Histidine

L-Histidine ((S)-alpha-amino-1 H-imidazole-4-propaooic acid. L-2-amino-3-<11 f-imidazol-4-yl) propionic acid alpha-amino-4-imiazolcpropionic acid alpha-amino-5-imiazolepropionic acid, levo-histidine. glyoxali ne-5-al an i nc, one-letter code H; molecular weight 155) is a basic amino acid with 27% nitrogen.

Abbreviations

GABA gamma-aminobutyric acid His L-histidtne

LAT2 L-type amino acid transporter 2 (SLC7A8)

PLP pyridoxal-5'-phosphate

RDA recommended dietary allowance

Nutritional summary

Function: The essential amino acid L-histidine I His) is used as a precursor of the mediator histamine, and for the synthesis of proteins. Several dipeptides involved in signaling and cell protection contain His.

His is also an energy fuel; its complete oxidation requires thiamin, riboflavin, niacin, v itamin B6, folate, pantothenate, lipoate. ubiquinone, iron, and magnesium. Food sources: Dietary proteins from different sources all contain His. Pork and beef protein has a slightly higher content (3-4% of total protein) than milk, chicken, egg or grain proteins (2 3% of total protein). Dietary supplements containing crystalline His are commercially available.

Requirements Adults arc thought to require about 520 7X0 mg J (FAO WHO UNU, 1985). Whether individuals with rheumatoid arthritis and other chronic inflammatory conditions benefit from additional intakes is uncertain.

Deficiency: Prolonged lack of His as of all essential amino acids or a lack of protein causes growth failure, loss of muscle mass and organ damage. Excessive intake: Very high intake of protein and mixed amino acids (more than three times the RDA or 2.4 g.'kg) is thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis. Dermatomyositis has been reported m a user of crystalline I lis. The health consequences of accumulation of the metabolite formiminoglutamic in folate-deficient consumers of His supplements are not known.

Dietary sources

1 lis is an essential amino acid that cannot be produced in the body and must be supplied from external sources. All dietary proteins contain llis. though the quantities vary between types of food. Pork (38 mg g). beef (34mg g). and other meats contain slightly more His than legumes (around 27mg gt and grains (around 23 mg g); corn (maize) has a slightly higher content (about 30mg g) than other grains.

The histidyl dipeptides carnosine and homocarnosine represent a significant proportion of the His in meats. Anserine (bcta-alany I-1 -methyl-L-histidinel is not biologically equivalent to I lis because it contains mcthylhistidmc. Bacterial synthesis in the ileum and colon can be a significant source (Mctgcs, 2000).

Note: Casein and soy protein hvdrolysates in some dietary supplements contain significant amounts of the diketopiperazine cyclo(His-Pro) which can be absorbed from the intestine (Mizumo et al., 1997). Cyclol His-Pro), which is normally produced during the specific degradation of thyroid-releasing hormone (TRH. py roglulamylhistidyipro-linamidc) by pyrogIutamyl-peptidase II (EC3.4.I9.6), affects motor functions, influences body temperature, inhibits prolactin secretion (Prasad. 1998), and might stimulate growth hormone output (Kagabu et ul.. 1998). Normal daily excretion with urine, which is likely to reflect endogenous production, is about 0.5 mg (Prasad et al. 1090).

Digestion and absorption

I Icalthy indiv iduals absorb amino acids and proteins in the proximal small intestine nearly completely. Food proteins arc hydroly/cd by an array of gastric, pancreatic, and enteral enzymes, which generate His as part of oligopeptides, and in free form. The former can be taken up through the hydrogen ion/peptide cotransporter (PepTl; SLCI5A1) His can be taken up by the sodium-driven transport system B" . The capacity of this transporter is expanded by the action of the rBAT (SLC3A1 l-glyeo-protein-anchored transporter HAT lb0, " (SLC7A9) which can exchange I lis for other neutral amino acids in either direction across the brush border membrane (Chairoungdua et at., 1999).

