Abstract
Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA); patients suffer from tissue ochronosis: dark brown pigmentation, especially of joint cartilage, leading to severe early osteoarthropathy. No molecular mechanism links elevated HGA to ochronosis; the pigment's chemical identity is still not known, nor how it induces joint cartilage degradation. Here we give key insight on HGA‐derived pigment composition and collagen disruption in AKU cartilage. Synthetic pigment and pigmented human cartilage tissue both showed hydroquinone‐resembling NMR signals. EPR spectroscopy showed that the synthetic pigment contains radicals. Moreover, we observed intrastrand disruption of collagen triple helix in pigmented AKU human cartilage, and in cartilage from patients with osteoarthritis. We propose that collagen degradation can occur via transient glycyl radicals, the formation of which is enhanced in AKU due to the redox environment generated by pigmentation.
Highlights
Alkaptonuria is one of the earliest known diseases resulting from an “inborn error of metabolism” as described by Archibald Garrod in 1909
The FDA considers homogentisic acid (HGA) elevation a biomarker but not a cause of ochronosis,[9] nitisinone is far not approved for US patients
We showed that NMR structural investigations can be applied to formalin-fixed samples, complementing histological approaches, magnetic resonance imaging,[17] and mass spectrometry.[18]
Summary
Alkaptonuria is one of the earliest known diseases resulting from an “inborn error of metabolism” as described by Archibald Garrod in 1909 It is caused by mutations in the HGD gene[1] of a key metabolic enzyme, homogentisate 1,2dioxygenase, responsible for the breakdown of homogentisic acid (HGA, structure in Supporting Information Figure S1). DNP-enhanced ssNMR has been successfully applied to non-isotope enriched (unlabelled) organic materials[12] and biological materials[13] to yield informative 2D spectra It has enabled 1H–13C heteronuclear correlation (HETCOR) experiments on heterogeneous biomaterials such as bone[14] and maize stems.[15] Here, we obtained 2D spectra of human cartilage samples and gained insight into the structural change in collagen proteins upon pigmentation in AKU. This comparison was designed to test the hypothesis that AKU is an extreme form of OA in which similar molecular changes occur, and propose a new mechanism for age-related cartilage degeneration that can lead to common osteoarthritis
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