Excess histidine may be converted to trans -urocanate by histidine ammonia lyase histidase in liver and skin. UV light in skin converts the trans form to cis -urocanate which plays an important protective role in skin. Liver is capable of complete catabolism of histidine by a pathway which requires folic acid for the last step, in which glutamate formiminotransferase converts the intermediate N-formiminoglutamate to glutamate, 5,10 methenyl-tetrahydrofolate, and ammonia.
Inborn errors have been recognized in all of the catabolic enzymes of histidine. Histidine is required as a precursor of carnosine in human muscle and parts of the brain where carnosine appears to play an important role as a buffer and antioxidant.
Histidine can be decarboxylated to histamine by histidine decarboxylase. This reaction occurs in the enterochromaffin-like cells of the stomach, in the mast cells of the immune system, and in various regions of the brain where histamine may serve as a neurotransmitter.
Histidine was first isolated from salmon protamine by Albrecht Kossel in 1. The pK for the side chain of the free amino acid is 6. The imidazolium side chain of histidine provides functions which are unavailable to other amino acids, such as general base catalysis in the catalytic triad of serine proteases 2. Histidine is one of the least abundant amino acids in whole body protein in humans. Tessari 6 calculated the total body protein content of various amino acids in humans.
The most abundant were proline g and glycine g , both important in structural proteins, whereas there were only g histidine, second only to tryptophan at 88 g. In addition to free and protein-bound histidine in the diet, histidine can be obtained from proteolysis of endogenous protein and from hydrolysis of histidine-containing peptides in the diet Figure 1.
Besides its role in protein synthesis, it can be converted to histamine or to carnosine and excess can be catabolized.
All of these pathways of histidine will be reviewed. Figure 2 shows the metabolic pathway for histidine metabolism. Histidase histidine ammonia lyase is the first and principal regulatory enzyme in the pathway, producing ammonia and trans -urocanate. It is a cytosolic enzyme, principally found in skin and liver, with a Km for histidine in the 1—4 mM range 7.
Liver and skin histidases are expressed from the same gene 8. Histidase contains an unusual modified amino acid, dehydroalanine, which is produced from serine 9. Trans -urocanate is nonenzymically converted to cis -urocanate in skin by UV light — nm , which has led to the suggestion it may serve as a natural protector against sunlight Alternatively, it may play a role in UV-induced immunosuppression A report suggests that cis -urocanate acts on human keratinocytes by generating reactive oxygen species, which in turn result in a transient modulation of epidermal growth factor receptor signaling, followed by induction of PGE 2 synthesis and increased apoptotic cell death Histidine catabolism in skin and liver.
When the plasma and tissue histidine concentrations become supraphysiological, histidine can be transaminated to imidazolepyruvic acid which can be detected in the urine of these patients It was thought that there was a specific histidine transaminase, but it has not been possible to isolate such an enzyme; the activity has been reported to copurify with glutamine transaminase in kidney 14 and with serine transaminase in liver Products of histidine transamination are only detected in urine if the histidine concentration is very high, such as in patients with histidinemia.
Trans -urocanate is hydrolyzed in the liver by urocanase to give 4-imidozoloneproprionate which, in turn, is converted to formiminoglutamate FIGLU. This step couples histidine catabolism to one-carbon metabolism because the 5,methenyl-THF formed by histidine catabolism may be metabolized to a variety of products.
This methionine may be converted to S-adenosylmethionine, the body's principal donor of methyl groups for transmethylation reactions.
The requirement of THF as a substrate for glutamate formiminotransferase implies that folate deficiency could limit histidine catabolism. Evidence for this idea is provided by the increased urinary FIGLU excretion that is found in folate-deficient individuals Glutamate, the other product of glutamate formiminotransferase, is used for many functions, including gluconeogenesis.
In common with many enzymes of amino acid catabolism 18 , 19 , liver histidase is hormonally regulated. Histidase activity is not apparent in rat liver until 4 d postpartum; thereafter it increases until puberty 8.
Sexual maturation in female rats is accompanied by an estrogen-driven doubling in hepatic enzyme activity. Both glucocorticoids and glucagon induce the synthesis of liver histidase 20 , as does a high-protein intake or a histidine load 8.
There are a number of other sources of one-carbon groups, however, of which serine is thought to be the most significant The one-carbon pool should be viewed as being continuously filled from a variety of sources and used for metabolic purposes, with excess one-carbon units being oxidized to carbon dioxide Thus it is likely that histidine contributes a relatively small proportion of the one-carbon groups that go to homocysteine remethylation and synthesis of purines and thymidylate.