The hetcroexchanger v * L AT I (SLC7A7) and, with lower affinity, LAT2(SLC7A8) in combination with their glycoprotein membrane anchor 4F2 (SLC3A2) can shuttle

L- Py rogl ut a myl - L-histidyl- L - proli na mide (T R H )

Pyroglutamyl-peptidase II (2n )

^HgO

Pyroglutamyl-peptidase II (2n )

l-Pyroglutamate - Cyclo(prolyl-histidine)

Figure 8.85 Some protein hydrolysates contain bioactive cydo(Hi5-ProJ

His across the basolateral membrane in exchange for other neutral amino acids in combination with a sodium ion.

Transport and cellular uptake

Blood circulation: Most of the His in blood is part of proteins and peptides, some of which are taken up into tissues \ia their specilic mechanisms. The small amounts of His circulating in free lorm, typically around 87 pmol l.can enter cells through different dl'tri peptides

Intestinal lumen dl'tri peptides

Intestinal lumen

Capillary lumen

Brush border membrane

Baso late ral membrane

Capillary endothelium

Figure 8.86 Intestinal absorption of L-htsudine

Capillary lumen

Brush border membrane

Baso late ral membrane

Capillary endothelium

Figure 8.86 Intestinal absorption of L-htsudine transporters, depending on the particular tissue. The sodium-independent transporter y LAT2 (SI C7A6) can exchange His for another neutral amino acid phis one sodium ion in many tissues. Anotherglycoprotein-lmked hetcroexchanger, LATI ISLC7A5), has lower affinity. ATA2, a representative of sodium-dependent system A in most tissues, can also accept His for transport, though with lower affinity (Sugawara t't at.. 2000). The same applies to ATA3 in liver.

Materno-fetal transfer: Net His transfer from the mother to the fetus appears to occur. The sodium-independent transporter y* and system L-related transporters, which exchange His for other neutral amino acids, are expressed in the microvillous and basal membranes {Jansson. 20011. One of these, the hetcroexchanger y LATI iSL(_'7A7. associated with 4F2), mediates transfer across the basal membrane I kudo and Boyd 2001). There is still some uncertainty about the exact location and contribution of the various transporters.

Blood-bram barrier: Transport of 1 lis across the blood brain barrier involves one or more of the system L transporters | Reichel et ai, 2000). ATA I in brain also accepts I lis. The exact location of these and other transporters remains uncertain.

Metabolism

Main pathway His breakdown is usually initiated by histidineammonia-lyase I lustidase. EC4.3.l.3).The next step is catalyzed by urocanate hydratase(urocanase. EC4.2.1,4'>). This enzyme is somewhat unusual because it contains a tightly bound NAD molecule,

COOH

COOH

COOH

PhefHrs) aminotransferase (PLP) or Aromatic amino acid glyoxyfate aminotransf t (PLP)

COOH

COOH

Pyruvate dehydrogenase ?

COOH

Pyruvate dehydrogenase ?

4-lmidazole-

5-i(-ketopropionate

4-lmidazole-

5-i(-ketopropionate

COOH I

CHr I

Urocanase (NAD]

4-Imidazoles-propionate

Imidazonolone propionase r

COOH

CHa I

N-Formimino glutamate

Glutamate lorm imi no-Ira nsf erase s- THF

S, 5-lorm* irnino THF

COOH f

COOH

L-Glutamate

HgurF 8.87 Metabolic fates of L-histidine which serves as a prosthetic group, not as a redox cosubstrate. Imidazolonepropionasc (EC3.5.2.7)and tetrahydrofbtate-dependent glutamate forrniminotransfenise (EC2.1.2.5) then complete the conversion to L-glutamate.

Alternative pathways; His can also be transaminase! hy pyridoxai-5'-phosphate-(PLP) requiring amino transferases including phenylalanine(histidine) aminotransferase

(EC2.6.1.58) and aromat ic-amino-acid-glyoxy I ate aminotransferase (EC2.6.1.60). The resulting imidazole pyruvate and its metabolites imidazole acetate and imidazole lactate cannot be utilized and excreted with urine. A small amount of His undergoes oxidative deaminatton by the peroxisomal flavoenzyme L-lysine oxidase t EC 1.4.3.14): the further fate of the resulting metabolite is unclear. Despite the significant activ ities of these enzymes, particularly of phenylalanine^ istidine) aminotransferase in liver, almost all 1 lis is metabolized via the main histidase pathway.

