Grant: Operating Grant

Vitamin B12 is an essential nutrient by helping maintain the metabolic activity of all cells. At least eight genetic diseases have been discovered which are blocked in the metabolism of vitamin B12 to its active forms, resulting in severe, potentially fatal illnesses in children. Our goal has been to identify the affected genes and determine how vitamin B12 is metabolized in cells. To date, seven of the genes have been identified and, with our colleagues, we have identified five of them. In the last grant period, we investigated the biochemical steps governed by the newly identified genes, investigated the mutations causing B12 diseases in patients and have continued to search for additional genes in human cells and other organisms that use B12 as a nutrient. We now propose to investigate the mechanism by which B12 is metabolized in human cells. We predict the existence of protein complexes, or small self-contained factories, in cells that process B12 to active form from beginning to end. We will isolate the complexes, determine their composition and how they metabolize B12 and how the predicted complexes are disrupted in patients. Our studies will increase our knowledge of vitamin B12 metabolism in humans and lead to the therapeutic strategies for the treatment of affected patients.