Genetic mutations have been reported in 3 enzymes of the histidine catabolic pathway in liver: histidase, urocanase, and glutamate formiminotransferase. All 3 disorders are thought to be relatively benign, although many of the patients have been reported to have mental retardation which may be independent of the enzyme defects.
Histidinemia is the most frequent inborn metabolic error in Japan with an incidence of It is characterized by increased concentrations of histidine in the blood and urine and decreased concentrations of urocanate in blood and skin. It results from decreased activity of the histidase protein.
The initial characterization of the condition included mental retardation and speech impairment but it is now apparent that these are diverse phenotypes of this disease, ranging from a benign phenotype in the majority of subjects to classical features, including mental retardation, in the minority of subjects. The original subjects were identified by newborn screening. Kawai et al. They identified a number of mutations, including 4 missense mutations and 2 exonic and 2 intronic polymorphisms, in the histidase gene.
Urocanic aciduria is caused by a defect in the enzyme urocanase, which is coded for by the gene urocanate hydratase 1 UROC1. Kalafatic et al. The few early cases that were reported all showed mental retardation of unknown etiology Recently, Glinton et al.
Both subjects were found to be compound heterozygotes for missense variants in UROC1. These authors suggest that urocanase deficiency is a benign disease, unrelated to developmental delay. Formiminoglutamic aciduria is characterized by increased excretion of FIGLU, due to deficiency of glutamate formiminotransferase 28 , coded for by the formimidoyltransferase cyclodeaminase FTCD gene.
This enzyme is a bifunctional protein formiminotransferase-cyclodeaminase in which the first domain releases glutamate and the second domain produces ammonia and 5,methenyl-THF. Patients present with various degrees of severity, ranging from mental and physical retardation 29 to relatively mild outcomes Hilton et al.
Because THF is a required cofactor for glutamate formiminotransferase, its activity is very low in patients with folate deficiency and FIGLU consequently also appears in the urine.
In all of these inborn errors, a histidine-deficient diet was tried but the diets did not seem to matter for the relatively benign disorders. In addition, the diets were difficult for caregivers to manage so no dietary treatment is recommended The lack of a specific treatment of histidinemia is the reason newborn screening was stopped some years ago The imidazole side chain of histidine in proteins, such as actin, may be methylated in the N-3 position, using S-adenosylmethionine as methyl donor.
Recently, Wilkinson et al. Until now, no function was known for 3-methylhistidine residues. When the modified protein is degraded, the 3-methylhistidine is released intact and is excreted in the urine, providing a useful estimation of muscle protein degradation There are significant quantities of histidine-containing dipeptides in most of the meat or fish that humans eat.
Histidine-containing dipeptides are not hydrolyzed by regular di peptidases, but are hydrolyzed by their own specific hydrolytic enzymes, the carnosinases. Carnosinase 1 occurs in human serum, but not in serum from most other animals.
Carnosinase 2 is located intracellularly in intestinal and kidney cells Transporters on the basolateral side of the membrane must be facilitated passive because the sodium gradient works in the wrong direction. The transporter for carnosine is unknown 34 ; PEPT1 is sodium-dependent and is only present on the apical side of the membrane so it cannot transport carnosine on the basolateral side In the kidney tubule, carnosine is transported by oligopeptide transporter 2 PEPT2 , then it is hydrolyzed by carnosinase 2 and the products enter the blood.
If intact carnosine reaches the blood, it will be rapidly hydrolyzed there by carnosinase 1 so that there is minimal carnosine circulating in the human body There is more carnosine in type II or fast-twitch muscle fibers. Thus there is considerable interest in carnosine function in the sports fraternity. Adult men, on average, have 33 kg of muscle Proton-coupled oligopeptide transporter 1, a member of the proton-coupled oligopeptide transporter family, is expressed in human skeletal muscle 40 but it is not yet clear how readily it transports carnosine out of muscle Intestinal handling of dietary histidine-containing dipeptides.
CN1, carnosinase 1 in plasma; CN2, carnosinase 2 in cytoplasm of intestinal cells; PEPT1, peptide transporter in brush border of intestine. Thus histidine can be recovered from carnosine and replace dietary histidine.
Histidine was thought to be nonessential in adult humans because it was not possible to show a deficiency in humans who consumed a diet containing purified amino acids for 2 wk, although it was known that infant humans and adults of many other animals do require it 43 , It is possible that muscle carnosine gave rise to histidine to allow positive nitrogen retention for the 2 wk of no histidine in the diet.
It is now known that histidine is a nutritional requirement for adult humans as well, because they are unable to synthesize it Histidine can be enzymatically decarboxylated to give histamine Figure 4A.
