The biochemical fate of N-glycolylneuraminic acid in human and non-human systems

• Applicant: Dr. Anne Katrin Bergfeld
• Subject Area: Biochemistry
• Term: from 2010 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 187896516

Sialic acids such as N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac) typically decorate the surface of mammalian cells. In the hominid lineage the CMAH gene is found exclusively inactivated in humans, who became incapable of synthesizing Neu5Gc. The human specific loss of Neu5Gc represents the first known genetic difference between humans and chimpanzees which could be directly linked to an altered phenotype. However, exogenous Neu5Gc from dietary sources can be metabolically incorporated into cell surface glycoconjugates and accumulates in human tissues in the face of an anti-Neu5Gc response, which potentially facilitates diseases via chronic inflammation. By contrast, cmah-/- mice which harbor the human-like defect in Neu5Gc de novo biosynthesis do not easily accumulate exogenous Neu5Gc. To date, there is not a single publication available which addresses the metabolic turnover of Neu5Gc. The hypothesis to be tested is that mammalian cells have an as yet unknown pathway to turnover Neu5Gc. Special interest will be given to the theory that this pathway may be defective in some or all humans, as CMAH inactivation would have left it without function for ~2 million years. The most likely possibility is degradation of Neu5Gc in an enzymatic reaction catalyzed by „enzyme X“. To identify the corresponding „gene X“, a cmah-/- CHO and a nearly haploid human cell line will be used for expression cloning. In parallel, a bioinformatic approach will be initiated to identify candidate genes that might contribute to the pathway. Although less likely, other possible mechanisms to eliminate Neu5Gc will be considered, not focused on the putative „gene X“. The elucidation of Neu5Gc degrading pathways in human and non-human systems will form the biochemical basis to further investigate the process and impact of Neu5Gc accumulation during serious human diseases related to chronic inflammation - such as cancer, arteriosclerosis, or autoimmune diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Ajit Varki