Ochronotic Deposition in Alkaptonuria: Semiquinone-Mediated Oxidative Coupling and Metabolic Drivers of Homogentisic Acid Accumulation
Year: 2025
Type: article
Abstract: Alkaptonuria (AKU) is a rare metabolic disorder caused by homogentisate 1,2-dioxygenase (HGD) deficiency, leading to homogentisic acid (HGA) accumulation and ochronotic pigment deposition, which drug therapy cannot reverse. The process of pigment formation and deposition is still unclear. This study offers molecular insights into the polymeric structure, with the goal of developing future adjuvant strategies that can inhibit or reverse pigment formation, thereby complementing drug therapy in AKU. HGA polymerisation was examined under physiological, acidic, and alkaline conditions using liquid and solid phase nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and polyacrylamide gel electrophoresis. At physiological pH, HGA polymerised slowly, while alkaline catalysis accelerated pigment formation while retaining the HGA aromatic scaffold. During the process, EPR detected a semiquinone radical intermediate, consistent with an oxidative coupling mechanism. Reactivity profiling showed the diphenol ring was essential for polymerisation, while –CH2COOH modifications did not impair reactivity. Pigments displayed a polydisperse molecular weight range (11–50 kDa) and a strong negative charge. Solid-state NMR has revealed the presence of phenolic ether and biphenyl linkages. Collectively, these identified structural motifs can serve as a foundation for future molecular targeting related to pigment formation.
DOI: 10.3390/ijms26199674
Institutions: University of Siena, University of Modena and Reggio Emilia
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W4414792970