nutrients Review Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement Milan Holeˇcek Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 38 Hradec Kralove, Czech Republic; [email protected] Received: 7 February 2020; Accepted: 20 March 2020; Published: 22 March 2020 Abstract: L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease. Keywords: histidine supplementation; HTK solution; carnosine; beta-alanine; ammonia; glutamine; branched-chain amino acids; Bretschneider’s solution 1. Introduction and Aims L-Histidine (HIS) is a nutritionally essential amino acid (EAA) with unique biochemical and physiological properties, which have created a good theoretical rationale to suggest the use of HIS as a nutritional supplement in a wide range of conditions. Initially, HIS was shown to treat rheumatoid arthritis and anaemia in patients with chronic renal failure [1,2]. Currently, HIS and/or HIS-containing dipeptides (HIS-CD) are investigated to prevent fatigue during strenuous exercise and for therapy in ageing-related disorders, metabolic syndrome, atopic dermatitis, ulcers, inflammatory bowel diseases, ocular diseases, and neurological disorders [3–9]. The first aim of the article is to provide an overview of main pathways of HIS metabolism; chemical and biological properties of HIS, such as proton buffering, metal ion chelation, and antioxidant functions; and a role of several proteins and peptides containing large amounts of HIS residues, such as carnosine (CAR), filaggrin, and histatins. With this explanation as a background, the results of studies examining the benefits and therapeutic potential of HIS and HIS-CD will be discussed or reviewed. Nutrients 2020, 12, 848; doi:10.3390/nu12030848 www.mdpi.com/journal/nutrients Nutrients 2020, 12, 848 2 of 20 Nutrients 2020, 12, x FOR PEER REVIEW 2 of 19 2. Histidine, Chemical, and Biological Properties The unique chemical properties of HIS, which are mainly attributed to the imidazole ring (Figure The unique chemical properties of HIS, which are mainly attributed to the imidazole ring 1), include proton buffering, metal ion chelation, and antioxidant activities. These cytoprotective (Figure1), include proton bu ffering, metal ion chelation, and antioxidant activities. These cytoprotective interactions may involve free HIS, HIS-containing peptides, HIS-CD, and HIS residues in proteins. interactions may involve free HIS, HIS-containing peptides, HIS-CD, and HIS residues in proteins. Figure 1. Histidine structure: histidine (HIS) contains an α-amino group, a carboxylic acid group, Figureand an 1. imidazole Histidine side structure: chain. histidine Under physiological (HIS) contains conditions, an α-amino the group, amino a group carboxylic is protonated acid group, and and the ancarboxylic imidazole group side is chain. deprotonated. Under physiological The imidazole co ringnditions, is responsible the amino for thegroup proton is protonated buffering, metal and the ion carboxylicchelating, andgroup antioxidant is deprotonated. properties. The imidazole ring is responsible for the proton buffering, metal ion chelating, and antioxidant properties. 2.1. HIS as a pH Buffer 2.1. HIS as a pH Buffer Of all the amino acid side chains in proteins, only the imidazole ring of HIS is suitable to function as a pHOf buffer all the [10 amino], and eitheracid side of the chains two nitrogensin proteins, of theonly imidazole the imidazole ring can ring bind of HIS or release is suitable a proton to function to form asthe a acidpH buffer or the base[10], form.and either The pKaof the values two nitrogens of imidazole of the group imidazole of free L-HISring can are bind 6.2 and or release 6.5 when a proton bound toin proteins,form the 7.0acid in or CAR, the base and 7.1form. in anserine The pKa [ 11values]. Therefore, of imidazole HIS-CD, group such of as free CAR L-HIS and anserine,are 6.2 and act 6.5 as whenpowerful bound buffers in proteins, and attenuate 7.0 in changesCAR, and in 7.1 intracellular in anserine