The enzyme involved is histidine decarboxylase HDC which requires pyridoxal phosphate as its essential cofactor. HDC has long been known to be localized to mast cells 47 in various tissues and enterochromaffin-like ECL cells of the oxyntic mucosa of the stomach 48 , but more recently it has also been discovered in the central nervous system 49 and in immune cells Release of histamine from mast cells occurs in response to IgE binding to mast cell membrane receptors as part of the response to allergens.
In stomach, histamine has been reported to increase hydrochloric acid secretion by parietal cells HDC activity in ECL cells has been reported to be increased after gastrin treatment, as are histamine synthesis and release from these cells, followed by gastric acid secretion It is not clear whether increased plasma histidine concentrations could lead to increased synthesis of histamine in ECL cells.
Histidine can be decarboxylated to histamine which may be subsequently methylated to N1-methylhistidine. A Conversion of histidine to histamine by histidine decarboxylase. Pyridoxal phosphate is the cofactor. B Inactivation of histamine by histamine N-methyltransferase in brain. In addition to the role of histamine in gastric acid secretion and the immune response, it also serves as a neurotransmitter in specific regions of the brain Histamine is synthesized in cells of the posterior hypothalamus which have projections in various brain regions In brain of rats, the normal histidine content does not saturate HDC, so an increase in histidine would increase the rate of histamine synthesis Brain histamine controls various functions, such as the sleep—wake cycle, appetite, memory, and stress response Histamine is removed from synapses by transport into cells and inactivated by histamine N-methyltransferase in the cytoplasm to give N-methylhistidine Figure 4B.
Too little histidine 57 , loss-of-function mutation of the HDC gene 58 , or too much histamine N-methyltransferase activity 59 would cause low histamine concentrations in brain and neurological symptoms such as anxiety in mice 57 or Tourette syndrome in humans It has recently been suggested that an increase in brain histamine might contribute to the improvement of brain disorders Histidine metabolism has been studied since histamine was first discovered at the beginning of the previous century.
The clinical and biochemical pictures were emphasized in the latter half of the century but there are still many questions to be answered. There is continuing disagreement over how much histidine an adult human needs or can safely ingest.
Urinary excretion of 3-methylhistidine has been used as a measure of proteolysis for 50 y 32 but a possible role of the methylated protein has just recently been identified 31 and more work is needed on a possible mechanism. Many protective functions of cis -urocanate in skin have been proposed, but a recent article showed apoptotic cell death due to reactive oxygen species caused by cis -urocanate 12 , so is it protective or harmful?
Studies on the definitive role of carnosine in muscle 37 are still needed, as are those on a possible role of histamine in providing protection in several brain disorders Thus histidine is a well-known, well-studied amino acid but there is still much to do.
Publication costs for this supplement were defrayed in part by the payment of page charges. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition. Jones ME. Albrecht Kossel, a biographical sketch. Yale J Biol Med. Google Scholar. Carter P , Wells JA. Dissecting the catalytic triad of serine protease. Baldwin J , Chothia C. Haemoglobin: the structural changes related to ligand binding and its allosteric mechanism.
J Mol Biol. Kilejian A. A unique histidine-rich polypeptide from the malaria parasite, Plasmodium lophurae. J Biol Chem. The hydrophobicity of vertebrate elastins. J Exp Biol. Tessari P. Nonessential amino acid usage for protein replenishment in humans: a method of estimation. Am J Clin Nutr. Histidase and urocanase activities of liver and plasma. Correlations between tissue enzyme levels and plasmatic increases during human and mouse viral hepatitis.
Clin Chim Acta. Histidase and histidemia. Abstraction of a proton from imidazole A or C results in the imidazolate ion D, a resonance hybrid of two practically equivalent contributors.
The pK a of imidazole itself is Thus this ionization, producing a free imidazolate ion, would not occur under physiological conditions. In proposing a reaction mechanism for a physioligical process, it is not plausible to propose loss of a proton from an imidazole tautomer A or C to form a free imidazolate ion D. Any proposal of free imidazolate ion as an intermediate in an enzymatic reaction is simply incorrect. Imidazolate ion can be produced in organic solvents by the action of strong irreversible bases, such as hydride ion.
The ion can also serve as a ligand in transition-metal complexes. Thanks to Professor Daryl Eggers of San Jose State University for pointing out to me that imidazolate ion makes at least one appearance in biology, in the histidine side chain that bridges copper and zinc ions in the enzyme copper-zinc superoxide dismutase.
Mutations in this enzyme can lead to amyotrophic lateral sclerosis ALS , also known as Lou Gehrig's disease. The bridging histidine is shown in the illustration below. Metal-bridging imidazolate in human Cu-Zn superoxide dismutase 1hl5. The side chain of histidine 63 appears to be an imidazolate ion, in which both protons of imidazolium ion are replaced by strong Lewis acids, copper I or II and zinc II ions.
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