Imidazole Dipeptides: Chemistry, Analysis, Function and Effects / Edition 1 available in Hardcover
Imidazole Dipeptides: Chemistry, Analysis, Function and Effects / Edition 1
- ISBN-10:
- 1849738904
- ISBN-13:
- 9781849738903
- Pub. Date:
- 08/13/2015
- Publisher:
- RSC
Imidazole Dipeptides: Chemistry, Analysis, Function and Effects / Edition 1
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Overview
This volume surveys the current state of play in these and other areas of interest, including chemistry and biochemistry, immunology and cellular homeostasis. Chapters look in depth at some of the functions and effects in the body particularly with regard to exercise and fatigue, wound healing, cancer treatment and age-related diseases. Providing an up to date, interdisciplinary approach, this book is of great interest to researchers and professionals in chemistry, food science, nutrition, biochemistry, health sciences and sports sciences.
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Imidazole Dipeptides
Chemistry, Analysis, Function and Effects
By Victor R Preedy
The Royal Society of Chemistry
Copyright © 2015 The Royal Society of ChemistryAll rights reserved.
ISBN: 978-1-84973-890-3
CHAPTER 1
Carnosine in the Context of Histidine-Containing Dipeptides
GIULIO VISTOLI
1.1 Introduction
Among the proteinogenic amino acids, histidine plays manifold roles mostly ascribable to the reactivity of the imidazole ring that characterizes its side chain. While being one of the least abundant residues (representing about 2% of the total protein residues), histidine plays key roles in protein folding and functions. Indeed, the histidine imidazole ring is the coordinating group in many metalloproteins and is involved in several enzymatic mechanisms such as in the catalytic triad in which histidine acts as a general base increasing the nucleophilicity of surrounding serine, threonine, or cysteine residues. Thus, histidine is able to shuttle protons by abstracting them through its basic nitrogen atom as seen in carbonic anhydrases, where it shuttles protons away from the zinc-bound water molecule to restore the active form of the enzyme (Fisher et al., 2005). Moreover, histidine is involved in regulating protein functions due to its post- translational modification by the addition of a phosphate group to yield the 1-phosphohistidine or the 3-phosphohistidine adducts (Attwood et al., 2007). Although an exhaustive characterization of this reversible modification in human cells is still lacking, mainly due to the instability of the phosphoramidate bond, accumulating evidence emphasizes the crucial role of histidine phosphorylation in cell signaling, as exemplified by its role in regulating the flux through the K+ channel KCa3.1 caused by histidine phosphorylation within the protein C-terminus (Beckman-Sundh et al., 2011).
When considering the roles of histidine in proteins, its key presence also in several peptides comes as no surprise. A relevant example of histidine-rich peptides is offered by the salivary histatins, which are metal-binding peptides endowed with potent antibacterial, antifungal and wound-healing activities (Kavanagh and Dowd, 2004). These few examples emphasize the role of histidine in the manifold protein world and represent an indirect but convincing explanation of the remarkable role played also by small histidine-containing dipeptides (HCD) among which carnosine and its congeners represent the most important group. Based on these premises, the chapter is focused on histidine dipeptides and starts from an introductory analysis of histidine as a single amino acid, discussing its reactivity, metabolism and physiological roles to move to histidine dipeptides as grouped into proteinogenic and nonproteinogenic dipeptides. Among the latter, the chapter analyzes indepth the biological profiles for carnosine and related dipeptides. While discussing the multifaceted properties of the histidine-containing dipeptides, the chapter is focused on their carbonyl-quenching activity detailing mechanisms, reactivity and structure-activity relationships.
1.2 Histidine: Reactivity, Metabolism and Physiological Roles
1.2.1 Histidine's Reactivity: The Key Role of the Imidazole Ring
The reactivity of the histidine residue is mostly ascribable to the physicochemical properties of its imidazole ring that can be seen as a combination of those of pyridine and pyrrole (Richaud et al., 2011). As shown in Figure 1.1, the N—H nitrogen atom has an acid character (pK = 14.52) which brings to mind (and surpasses) that of pyrrole (pK = 17.51), while the multiply bound nitrogen atom resembles that of pyridine, while being more basic (pK = 7.01 vs. pK = 5.20 for pyridine). Besides its amphoteric nature, tautomerism is another feature characterizing the imidazole ring that indeed exists in two identical tautomers showing such rapid equilibria that they cannot be separated or isolated. The imidazole basicity renders it an optimal buffer at physiological pH and several studies showed that the buffering capacity in human tissues is mostly related to the histidine concentration (Li and Hong, 2011).
With regard to the coordination abilities, imidazole is considered as a moderate σ-donor due to the lone pair located at the basic nitrogen atom and a weak π-acceptor, albeit its π-excessive nature. Hence, it prevalently forms η1-(σ-N) complexes that are favored with electron-rich metals in low-oxidation states with high-energy d-orbitals although in rare cases imidazole was found to behave as a π-donor.
