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Discovery of a new mechanism in the rare genetic disease Alkaptonuria

Alkaptonuria is a rare genetic disease that is characterized by high levels of homogentisic acid (HGA) and unusual tissue pigmentation. The so-called ochronotic pigment leads to cartilage degradation and severe joint pain, which is why young adults with this disease often need a joint replacement. Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Free University of Berlin, together with British collaborators, have discovered a new mechanism for disease progression. In their proposed mechanism, transient glycyl radicals play a major role in the destruction of collagen, one of the main building blocks of cartilage tissue. The work contributes to a better understanding of this rare disease and may enable patients to access promising medication more quickly.

Affecting around one person per 100,000 to 250,000 in the population, Alkaptonuria is a very rare genetic disease. The disease is caused by a lack of functionality of a particular metabolic enzyme, which means that the amino acid tyrosine cannot be completely broken down, and homogentisic acid (HGA) accumulates in the body. Over time, the high concentration of HGA converts into a brown-black substance through biochemical processes. This so-called ochronotic pigment causes brown-black deposits to damage the cartilage in particular, but other connective tissue, skin, and organs such as the heart and kidneys can also be affected. The disease may be unnoticed in childhood, but often often worsens rapidly in young adulthood. The painful cartilage breakdown, similar to that seen in osteoarthritis, can lead to joint replacement at the age of 40, and increasingly limits the mobility of patients.
To date, little is known about what exactly happens at the molecular and chemical level in Alkaptonuria.
Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Free University of Berlin, in collaboration with colleagues from the universities of Liverpool and Cambridge, have now been able to gain new insights into the mechanisms of pigmentation and cartilage destruction.

A missing electron in the pigmentation process
With dynamic nuclear polarization (DNP), a signal-enhancement method in solid-state NMR spectroscopy, the German/British team of researchers succeeded for the first time in interrogating the molecular composition of pigmented patient tissue. Surprisingly, no benzoquinone acetic acid (BQA) was detected, which arises from the oxidation of HGA and has previously been held responsible for the pigmentation.
Analyses with electron spin resonance (EPR) spectroscopy on synthetically produced pigment provided an explanation: normally, the oxidation of HGA to BQA requires a pair of electrons; in this case, however, the oxidation resulted in a molecule with an unpaired electron. This has never been shown before for alkaptonuria and provides a completely new clue for the pigmentation process. “Due to many molecules with unpaired electrons, the chemical environment in the tissue can change and this may lead to a increase in redox reactions, which leads to the typical brown-black pigmentation,” explains Dr. Wing Ying Chow, first author of the study and former post-doctoral researcher at FMP. “Our investigation suggests that the pigment molecule itself is a radical.”

Glycyl radical – a new candidate for cartilage degradation
The researchers made yet another discovery: on one hand, the DNP/NMR investigations showed that surprisingly small amounts of pigment are present in the tissue samples of AKU patients, despite severe discolouration; on the other hand, the researchers could see how the rope-like structure of collagen proteins, an essential part of cartilage, had been destroyed. The damage is proposed to occur through volatile, transient glycyl radicals, which arise from glycine, a key component of collagen proteins.
“We suspect that the pigment triggers redox reactions in the tissue, which creates transient glycyl radicals, which then break the hydrogen bonds in the collagen,” says Dr. Chow. This process can trigger a chain reaction in which more and more pigment molecules are formed and more and more collagen is destroyed. “That explains why the pigmentation is accompanied by painful arthritic symptoms.”
The research team was thus 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.

New hope for patients
For patients with alkaptonuria, the new findings from this basic research can aid treatment in the following ways:
Nitisinone (Orfadine) is a drug that can inhibit the production of HGA. However, since the molecular mechanisms that convert HGA into pigment and how the pigment damages cartilage and organs was previously unclear, it is not licensed for treating alkaptonuria in many countries outside Europe, including the United States. There is also no direct evidence yet that a reduction in HGA can actually bring the disease to a halt in humans.
Chow and her colleagues therefore hope that their work can better explain the effects of Nitisinone, which would be extremely important for the approval process. “Although we are still missing some intermediate steps, and can only propose the presence of glycyl radicals so far, we now have a much clearer picture of the molecular relationships,” explains Chow. “Above all, our colleagues from Liverpool will support the ongoing clinical investigations with their extensive expertise, so that alkaptonuria patients around the world will hopefully soon be able to benefit from the promising substance.”
Chow, W.Y., Norman, B..P., Roberts, N..B., Ranganath, L..R., Teutloff, C., Bittl, R., Duer, M..J., Gallagher, J..A. and Oschkinat, H. (2020), Pigmentation chemistry and radical‐based collagen degradation in alkaptonuria and osteoarthritic cartilage. Angew. Chem. Int. Ed.. Accepted Author Manuscript. doi:10.1002/anie.202000618
German translation:
Pigmentierungchemie und radikal-basierter Kollagenabbau bei Alkaptonurie und Arthrose. doi:  10.1002/ange.202000618

Prof. Dr. Hartmut Oschkinat
Department of NMR-Supported Structural Biology
Leibniz-Forschungsinstitut für Molekulare Pharmakologie  (FMP)
Tel.: +49 30 947 93 160

Dr. Wing Ying Chow (previously FMP, now CEA Grenoble/IBS/CNRS):

Öffentlichkeitsarbeit/Public Relations
Silke Oßwald
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
13125 Berlin, Campus Berlin-Buch
E-Mail: osswald(at)

The Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB), who legally represents eight non-university research institutes - members of the Leibniz Association - in Berlin. The institutions pursue common interests within the framework of a single legal entity while maintaining their scientific autonomy. More than 1,900 employees work within the research association. The eight institutes were founded in 1992 and emerged from former institutes of the GDR Academy of Sciences.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
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