National Institute of Diabetes and Digestive and Kidney Diseases 5R01DK045776-35

B12 Trafficking and Inherited Defects

This award funds research on the trafficking and inherited defects of Vitamin B12, focusing on its transport mechanisms and related genetic disorders. The project aims to elucidate the biochemical pathways and molecular mechanisms involved in B12 metabolism and its implications for diseases such as homocystinuria and methylmalonic aciduria.

Description

Vitamin B12 (or cobalamin) supports just two enzymes in the human proteome, but its absence is incompatible with life. This high-value dietary commodity is escorted by an elaborate system of chaperones to its two client enzymes: methionine synthase (MS) in the cytoplasm and methylmalonyl-CoA mutase (MCM) in the mitochondrion. Clues to the complexity and multicompartment geography of the B12 trafficking pathway had emerged from clinical genetics studies on patients with inborn errors of cobalamin metabolism, which led to their classification into nine complementation groups (cblA-G, cblJ, and mut). Translocation of this organometallic cofactor, complete with a tail absent in other tetrapyrroles, presents chemical and steric challenges. The PI’s group has led efforts to decipher function, illuminating structural, spectroscopic, and kinetic details of the redox-linked coordination chemistry. Advances position us to address gaps in understanding of B12 trafficking, relevant to homocystinuria and methylmalonic aciduria. Specific aims include elucidating the mechanism of B12 traffic at the cytoplasmic branch, the transfer from CblD to MS, and the molecular traffic lights in the mitochondrial branch involving ATR, MCM, and CblA. Additionally, the potential for rhodibalamin to form rhodium-carbon bonds and target Mtb growth will be assessed.

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