Due to its electronic properties, imidazole undergoes electrophilic substitutions which can occur at the basic nitrogen atom and at the electron-rich C4 and C5 atoms. The imidazole reactivity towards electrophilic reagents is greater than in benzene but lower than in the five-membered heterocycles with only one heteroatom. The reactivity decreases for reactions requiring acidic conditions and is increased by electron-donating substituents. Nucleophilic substitutions can occur only when an appropriate leaving group is located at the electron deficient C2 atom. The imidazole ring is moderately susceptible towards nucleophilic substitutions and its reactivity is enhanced by electron-withdrawing substituents (Bhatnagar et al., 2011).
With regard to the Michael addition (a reaction that plays a pivotal role for the carbonyl quenching of the histidine dipeptides), imidazole can act as a donor due to the nucleophilicity of its basic nitrogen atom (the so-called aza-Michael addition). However, the imidazole ring is not nucleophilic enough to react with α,β unsaturated carbonyls at neutral pH values and requires the presence of catalysts, as seen in the organocatalytic mechanisms where the Michael addition is promoted by the initial formation of more reactive enamines (Lakhdar et al., 2012).
As seen for other heterocycles, imidazole can directly react with the hydroxyl radical giving the hydroxyimidazolyl radical anion that then undergoes a slow elimination of water to yield the dehydroimidazolyl radical that is reasonably more stable than the starting hydroxyl radical. Such a reaction can explain antioxidant effects of the imidazole-based compounds as seen in urocanic acid and imidazole-4-acetic acid that come from histidine metabolism (Hartman et al., 1990).
1.2.2 Histidine Metabolism and Physiological Roles
Histidine is an essential amino acid; its de novo biosynthesis is highly conserved from archea to plants. While children have to obtain histidine from diet, adults are independent on the dietary sources due to both the low daily requirement and the protein turnover. Dairy, meat, poultry and fish are good sources of histidine as well as rice, wheat and rye. Furthermore, the intestinal flora can produce absorbable histidine.
As schematized in Figure 1.1, the histidine catabolism involves three major pathways. The first is based on the histidinase enzyme that converts histidine into urocanic acid by catalyzing the irreversible elimination of ammonia. By hydration and rearrangement, urocanic acid is transformed into imidazolone-5-propionate that in turn can yield glutamate via the N-formimino glutamate intermediate (FiGlu) and successive transformylation. Since the last step involves the transfer of the formyl group to tetrahydrofolate, a folate deficiency can be detected by the urinary accumulation of the FiGlu intermediate (Cooperman and Lopez, 2002). The second pathway plays a key role in signal transduction since it involves decarboxylation to give histamine by histidine decarboxylase (Ohtsu, 2010). Lastly, transaminase enzymes can convert histidine into imidazole pyruvate and then into imidazole lactate.
The major disorders in histidine metabolism are histidinemia and urocanase deficiency. The former is a benign recessive autosomal disorder due to a deficiency of histidinase resulting in a limited histidine metabolism and consequent accumulation in liver and blood. The latter is a rare normally benign recessive autosomal disorder caused by a deficiency of urocanase and involving a block in conversion of the urocanic acid and its consequent accumulation, while histidine levels remain substantially unchanged (Bender, 2012).
1.3 Proteinogenic Histidine Dipeptides
While considering the greater relevance of nonproteinogenic histidine-containing dipeptides (see Section 1.4), this section is focused on some important proteinogenic histidine dipeptides to frame carnosine and its derivatives in the context as broadly as possible.
For completeness, this section analyzes dipeptides in which histidine is in both the C-terminal and N-terminal position. Notably, the former usually exist in their linear form, while the latter are often present as cyclic diketopiperazines, which are rather stable derivatives, although either of the lactamic groups can hydrolyze resulting in two different dipeptides (Wang et al., 2013). First, the specific roles of the proteinogenic dipeptides are discussed (see Section 1.3.1), while their common carbonyl quencher activity is analyzed in the following paragraph (see Section 1.3.2).
1.3.1 Specific Activity Profiles
The activity profiles of the histidine-containing dipeptides can be roughly subdivided into two major groups since they can be related to the discussed imidazole reactivity or to specific receptor binding. Besides the specific roles discussed below, it is worth remembering that all hydrolyzable histidine containing (di)peptides can be seen as reservoirs of histamine. Similarly, all histidine (di)peptides act as proton buffers due to the imidazole basicity.
With regard to the first group, almost all histidine dipeptides conserve the capacity to chelate metal ions. This feature is particularly relevant for the His-His dipeptide that chelates Cu(1) ions in a very favorable geometry (Himes et al., 2007). Again, several studies investigated the capacity of GlyHis (Figure 1.2, 8) to form complexes with metal ions, among which gold-based complexes have attracted great interest because of their potential use as anticancer agents. Notably, the metal chelation is often combined with the imidazole-based radical scavenging and determines the antioxidant profile exhibited by several histidine-containing dipeptides (Hartman et al., 1990).
