1 in the image.^[15] His4 gene product then hydrolyzes the product of the condensation, phosphoribosyl-ATP, producing phosphoribosyl-AMP (PRAMP), which is an irreversible step. His4 then catalyzes the formation of phosphoribosylformiminoAICAR-phosphate, which is then converted to phosphoribulosylformimino-AICAR-P by the His6 gene product.^[16] His7 splits phosphoribulosylformimino-AICAR-P to form d-erythro-imidazole-glycerol-phosphate. After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes l-histidinol-phosphate, which is then hydrolyzed by His2 making histidinol. His4 catalyzes the oxidation of l-histidinol to form l-histidinal, an amino aldehyde. In the last step, l-histidinal is converted to l-histidine.^[16][17]

The histidine biosynthesis pathway has been studied in the fungus Neurospora crassa, and a gene (His-3) encoding a multienzyme complex was found that was similar to the His4 gene of the bacterium E. coli.^[18] A genetic study of N. crassa histidine mutants indicated that the individual activities of the multienzyme complex occur in discrete, contiguous sections of the His-3 genetic map, suggesting that the different activities of the multienzyme complex are encoded separately from each other.^[18] However, mutants were also found that lacked all three activities simultaneously, suggesting that some mutations cause loss of function of the complex as a whole.

Just like animals and microorganisms, plants need histidine for their growth and development.^[10] Microorganisms and plants are similar in that they can synthesize histidine.^[19] Both synthesize histidine from the biochemical intermediate phosphoribosyl pyrophosphate. In general, the histidine biosynthesis is very similar in plants and microorganisms.^[20]

Degradation

Histidine is one of the amino acids that can be converted to intermediates of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle).^[22] Histidine, along with other amino acids such as proline and arginine, takes part in deamination, a process in which its amino group is removed. In prokaryotes, histidine is first converted to urocanate by histidase. Then, urocanase converts urocanate to 4-imidazolone-5-propionate. Imidazolonepropionase catalyzes the reaction to form formiminoglutamate (FIGLU) from 4-imidazolone-5-propionate.^[23] The formimino group is transferred to tetrahydrofolate, and the remaining five carbons form glutamate.^[22] Overall, these reactions result in the formation of glutamate and ammonia.^[24] Glutamate can then be deaminated by glutamate dehydrogenase or transaminated to form α-ketoglutarate.^[22]

Conversion to other biologically active amines

• The histidine amino acid is a precursor for histamine, an amine produced in the body necessary for inflammation.^[25]
• The enzyme histidine ammonia-lyase converts histidine into ammonia and urocanic acid. A deficiency in this enzyme is present in the rare metabolic disorder histidinemia, producing urocanic aciduria as a key diagnostic finding.
• Histidine can be converted to 3-methylhistidine, which serves as a biomarker for skeletal muscle damage, by certain methyltransferase enzymes.^[26]
• Histidine is also a precursor for carnosine biosynthesis, which is a dipeptide found in skeletal muscle.^[27]
• In Actinomycetota and filamentous fungi, such as Neurospora crassa, histidine can be converted into the antioxidant ergothioneine.^[28]