Protein histidyl methylation: Specific hist idyl residues in actin. myosin, and other proteins arc methylated by protein-histidine N-methyltransferase (EC2.1.I.8S) which uses S-adenosyI-L-methionine as a methyl group donor. In human the daily rate of His 3-methylation has been estimated at 3 t pmol/kg (Rathmacher and Nissen, 1998). It is of note that the methylhistidine from modified proteins and anserine cannot be incorporated into proteins nor can it be metabolized and utilized as an energy fuel.

Storage

On average, the His content of human proteins is 24 mg g (Smith, IMSO). presumably corresponding in a 7(1 kg man to a mobilizable reserve of about 144 g, Hemoglobin is a particularly His-rich protein (84 mg g) whose normal turnover alone provides more than 0.5g I lis per day.

Carnosine (beta-alanyl-L-histidine) in muscle and homocarnosine (gatnma-aminobutyryl-1 -hisiidine) in brain are His-rich peptides that can provide significant amounts of His in times of need. Carnosine ts synthesized by carnosine synthase (EC6.3.2.11) from His and beta-alanine. This enzyme in brain, muscles and other tissues uses NAD as a prosthetic group. Beta-alanine feeding, but not His feeding, was found to increase carnosine stores in horses (Dunnett and Harris. 1999): this has not yet been investigated in humans.

I lis stored with carnosine and other ¿¡peptides can be released in blood, brain, and other tissues by the zinc-enzyme camosinase (EC3.4.I3.3). Another enzyme, beta-ala-llis dipeptidase (EC3.4.I3.20), appears to exist only in humans and other primates. The enzyme is activated best by cadmium, and only half as well by manganese; the physiological significance of this unusual activation pattern is unclear.

Hemoglobin is another His-rich protein (91.3 mg/g) whose degradation can provide significant amounts of His when dietary sources are inadequate. Al a breakdown rale of 20ml red blood cells or (Sg hemoglobin per day this corresponds to a daily release of548 mg His.

Excretion

Free His is filtered in the kidneys and reabsorbed in the proximal tubule more or less via the same transporters that mediate absorption from the small intestinal lumen. Transporters B"'. b0'4 and BATI arc located on the luminal side, transporters y' LATI (SLC7A7) and LAT2 (SLC7A8) on the basolateral membrane side. Little of the filtered methylhistidine w ill he reabsorbed and most is excreted with urine.

Figure 8.8« L-Hisndinc-nch peptides c.m cover needs for some lime

Regulation

Little is known how. if at all. the body keeps its i lis content constant or ensures adequate availability for critical functions.

larnosme

O ii

Camicine

0 COOH Ii I

H,C 9h2

0 COOH Ii I

H,C 9h2

Homocamosine larnosme

Camicine

Homocamosine

Function

Energy fuel: Eventually a large proportion of ingested I lis is oxidized with an energy yield of3.4kcal/g (May and Hill. 1990). Complete oxidation depends on adequate supplies of thiamin, riboflavin, niacin, vitamin B6. folate, pantothenate, lipoate. ubiquinone, iron, and magnesium. The fraction that is converted to methyl hist id ine does not contribute to energy production.

Protein synthesis: 1 listidine-tRNA ligase (EC6.l-l.2l) loads His onto tRNA"1'' that can then proceed to participate in protein synthesis.

Histidine-contaimngdipeptides: Carnosine (20 mmol'l in heart) is likely to be important as a I lis storage molecule, but also contributes to the proton buffering (Dunnett and Harris. 1999). free radical scavenging (Choi et al., 1999), and aldehyde scavenging (Swearengin ei til., 1999) capacity of muscle. Dietary carnosine (in the millimole range) appears to have vasodilalory effects on aortic muscle (Ririe ei ul.. 2000).

