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Oxidative Stress and Mechanisms of Ochronosis in Alkaptonuria

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Oxidative Stress and Mechanisms of Ochronosis in Alkaptonuria Free Radical Biology and Medicine ∎ (∎∎∎∎) ∎∎∎–∎∎∎ Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Oxidative stress and mechanisms of ochronosis in alkaptonuria Daniela Braconi, Lia Millucci, Giulia Bernardini, Annalisa Santucci n Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy article info abstract Article history: Alkaptonuria (AKU) is a rare metabolic disease due to a deficient activity of the enzyme homogentisate Received 1 December 2014 1,2-dioxygenase (HGD), involved in Phe and Tyr catabolism. Due to such a deficiency, AKU patients Received in revised form undergo accumulation of the metabolite homogentisic acid (HGA), which is prone to oxidation/ 29 January 2015 polymerization reactions causing the production of a melanin-like pigment. Once the pigment is Accepted 19 February 2015 deposited onto connective tissues (mainly in joints, spine, and cardiac valves), a classical bluish-brown discoloration is imparted, leading to a phenomenon known as “ochronosis”, the hallmark of AKU. A Keywords: clarification of the molecular mechanisms for the production and deposition of the ochronotic pigment Amyloid in AKU started only recently with a range of in vitro and ex vivo human models used for the study of Homogentisic acid HGA-induced effects. Thanks to redox-proteomic analyses, it was found that HGA could induce Lipid peroxidation significant oxidation of a number of serum and chondrocyte proteins. Further investigations allowed Protein carbonyls highlighting how HGA-induced proteome alteration, lipid peroxidation, thiol depletion, and amyloid Proteomics Redox proteomics production could contribute to oxidative stress generation and protein oxidation in AKU. This review fl fi Serum amyloid A brie y summarizes the most recent ndings on HGA-induced oxidative stress in AKU, helping in the Thiol oxidation clarification of the molecular mechanisms of ochronosis and potentially providing the basis for its pharmacological treatment. Future work should be undertaken in order to validate in vivo the results so far obtained in in vitro AKU models. & 2015 Elsevier Inc. All rights reserved. Introduction Globally, homogentisic aciduria, ochronosis, and arthritis-like damage constitute the temporally related triad characterizing AKU Alkaptonuria (AKU, OMIM: 203500) is an ultrarare disease [21]. After birth and early in the course of the disease, the (estimated incidence is 1:250,000–1,000,000 in most ethnic abnormal renal excretion of HGA due to HGD defects can be easily groups [1,2]) associated with a defective catabolic pathway of identified because HGA undergoes a spontaneous oxidation (on air Phe and Tyr due to low activity of the enzyme homogentisate 1,2- oxidation or alkalinization) with production of a dark-brown dioxygenase (HGD, EC.1.13.11.5) following HGD gene mutations. pigment. The blackening of urine is a pathognomonic sign of the HGD is expressed in liver, kidney, prostate, small intestine, colon, disease. The HGA that is not excreted undergoes oxidation and and human osteoarticular cells [3]; in healthy subjects, HGD polymerization in nonmineralized connective tissues of skeletal, converts homogentisic acid (HGA) to maleylacetoacetic acid. In integumentary, ocular, and cardiovascular systems, leading to a AKU patients, on the contrary, HGA is not further metabolized and pathological bluish-black discoloration, a phenomenon known as it is partly excreted with urine, partly accumulated in the body. “ochronosis” that is the hallmark of AKU. Ochronosis is visible to Several different HGD mutations have been identified so far in the naked eye as blue/black pigmentation of the eye and ear; patients from various populations [4–17], and most of them are microscopically, the ochronotic pigmented tissues appear firm and collected into a dedicated database [18]. However, a clear correla- inelastic [21]. In early life, AKU is mainly asymptomatic, with tion between genotype and residual HGA enzyme activity or severe symptoms occurring later when the third and clinically disease phenotype is still lacking, hindering also the development most relevant component of the triad appear [1,21]; the reasons of a disease severity scoring system, which now is only ques- for such a delay are still to be clarified. Usually, arthritic manifes- tionnaire based [19,20]. tations appear in AKU patients at an age significantly earlier Abbreviations: AKU, alkaptonuria; BQA, 1,4-benzoquinone-2-acetic acid; HGA, homogentisic acid; HGD, homogentisate 1,2-dioxygenase; HSP, heat shock protein; LPO, lipid peroxidation; OA, osteoarthritis; PTM, posttranslational modification; SAA, serum amyloid A n