The general consensus that cells obtain their Coenzyme A via a de novo biosynthesis pathway starting with the uptake of vitamin B5 is challenged by work of the Sibon group, demonstrating, that cells and organisms can take up Coenzyme A from external sources. The mechanism behind this newly discovered manner of obtaining Coenzyme A is one of the topics of the Sibon lab. The presence of alternative routes towards intracellular Coenzyme A is not only of high importance for subjects suffering from inborn genetic errors of impaired Coenzyme A de novo biosynthesis, resulting in severe neurodegenerative and cardiac diseases. It is also essential to understand how certain pathogenic microorganisms which depend on alternative sources for CoA survive. Fundamental basic research findings are translated into novel therapies for Coenzyme A-linked diseases.
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is an ultra-rare neurodegenerative disease (prevalence of 1 case per 1-3 million), caused by mutations in the genetic material, called the PANK2-gene. Patients suffer from progressive movement disorders, in particular generalized dystonia and parkinsonism, although other symptoms can also occur, such as cognitive impairment and psychiatric problems.
A characteristic MRI pattern in the brain is found in PKAN patients, caused by iron accumulation in the basal ganglia. PKAN often presents itself at a young age (around 2 years of age) and the symptoms progress rapidly. Patients at a young age initially suffer from mild symptoms, such as delayed development and poor balance, but within 5-10 years patients lose their ability to move independently. In exceptional cases PKAN symptoms arise during adolescence. To date, no effective treatment exists for this severe brain disorder.
The laboratory run by Professor Sibon at the UMCG has, among others, conducted extensive research into the mechanism of PKAN, predominantly in fruit flies. The PANK2 gene encodes an enzyme pantothenate kinase 2, which is in turn required to convert vitamin B5 into coenzyme A (CoA). The end product, CoA, is required for normal metabolism in our bodies. A downstream metabolic product from this conversion into CoA is called 4’-phosphopathetheine (4’-PPT). In PKAN patients, 4’-PPT and therefore CoA are not properly produced. The idea is that, by administering additional 4'-PPT to PKAN patients, their deficiency of CoA is compensated. In PKAN animal models, 4'-PPT was indeed found to have a beneficial effect.
In September 2021, we started our clinical trial with 10 Dutch and Belgian PKAN patients. Throughout the two year trial these patients receive the vitamin supplement 4’-PPT in varying doses. Our research focusses on the effect of the 4’-PPT supplement on several parameters in the patients’ blood, while monitoring safety and tolerability. The study is subsidized by ZonMw/ Hersenstichting, dossier number 40-44600-98-323.
Involved researchers:
The general consensus that cells obtain their Coenzyme A via a de novo biosynthesis pathway starting with the uptake of vitamin B5 was recently challenged by work of the Sibon group, demonstrating, that cells and organisms can take up Coenzyme A from external sources. The mechanism behind this newly discovered manner of obtaining Coenzyme A is one of the topics of the Sibon lab.
University Medical Center Groningen (UMCG)
Department of Biomedical Sciences of Cells and Systems
Ody Sibon - Coenzyme A metabolism in health and disease
Internal Zip code FB31
Antonius Deusinglaan 1
9700 AD Groningen
The Netherlands
Visiting Address
University Medical Center Groningen (UMCG)
Department of Biomedical Sciences of Cells and Systems
Antonius Deusinglaan 1
Building 3215, 5th floor, room 525
9713 AV Groningen
The Netherlands
