2-Deoxy-2-fluoro-D-mannose NEW

2-Deoxy-2-fluoro-D-mannose (2FDM) is a synthetic, fluorinated derivative of the natural sugar D-mannose. Here's a breakdown of its key aspects:

1. Chemical Structure:

• The hydroxyl group (-OH) found in natural mannose is removed (deoxy).

• A fluorine atom (-F) is added in its place (fluoro).

• It's based on the D-mannose pyranose ring structure (a 6-membered ring).

• At the carbon 2 (C2) position:

• The "D" specifies the stereochemistry at C5, matching natural D-mannose.

2. Key Properties:

• Metabolic Inhibitor: It acts as an antimetabolite of mannose. The fluorine atom mimics the size of a hydroxyl group but cannot be enzymatically processed in the same way. This disrupts specific metabolic pathways involving mannose.

• Glycosylation Inhibitor: Its primary known biological effect is the inhibition of protein N-linked glycosylation, particularly the processing of oligosaccharides on glycoproteins. It interferes with enzymes like mannosidases in the Golgi apparatus.

• Stability: The C-F bond is strong and stable, making the compound resistant to enzymatic degradation (like hydrolysis) that natural sugars undergo.

• Isosteric Mimic: Fluorine is a good mimic for hydrogen or the oxygen of a hydroxyl group in terms of size, but its electronegativity significantly alters the electronic properties and reactivity at C2.

3. Primary Significance:

• Glycoprotein synthesis and processing.

• The role of N-linked glycosylation in protein folding, trafficking, and function.

• Mannose metabolism pathways.

• Research Tool: It's primarily used in biochemical and cell biological research to study:

• Precursor for PET Tracers: Its most important practical application is as a key synthetic intermediate in the production of the vital PET (Positron Emission Tomography) imaging agent [¹⁸F]FDG (2-Deoxy-2-[¹⁸F]fluoro-D-glucose). While 2FDM itself isn't typically injected, it serves as a crucial building block in the radiosynthesis of FDG, which is used to image glucose metabolism in cancer, heart disease, and neurology.

4. Mechanism of Glycosylation Inhibition:

• 2FDM enters cells via glucose/mannose transporters.

• It is phosphorylated by hexokinase to 2-Deoxy-2-fluoro-D-mannose-6-phosphate (2FMan-6-P).

• This phosphate form accumulates in cells.

• 2FMan-6-P inhibits specific Golgi mannosidases (like mannosidase II) involved in trimming mannose residues from the core oligosaccharide chain during N-glycan processing. This leads to the accumulation of hybrid or high-mannose type glycans and disrupts normal glycoprotein maturation.

In summary:

2-Deoxy-2-fluoro-D-mannose is a fluorinated analog of mannose designed to disrupt mannose metabolism and, most notably, the processing of N-linked glycoproteins. While valuable as a research tool to study glycosylation, its most critical role is as an essential precursor in the synthesis of the widely used PET imaging tracer [¹⁸F]FDG. Its biological activity stems from its ability to be phosphorylated and then inhibit key enzymes in the glycan processing pathway.