pH [11]. in musclesTherefore, during HIS-CD, anaerobic such exerciseas CAR and [11]. anserine,The role of act HIS as as powerful an efficient buffers H+ buffer and enablesattenuate use changes of HIS as in a componentintracellular of pH solutions in muscles employed during for anaerobicorgan preservation exercise [11]. before The transplantation role of HIS as andan efficient myocardial H+ buffer protection enables in cardiac use of HIS surgery as a [component12–14]. of solutions employed for organ preservation before transplantation and myocardial protection in cardiac2.2. HIS surgery and Metal [12–14]. Ion Chelation Several studies have reported the ability of HIS and HIS-CD, particularly CAR, and HIS-rich 2.2.proteins HIS and to formMetal complexes Ion Chelation with metal ions, such as Fe2+, Cu2+, Co2+, Ni2+, Cd2+, and Zn2+ [15,16]. Specifically,Several HISstudies is responsible have reported for bindingthe ability of ironof HIS in haemoglobin and HIS-CD, and particularly myoglobin CAR, molecules and HIS-rich and is proteinsfrequently to presentform complexes in the active with sites metal of metalloenzymes, ions, such as Fe such2+, Cu as2+, carbonicCo2+, Ni2+ anhydrase,, Cd2+, and cytochromes, Zn2+ [15,16]. Specifically,heme peroxidases, HIS is nitricresponsible oxide synthase,for binding and of catalases,iron in haemoglobin where plays and a role myoglobin in regulating molecules their activity. and is frequentlyHistidine-rich present glycoprotein in the active present sites in of plasma metalloen of vertebrateszymes, such interacts as carbonic with anhydrase, many ligands, cytochromes, including hemezinc, hasperoxidases, an important nitric role oxide in immunity synthase, [and15]. catalases, where plays a role in regulating their activity. Histidine-richSeveral metal glycoprotein ions promote present the in production plasma of of vertebrates free radicals interacts through with the many Fenton ligands, reaction including [17] and zinc,exert has toxic an e importantffects on organism, role in immunity which can [15]. be attenuated by HIS or HIS-CD. It has been proven that CARSeveral protects metal against ions copper- promote and the zinc-induced production neurotoxicityof free radicals [18 through]. the Fenton reaction [17] and exert toxic effects on organism, which can be attenuated by HIS or HIS-CD. It has been proven that 2.3. HIS as an Antioxidant CAR protects against copper- and zinc-induced neurotoxicity [18]. The antioxidant activity of HIS is mediated by metal ion chelation (see above), by the scavenging 2.3.of reactive HIS as an oxygen Antioxidant (ROS) and nitrogen (RNS) species, and by sequestering advanced glycation (AGE; e.g., glyoxalThe antioxidant and methylglyoxal) activity of HIS and is advanced mediated lipoxidation by metal ion (ALE; chelation e.g., malondialdehyde(see above), by the and scavenging acrolein) ofend reactive products oxygen [19–24 (ROS)]. High and concentrations nitrogen (RNS) of species, AGE/ALE and are by recognizedsequestering as advanced noxious factors glycation related (AGE; to e.g.,various glyoxal complications, and methylglyoxal) notably, microangiopathy and advanced and lipoxidation retinopathy (ALE; of diabetes e.g., [malondialdehyde23]. and acrolein)HIS-CD, end products particularly [19–24]. CAR, High is more concentrations effective ROS of AGE/ALE/RNS and are AGE recognized/ALE scavengers as noxious than factors free relatedHIS [19 ,to20 various]. The underlying complications, mechanisms notably, of micr the antioxidantoangiopathy e ffandects retinopathy of imidazole-containing of diabetes [23]. compounds remainHIS-CD, obscure particularly [25]. CAR, is more effective ROS/RNS and AGE/ALE scavengers than free HIS [19,20]. The underlying mechanisms of the antioxidant effects of imidazole-containing compounds remain obscure [25]. 3. HIS Requirements and Sources 3.1. Effects of a HIS-deficient Diet Nutrients 2020, 12, 848 3 of 20 3. HIS Requirements and Sources 3.1. Effects of a HIS-Deficient Diet