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Photosensitization of Peptides and Proteins by Pterin Derivatives

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Photosensitization of Peptides and Proteins by Pterin Derivatives Pteridines 2017; 28(3–4): 105–114 Review Maria Laura Dantola*, Lara O. Reid, Carolina Castaño, Carolina Lorente, Esther Oliveros and Andrés H. Thomas Photosensitization of peptides and proteins by pterin derivatives https://doi.org/10.1515/pterid-2017-0013 Received July 2, 2017; accepted August 28, 2017; previously published Introduction online October 17, 2017 Solar radiation induces modifications in different biomol- Abstract: Proteins are one of the preferential targets of the ecules and is implicated in the generation of human skin photosensitized damaging effects of ultraviolet (UV) radi- cancer [1]. Most of the solar ultraviolet (UV) energy inci- ation on biological system. Pterins belong to a family of dence on Earth’s surface corresponds to UV-A radiation heterocyclic compounds, which are widespread in living (320–400 nm), which can induce damage mostly through systems and participate in relevant biological functions. photosensitized reactions [2]. A photosensitized reaction In pathological conditions, such as vitiligo, oxidized is defined as a photochemical alteration occurring in one pterins accumulate in the white skin patches of patients molecular entity as a result of the initial absorption of suffering this depigmentation disorder. It is known that radiation by another molecular entity called photosen- pterins are able to photosensitize damage in nucleotides sitizer [3]. Proteins and peptides are one of the preferen- and DNA by type I (electron transfer) and type II (singlet tial targets of the photosensitized damaging effects of UV oxygen) mechanisms. Recently, it has been demonstrated radiation on biological systems [4]. These processes may that proteins and its components may also be damaged be mediated by endogenous or exogenous photosensitiz- when solutions containing both proteins and pterin are ers and can take place through different mechanisms: the exposed to UV-A radiation. Therefore, given the biological generation of radicals (type I mechanism), e.g. via elec- and medical relevance of the photosensitizing properties tron transfer or hydrogen abstraction, and the produc- 1 of these molecules, we present in this article an overview tion of singlet oxygen ( O2) (type II mechanism) [5, 6]. In of the capability of different pterin derivatives to photoin- general, it is accepted that the photosensitization of pro- 1 duce damage in proteins present in the skin, focusing our teins occurs mainly through the reactions of O2 with tryp- attention on the chemical modifications of tyrosine and tophan (Trp), tyrosine (Tyr), histidine (His), methionine tryptophan residues. (Met) and cysteine (Cys) side-chains [7]. Nevertheless, in recent reports, it has been demonstrated that pterins pho- Keywords: electron transfer; photosensitization; proteins; tosensitize peptides [8, 9], proteins [10, 11] and their com- pterins; UV-A radiation. ponents [12–14] mainly through a type I mechanism. Pterins, a family of heterocyclic compounds (Figure 1), are present in biological systems in multiple forms and *Corresponding author: Maria Laura Dantola, Facultad de Ciencias play different roles ranging from pigments to enzymatic Exactas, Departamento de Química, Instituto de Investigaciones cofactors for numerous redox and one-carbon transfer Fisicoquímicas Teóricas y Aplicadas (INIFTA), Universidad Nacional reactions [15, 16]. The most common pterin derivatives de La Plata, CCT La Plata-CONICET, Casilla de Correo 16, Sucursal 4, are six-substituted compounds (Figure 1). According to 1900 La Plata, Argentina, E-mail: [email protected] Lara O. Reid, Carolina Castaño, Carolina Lorente and Andrés H. the molecular weight and the functional groups of these Thomas: Facultad de Ciencias Exactas, Departamento de Química, substituents, pterins can be divided into two groups: (1) Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas unconjugated pterins, containing substituents with one (INIFTA), Universidad Nacional de La Plata, CCT La Plata-CONICET, carbon atom or a short hydrocarbon chain, and (2) con- Casilla de Correo 16, Sucursal 4, 1900 La Plata, Argentina jugated pterins, with larger substituents containing a Esther Oliveros: Laboratoire des Interactions Moléculaires et Réactivité Chimique et Photochimique (IMRCP), UMR 5623-CNRS/ p-aminobenzoic acid (PABA) moiety (Figure 1). Pterins can UPS, Université Toulouse III (Paul Sabatier), 118, route de Narbonne, exist in living systems in different redox states and may F-31062 Toulouse Cédex 9, France be classified into three classes according to this property: Unauthenticated Download Date | 3/29/19 12:49 AM 106 Dantola et al.: Photodamage of proteins by pterins O proteins photoinduced by pterin derivatives. We have N R HN focused our attention on the chemical modifications of 12 Oxidized pterin tyrosine (Tyr) and tryptophan (Trp) residues because these H N N N 2 amino acids are particularly susceptible to a variety of oxi- Pterin (Ptr) –H 10 dizing agents [26]. Moreover, the photosensitization of free 6-Formylpterin (Fop) –CHO Trp and Tyr by Ptr has previously been reported [12, 13]. –1 8 6-Carboxypterin (Cap) –COOH The most relevant results, from a biological point of view, cm –1 are summarized and discussed in this review. Biopterin (Bip) –(CHOH) –CH M 2 3 3 OH 10 6 O Folic acid (PteGlu) O ε, CH2 N C H N H O 4 HO General mechanism of photooxida- tion of biomolecules by pterins 2 In 1997, Ito and Kawanishi demonstrated for the first time 0 that upon excitation with UV-A radiation, pterins are able 200 250 300 350 400 450 to photoinduce DNA damage [27]. More recently, the mech- λ, nm anism involved in the photosensitization of biomolecules by pterins were investigated in a series of studies carried Figure 1: Molecular structures of common aromatic pterin deriva- tives and the absorption spectrum of pterin (Ptr) in air equilibrated out with free nucleotides [28–30] and amino acids [12–14]. It aqueous solution at pH = 6.0. was shown that pterins can act as photosensitizers through both type I and type II mechanisms and that the predomi- nant one depends on a combination of many factors, such 1 fully oxidized (or aromatic) pterins, dihydro and tetrahy- as quantum yields of O2 production by the photosensitizer, 1 dro derivatives. The latter are the most important pterins ionization energy and reactivity of the substrate towards O2 derivatives due to their biological activity. and presence of selective scavengers in the media. Pterins are present in human epidermis given that Taking into account the studies mentioned in the 5,6,7,8-tetrahydrobiopterin (H4Bip) is an essential cofac- previous paragraph, a set of competitive mechanisms tor for aromatic amino acid hydroxylases [17] and par- can be summarized to explain the photooxidation of dif- ticipates in the regulation of melanin biosynthesis [18]. ferent biomolecules (S) by pterin derivatives (Pt) (reac- In vitiligo, a skin disorder characterized by a defective tions 1–12). After UV-A excitation of Pt and formation of protection against UV radiation due to the acquired loss its triplet excited state (3Pt*, reaction 1), three reaction of constitutional pigmentation [19], H4Bip metabolism is pathways compete for the deactivation of the latter: altered [20]. Dihydro and oxidized pterin derivatives accu- intersystem crossing to singlet ground state (reaction 2), mulate in the affected tissues at concentrations that are energy transfer to O2 leading to the regeneration of Pt and 1 significantly higher than those reported for healthy cells the production of O2 (reaction 11), and electron transfer [20, 21]. Although intracellular concentrations were not from S to 3Pt* yielding the corresponding pair of radical determined, it can be assumed that pterins can reach any ions (pterin radical anion (Pt˙−) and biomolecule radical + − cellular compartment since these compounds can freely cation (S˙ ), reaction 3). Pt˙ is quenched by ground state O2 − cross phospholipid membranes [22]. to produce the superoxide anion (O2˙ ) and regenerate Pt The photochemistry of pterins is relevant to understand (reaction 4) [31, 32]. The spontaneous disproportionation − the harmful effects of radiation on skin and is of particu- of O2˙ in aqueous solution leads to the formation of hydro- + lar interest in depigmentation disorders, such as vitiligo. gen peroxide (H2O2) (reaction 5) [33]. The radical S˙ (or its Pterins are photochemically reactive in aqueous solutions, deprotonated form, S(-H)˙) may react with Pt˙− (reaction 6) − and upon UV-A excitation, they can fluoresce, produce or/and O2˙ (reaction 7) to regenerate the biomolecule (S). + − reactive oxygen species (ROS) [23–25] and, as mentioned Alternatively, S˙ or S(-H)˙ may react with O2, H2O or O2˙ to above, photosensitize the oxidation of biomolecules [8–14]. yield oxidized products (reaction 8) or with other radi- In the context of our investigations on the photochem- cals to form dimeric products (reaction 9) or S-Pt adducts istry and photosensitizing properties of pterins, we present (reaction 10). On the other hand, the oxidation of S can 1 in this article an overview of the damage in peptides and occur by reaction with O2 (reaction 12). Unauthenticated Download Date | 3/29/19 12:49 AM Dantola et al.: Photodamage of proteins by pterins 107 hv 13**ISC Pt →Pt → Pt (1) Type I mechanism 3* Pt → Pt (2) 3*+→ ii– + + Pt SPtS (3) Scheme 1: Molecular structures of α-MSH and the modified pep- tides: α-MSHW9G and α-MSHY2G, in which the Trp and the Tyr residues ii–– of α-MSH where mutated to Gly residues, respectively. Pt +→OP22tO+ (4) + +→i– + 2H 2O22HO22O (5) spectra indicated that both residues were damaged and new fluorescent compounds were formed. One of these ii– + Pt +→SPtS+ (6) compounds exhibits an emission band with a peak maximum coinciding with that expected for tyrosine SOii+ +→– SO+ 22 (7) dimers (Tyr2). The cross-linking between two Tyr residues was confirmed by ultra-high performance liquid chro- O/HO/O i– SSi+ 22 2 → (ox) (8) matography coupled to a mass spectrometry detector (UPLC-MS). In addition, analysis of mass spectra of irradi- i++ ated solutions showed new peaks with m/z values corre- 2S →−SH2 ( 2 )+ 2H (9) sponding to monooxygenated and dioxygenated products.
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