Homocarnosin (gamnia-aminobutyi yl-L-histidine) is synthesized from the neurotransmitter gamma-aminobutyric acid (GABA) and His by carnosine synthase I EC6.3.2.11) in brain. A role of this dipeptide in the symhesis of GABA has been suggested. Another important role of carnosine appears to be the scavenging of peroxyl and other free radicals in vitro. Its potency is enhanced when it is chelated with copper (Decker et a!., 2000). It has been suggested that due to its high concentration in muscle carnosine is the main protector against polyunsaturated and saturated aldehydes, Carnosine may also affect immune function by potentiating the respiratory burst of neutrophils and protecting them against free-radical-tnduccd apo ptosis (Tan and Candlish, 199K). Carnosine can be decarboxylated through an as yet unknown mechanism to camicine. Another His-derivative, ergothioneine (2-mercaptohistidinc betatne), is present in erythrocytes, ocular lens, liver, and a few other tissues in millimolar

COOH

COOH

Anserine

Figure 8.89 L-histidtne-Con taming dipeptides havt diverse biological functions

Balenine

Anserine

Figure 8.89 L-histidtne-Con taming dipeptides havt diverse biological functions

Balenine

COOH

COOH

Histtdine decarboxylase (PLP)

L-Hrstidine

Histtdine decarboxylase (PLP)

L-Hrstidine

Figure B.90 Histamine is a potent neurotransmitter and paracrine agent concentration (Misiti et ul.. 2001). Since no hiosynthetic pathways have been identified in humans or other mammals, it has been suggested that all ergothioneine in humans must be derived from food. 1 lowcver, the consistently high concentrations of this compound in blood and tissues of diverse populations appear to argue against this assumption. Ergothioneine acts as an antioxidant and facilitates the decomposition of S-nitrosogluiathione in blood, liver and kidney.

Balenine (heta-alanyl-L-3-methylhistidine. ophidine) is generated by proteolysis of methylated proteins. Swine and other mammals produce much larger quantities than humans do. Antioxidant and other specific properties have been attributed to this compound, but the significance in humans is uncertain.

Additional histidyl dipeptides, including acetylcarnosme. anserine, and acetylanser-ine. are present in various tissues; some may* be primarily or exclusively of dietary origin. Such carnosine-related compounds could be important for the regulation of intracellular oxygen free radical concentrations (Boldyrev and Abe. 1999), but questions about their precise role remain (Mitsuyama and May. 1999). Receptor ligands: Many tissues contain specific PLP-dependent histidine decarboxylases (EC4.1.1.22) which can release histamine, a potent neurotransmitter and paracrine agent. HI-histamine receptors (in mast cells and many peripheral tissues) and H2-histamhie receptors (parietal cells of the stomach) respond to binding of agonists by increasing histamine release which in turn affects tissue functions such as hydrochloric acid release in the stomach.

Camosine complexed with zinc also appears to specifically interact with both III and 112 receptors. This complex lias been found to provoke saphenous vein contractions w ith a potency comparable to that of histamine (Miller and O'Dowd, 2000). Effect on trace metal bioavailability: Dietary I lis has been reported to improve intestinal zinc absorption t Lonnerdal. 200(1).

Biomarkers of dietary intake

Urinary 3-methyllnstidine excretion correlates with His intakes (Prescott etui, 19X8). References

Bo I dy rev A, Abe H, Metabolic transformation of neuropeptide camosine modifies its biological activity. Celt Molec Neumhiol 1999:19:163 75 Chairoungdua A. Segawa H. Kim JY. Miyamoto K. Haga H, Fukni Y. Mizoguchi K. Ito H, Takeda F, F.ndou li, Kanai Y, Identification of an amino acid transporter associated with the cystinuri a-related type II membrane glycoprotein../ Biol Chem 1999:274: 2S845-8

