Disorders of Human Valine Catabolism – Key Metabolites and Pathomechanisms

• Applicant: Professor Dr. Jörn Oliver Sass
• Subject Area: Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538669957

While branched-chain amino acids leucine, isoleucine and valine are well known as substrates for protein synthesis and resource for energy production, more recently they and some of their metabolites have also been recognized as regulatory molecules. 3-hydroxyisobutyric acid (HIB) has been reported as as a paracrine regulator of transendothelial fatty acid uptake and transport into skeletal muscle suggest biological effects in disorders with accumulation of this metabolite and has been linked to hyperglycemia and diabetes type 2. Recently we have identified 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency as a novel inborn error in human valine catabolism which is due to biallelic mutations in the HIBADH gene. As there is little overlap between the clinical presentations of the few individuals diagnosed with this disorder, although failure to thrive and developmental/ neurological problems have been notes, it is not yet clear, whether this is a disease or a mere biochemical variant. Since HIBADH deficiency results in accumulation of HIB, a better understanding of the biological functions of HIB is needed. Mutations in the ALDH6A1 gene which codes for methylmalonate semialdehyde dehydrogenase, the enzyme that catalyzes the subsequent step in valine degradation, result in the accumulation of HIB and additional metabolites. This will let us to knock out HIBADH and ALDH6A1 in several cell lines, using CRISPR-Cas9 genome editing, and subsequently introduce selected mutations into their HIBADH. Effects on gene expression, enzyme activity, HIB metabolism and levels, mitochondrial energy metabolism, production of reactive oxygen species, cell proliferation and apoptosis will be studied in particular in cell lines derived from the nervous system. To extend the biochemical studies to physiological aspects, we will also characterize various strains of the nematode Caenorhabditis elegans with mutations in the orthologs of human genes HIBADH and ALDH6A1 (B0250.5 and alh-8). In addition, HIBADH sequence variants will be overexpressed in Escherichia coli and studied for enzyme kinetics and substrate binding. We expect that our study will provide more insight into the biological roles of HIB and consequences of its accumulation in metabolic disorders. This will contribute to a better understanding of two inborn errors of valine metabolism and may help to decide whether specific treatment might be helpful or not.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Professor Wyatt W. Yue, Ph.D.