Biological Projects

Alkaptonuria (AKU) is a rare genetic disease that is characterized by high levels of homogentisic acid and unusual tissue pigmentation. The so-called ochronotic pigment causes brown-black deposits that leads to cartilage degradation and severe joint pain. Other connective tissue, skin, and organs such as the heart and kidneys can also be affected. As part of a multidisciplinary research in collaboration with the FU Berlin and the universities of Liverpool and Cambridge, new insights have been gained into the mechanisms of pigmentation and cartilage destruction. With help of DNP NMR, the molecular composition of pigmented patient tissue was studied, leading to the surprising insight that only small amounts of the pigment are present in the tissue samples of AKU patients, despite severe discoloration. In addition, DNP NMR revealed that collagen, an essential part of cartilage, had been destroyed. With help of electron spin resonance, it was found that the pigment triggers redox reactions in the tissue, which creates transient glycyl radicals that arise from glycine, a key component of collagen proteins. The radicals may lead to an increase in redox reactions and can break the hydrogen bonds in the collagen. This process can trigger a chain reaction in which more and more pigment molecules are formed and more and more collagen is destroyed. The research team was able to propose a new mechanism of collagen degradation in alkaptonuria, that may also apply to osteoarthritis, as suggested by control experiments with the corresponding patient tissues.

 

Reference:

Chow WY, Norman BP, Roberts NB, Ranganath LR, Teutloff C, Bittl R, Duer MJ, Gallagher JA, Oschkinat H (2020) Pigmentation chemistry and radical-based collagen degradation in alkaptonuria and osteoarthritic cartilage. Angew Chem Int Ed Engl 59, 1-7. DOI: 10.1002/anie.202000618

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