Choi SY. Kvvon HY. Kwon OB. Kang JH. Hydrogen peroxide-mediated Cu, Zn-superoxide dismulase fragmentation: protection by camosine, homocarnosine and anserine. Biochim Biophys Acta 1999;1472:651-7 Decker EA. Livisay SA. Zhou S. A re-evaluation of the antioxidant activity of purified camosine. Biochem (Moscow) 2000:65:766-70 Dunnett M. Harris RC. Influence of oral beta-alanine and L-histtdine supplementation on the camosine content of the gluteus medius. Equine Vet J 1999:30:499 504 FAO/WHO/UNLL Energy and protein requirements. Work! Health Organ Tech Rep Set 19« 5; 724:204

Jansson T. Amino acid transporters in the human placenta. Pediatr Res 2001:49:141 7 Kagabu Y. Mishiba T. Okino T. Yanagisawa T, Elfects of thyrotropin-releasing hormone and its metabolites. Cyclo(Mis-Pro) andTRH-OH, on growth hormone and prolactin sy nthesis in primary cultured pituitary cells of the common carp, Cyprinus carpio. Gen Camp Endocrinol 1908:111:395 403 Kudo Y, Boyd CA. Characterisation of L-tryptophan transporters in human placenta: a comparison of brush border and basal membrane vesicles. J Physiol 2001 ;531:405-l 6 Lonnerdal B. Dietary factors influencing zinc absorption../ Nutr 2000:130:I378S-1383S May ME, Hill JO. Energy content of diets of variable amino acid composition. Am J Clin Nutr 1990:52:770-6

Miller D.I, O'Dowd A. Vascular smooth muscle actions of camosine as its zinc complex are mediated by histamine H( I land H(2)receptors.Biochem(Moscow)2000:65:798-N06 Misiti F. Castagnola M, Zuppi C, Giardina B. Messana I, Role of ergothioneine on

S-nitrosoglutathione catabolism. Biochem J200]:356:799-804 Mitsuyama II, May JM. Uptake and antioxidant elfects of ergothioneine in human erythrocytes, Clin Sci 1999:97:407-11 Mizumo H. Svec F, Prasad C. Hilton C. Cyclo(His-Pro) augments the insulin response to oral glucose in rats. Life Sci 1997;60:369-74

Prasad C. Ragan J-'A Jr. Hilton CW. Isolation of cydo(His-Pro)-like immunoreactivity from human urine and demonstration of its immunologic, pharmacologic, and physico-chemical identity with the synthetic peptide, Biochem Int 1990;2 1:425 34 Prasad ( . 1 imited proteoly sis and physiological regulation: an example from thyrotropin-

releasing hormone metabolism. Thyroid 1998;8:969-75 Prescoti SL. Jenner DA. Beilin LJ. Margetts UM, Vandongen R. A randomized controlled trial of the effect on blood pressure of dietary non-meat protein \crsus meat protein m normotensive omnivores, Clin Sci 1988;74:665 72 Rathmacher J A, Nissen SL. Development and application of a eom part mental model of 3-methylhistidine metabolism in humans and domestic animals. Adv Exp Med Biol 1998;445:303-24

Reichel A. Degley DJ. Abbott NJ, Carrier-mediated delivery of metabotrophic glutamaie receptor ligands to the central nervous system: structural tolerance and potential of the L-system amino acid transporter ai the blood-brain barrier,,/ Cenrh Blond Flow Metuh 2000:20:168 74 Ririe DG, Roberts PR. Shouse MS. ZalogaGP. Vasodilate ry actions of the dietary peptide carnosine. Nutr 2000; 16:168-72 Smith RH. Comparative amino acid requirements. Pmc Nutr Sac |980;39:7l 8 Sugawara M. Nakanishi T, Hei VJ. Huang W, Ganapathy ME, I eibach FH. Ganapathv V. Cloning of an amino acid transporter with functional characteristics and tissue expression pattern identical to that of system A../ Biol Chem 2000;275:16473 7 Swearengin TA. Fitzgerald C. Seidlcr NW. Carnosine prevents glyceraldehyde 3-phos-phate-mediated inhibition of aspartate aminotransferase. Arch Toxicol 1999;73:307 9 Tan KM. Candlish JK. Carnosine and anserine as modulators of neutrophil function. Clin Lab Haematol 1998;20:239- 44

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