Another feature connected to the imidazole reactivity and characterizing some histidine dipeptides is related to its catalytic role as a general base. Accordingly, Ser–His, and less markedly Ala–His, were found to catalyze the formation of a RNA phosphodiester bond, thus promoting the RNA polymerization. Interestingly, this feature might explain the nonenzymatic prebiotic formation of catalytic nucleic acids that are believed to have had a key role in the origin of life. Ser-His was also found to catalyze the formation of peptide bonds, as seen in short dipeptides and also this feature may have played a role for the origin of biomacromolecules (Wieczorek et al., 2013).
The second group collects those dipeptides the biological profile of which is related to their interaction with well-defined biological targets. A first set of histidine-containing dipeptides was found to possess significant anxiolytic and sedative activities. For example, the dipeptide Met–His (aka, wheylin-1), which arises from the digestion of β-lactoglobulin by termolysin, was found to exert an anxiolytic-like activity in mice that is ascribable to activation of the GABAA receptor (Yamada et al., 2014). Moreover, several cyclodipeptides were found to induce a significant prolongation of the pentobarbital narcosis due to a GABAA potentiation, as demonstrated for cyclo(His-Pro) (Suzuki et al., 1981).
Cyclo(His-Pro) (Figure 1.2, 1) is an endogenous dipeptide structurally related to a tyreotropin-releasing hormone. Besides the already mentioned GABA potentiation, it elicits in the central nervous system multiple biological activities, which can be related to a presynaptic dopaminergic mechanism and involve a leptin-like function. At the gastrointestinal level, cyclo(His-Pro) was found to act as a gut peptide influencing the entero-insular axis and improving glycemic control (Minelli et al., 2008). Notably, other histidine-containing dipeptides (such as His-Ala and His-Leu) were found to influence the glucose metabolism mainly through inhibition of the intestinal dipeptidyl peptidase-4 (DPP-4) (Nongonierma et al, 2013).
Cyclo(His-Pro) has recently attracted great interest for its neuroprotective role that was first observed in traumatic injuries of the spinal cord and then confirmed in other models of experimental injuries of the nervous system. The involved mechanism still remains unclear even though recent studies suggest the contribution of the expression of small heat-shock proteins.
Another set of histidine-containing dipeptides were found to exert biological activities at the cardiovascular level. Among them, the Trp-His dipeptide was found to possess a vasorelaxant activity that is ascribable to its ability to decrease the intracellular [Ca++] concentration by blocking a voltage-dependent l-type Ca++ channel (VDCC) (Wang et al., 2010). Moreover, Trp-His was found to prevent atherosclerosis in apo E deficient mice by multiple (and still poorly understood) mechanisms that do not include the regulation of lipid metabolism (Matsui et al., 2010). Furthermore, some dipeptides such as cyclo(His-Gly) (Figure 1.2, 2) were found to inhibit thrombin-induced platelet aggregation.
Moreover, some histidine-containing dipeptides showed anticancer activity. For example, cyclo(His-Phe) displays a remarkable antitumor activity, as demonstrated by a great reduction of cell viability in cervical carcinoma cells. Again, cyclo(His-Gly) and, more markedly, cyclo(His-Ala) (Figure 1.2, 3) show an inhibition of HeLa cells comparable to cisplatin at the same concentration, while the greater activity of the latter can be explained by increased lipophilicity that promotes permeation into cells and enhances its effects (Lucietto et al., 2006).
Similarly, some histidine-containing dipeptides were found to exert significant antimicrobial activities. Among them, Trp-His and His-Arg represented relevant frameworks to design analogs that were found to be active against several Gram-negative and Gram-positive bacterial strains as well as against a fungal strain and to be devoid of cytotoxic effects (Sharma et al., 2009). Finally, some histidine-containing dipeptides, such as γ-Glu-His, are kokumi molecules that enhance complex taste of the matured cheese (Toelstede et al., 2009).
1.3.2 Carbonyl-Quencher Activity
As mentioned in Section 1.1, this chapter is mostly focused on the quenching activity of histidine-containing dipeptides towards reactive carbonyl species (RCS). Regardless of their source, RCS can be subdivided into the two major groups, namely α, β unsaturated carbonyls (e.g., 4-hydroxynonenal and acrolein) and dicarbonyls (e.g., glyoxal and methylglyoxal).
The enhanced reactivity of the former is mainly ascribable to their capacity to yield Michael-type adducts due to the marked electrophilicity of the β carbon atom that is combined with that of the carbonyl group, which maintains its ability to condense with suitable nucleophilic molecules. As seen with carnosine, there can be a crosstalk mechanism between the two electrophilic groups since a nucleophilic molecule can first react with the carbonyl group and the so-obtained intermediate can promote the Michael addition on the β carbon atom through an organocatalytic mechanism.
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Excerpted from Imidazole Dipeptides by Victor R Preedy. Copyright © 2015 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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