PIL on Tuesday, Februari 12th
|When:||Tu 12-02-2019 12:00 - 13:00|
Enzyme promiscuity and personalised medicine for metabolic disease
Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Although the reactions and enzymes involved have been known for decades, the dynamic regulation of the pathway is not well understood. Deregulation of mFAO plays a pivatol role in many diseases, including prevalent multifactorial diseases, such as diabetes, but also rare inherited mFAO deficiencies. Symptoms differ between individuals even with the same primary disease mutation. We therefore embarked on a systems biology programme combining wet-lab biochemistry and computational modelling, to understand the dynamics, control, and robustness of the mFAO pathway in health and disease.
Enzymes in lipid metabolism, including those in the mFAO, typically recognize a class of substrates, rather than a unique substrate. In the case of mFAO there is limited specificity to the carbon chain-length of the substrate. This substrate promiscuity gives rise to a complex network of feedback and feedforward competitive inhibition. We developed and validated a dynamic computational model of the mFAO, based on detailed biochemical kinetics. Model simulations showed that substrate promiscuity may trigger a vicious cycle in which so much coenzyme A (CoA) is sequestered in esters with mFAO intermediated that this cofactor becomes limiting and the flux drops. Targeted proteomics and metabolomics are used to model individual patients. Initial personalised simulations suggest that we can explain the difference in disease severity between individual patients suffering from inherited enzyme deficiencies, thus providing a basis for a personalised medicine approach.
In the talk I will highlight our ongoing research into the role of surrounding metabolic pathways, how to translate our findings to clinical symptoms, and applications in inherited diseases as well as type 2 diabetes.
1. Van Eunen et al. (2013) Biochemical competition makes fatty-acid b -oxidation vulnerable to substrate overload. PloS Comp. Biol. 9: e1003186. doi: 10.1371/journal.pcbi.1003186.
2. Wolters et al. (2016) Translational targeted proteomics profiling of mitochondrial energy metabolic pathways in mouse and human samples. J. Proteome Res.15: 3204-13.
3. Van Eunen et al. (2016) Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. BMC Biology 14, 107.
4. Martines et al. (2017) The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation. PLoS Comp Biol, 13: e1005461.The dates and locations of the PILin 2019 are as follows:
Tuesday, February 12th: Boeringzaal - Barbara Bakker
Tuesday, March 12th: Boeringzaal - Marcel Kenter
Tuesday, April 9th: Boeringzaal - Liset van Dijk
Tuesday, May 14th: Boeringzaal - Frank Dekker
Tuesday, June 11th: Pharmacy Day
You are all more than welcome to attend the PIL. The PILcommittee hopes that you will come in great numbers.
Best regards, also on behalf of the new PIL committee: Wim Quax, Matthew Groves, Amalia Dolga, Klaus Mathwig, Peter Horvatovich & Anna Salvati.