Correspondence to: via Aldo Moro 2, 53100 Siena (SI) Italy. Fax: þ39 0577 234254. E-mail address: [email protected] (A. Santucci). http://dx.doi.org/10.1016/j.freeradbiomed.2015.02.021 0891-5849/& 2015 Elsevier Inc. All rights reserved. Please cite this article as: Braconi, D; et al. Oxidative stress and mechanisms of ochronosis in alkaptonuria. Free Radic. Biol. Med. (2015), http://dx.doi.org/10.1016/j.freeradbiomed.2015.02.021i 2 D. Braconi et al. / Free Radical Biology and Medicine ∎ (∎∎∎∎) ∎∎∎–∎∎∎ compared to the general population (namely, around the fourth human serum-, cell-, and tissue-based human AKU models where decade of life) and mainly affect [21]: the effects of HGA could be investigated [26–39] (Table 1). These models unequivocally pointed out that oxidative stress was one of i. Joints and spine, where a premature severe disabling the most important factors for explaining HGA toxicity. Though it osteoarthritis-like damage develops, increasing the risk of was originally thought that HGA may act as a chemical irritant fractures and ruptures of ligaments and tendons and signifi- inducing tissue degeneration through inflammation, it was found cantly reducing patients' quality of life [22]. that HGA could first undergo spontaneous oxidation into 1,4- ii. The cardiovascular system, due to deposition of HGA-induced benzoquinone-2-acetic acid (BQA) (Fig. 1) and then polymerization ochronotic pigment in cardiac valves, increasing the risk of devel- into a compound of as yet undefined composition and properties oping aortic valve disease and coronary artery disease [23]. (first hypothesized structure is reported in Fig. 1A) [40–42]. The conversion of HGA into BQA is also concomitant with the produc- – tion of oxygen radicals such as superoxide anion (O2 ), hydroxyl For AKU, similar to many other rare conditions, gaining insights radical (OH ), and hydrogen peroxide (H2O2) [43] and of a into the molecular mechanisms by which the metabolic defect fluorescent, melanin-like ochronotic pigment [44,45]. Free radicals leads to the pathological manifestations has been hindered by the generated by the conversion of HGA into BQA were hypothesized rarity of the disease itself. The difficulty of collecting ochronotic to be responsible for the alterations of connective tissues observed samples (requiring very invasive techniques) should also be taken in AKU, similar to that found in other rheumatic diseases [46] and into account for AKU, together with the fact that ochronosis often disorders of Tyr metabolism [47–49]. In particular, it was sug- causes severe damage to tissues so that the collection of suitable gested that hydroxyl radicals could damage hyaluronic acid found samples from biopsies might be more problematic. Globally, all in synovial fluid of joints [45]. The interactions between HGA or these issues also hindered finding a dedicated cure for AKU and BQA and collagen have been analysed in vitro as well. It has been ochronosis. Current treatments are only palliative and do not shown in vitro that the interaction between HGA and collagen is address the intrinsic causes of AKU; surgery for total joint and mainly a reversible and pH-dependent phenomenon unlikely to heart valves replacement is often necessary. Two clinical trials for have significant effects in vivo [50]. Conversely, the interaction the use of the drug nitisinone in AKU have been undertaken with the oxidized (BQA)/polymerized forms seemed to involve a recently (http://clinicaltrials.gov/show/NCT01828463, http://clini- direct irreversible binding to collagen molecules occurring in vitro caltrials.gov/show/NCT01916382) [24]. However, since nitisinone quite irrespective of pH and allowing us to hypothesize that a is a competitive inhibitor of the enzyme that precedes HGD in the tanning phenomenon is likely responsible in vivo for the morpho- catabolic pathway [25], it is associated with Tyr buildup and logical changes observed in AKU [21,50]. BQA, through: related side effects. Furthermore, nitisinone can at best stop or delay the disease progression without modifying the underlying i. Salt linkages between the carboxyl group of its polymerized molecular HGD defect. form and the collagen ionic groups, Today, evidence is growing that AKU can be considered as a ii. coordinate bonds between hydroxyl groups and/or adjacent model for other more common rheumatic diseases such as activated ¼CH- groups of its polymerized form and keto-imide osteoarthritis (OA) and rheumatoid arthritis [26]. Although the bonds of collagen, disease is rare, the social and economic impact of studying AKU could be much wider than what was originally expected and this should boost related scientific research. was found to significantly increase collagen cross-linking, To overcome the difficulties related to the study
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