So far in this metabolism series, we’ve painstakingly talked about glycolysis, its chemical “logic”, touched on some regulation, and most recently explored fructose metabolism. To wrap things up before getting deeper into regulation, I want to briefly talk about galactose and mannose – two sugars common to our diets and integral to our biology. I’ll go light on the biochemistry as the mechanisms here are nearly identical to everything I’ve gone over in the past four blog posts.
Galactose Metabolism
Galactose is a monosaccharide probably most associated with dairy foods. It is one half of the milk sugar lactose (the other half being glucose). But, it’s also found in cruciferous vegetables, beets, and avocados. In the body, it’s a common component of glycolipids and glycoproteins.
Galactose is the C4 epimer of glucose – that is, the stereochemistry in the 4 position is inverted from what we’d see in glucose. Because of this, galactose can’t directly enter the glycolytic pathway. Harkening back to my spiel on chemical logic, if galactose were to enter glycolysis as is, we’d end up with metabolites with the incorrect stereochemistry downstream. If you’ve read my previous posts, you know how this would result in severe metabolic consequences. Rather, galactokinase, an enzyme specific to galactose, phosphorylates the molecule at its C1 position. The resulting galactose-1-phosphate can then be converted into glucose.
Galactose-1-phosphate is converted first to glucose-1-phosphate via an exchange reaction with UDP-glucose. The “UDP” here stands for uridine diphosphate which is attached to the 1 position of glucose. Through the enzymatic action of galactose-1-phosphate uridylyl transferase, this glucose gets exchanged with galactose, leaving us with glucose-1-phosphate and UDP-galactose:
UDP-galactose plays a role in the production of complex carbohydrates (especially for our cartilage), modifying proteins by placing sugars on them, and can also be recycled back to UDP-glucose. UDP-galactose-4-epimerase flips the hydroxyl on the 4 position of galactose, subsequently converting it to glucose. This is done in a redox cycle, utilizing NAD+.
Glucose-1-phosphate cannot be fed directly into the glycolytic pathway. An enzyme called phosphoglucomutase transfers the molecule’s phosphate to the 6 position, producing glucose-6-phosphate. This enzyme’s mechanism is identical to phosphoglycerate mutase that we saw previously. Glucose-6-phosphate can then proceed down the glycolytic pathway as normal.
Mannose Metabolism
Mannose is an essential component in the modification and processing of proteins within the endoplasmic reticulum. Most extracellular proteins have some sort of glycosylation on them, and mannose is one of the primary sugars part of this. This is a long and complex topic best reserved for its own dedicated blog series.
Mannose is the C2 epimer of glucose. Hexokinase doesn’t care about this – this C2 position is going to be converted to a carbonyl early on in glycolysis anyways. So, hexokinase will convert mannose to mannose-6-phosphate.
Now, mannose-6-phosphate cannot be converted to the fructose form by the phosphoglucose isomerase enzyme that converts glucose-6-phosphate to fructose-6-phosphate. Rather, a different enzyme is needed – phosphomannose isomerase. The mechanism is identical to that of phosphoglucose isomerase and thus, produces fructose-6-phosphate.
The Takeaway?
Different sugars like fructose, galactose, and mannose can all be converted into glycolytic intermediates relatively easy. Here, we get to see more examples of the specificity of enzymes in action. For me at least, this was a tough concept to visualize. With enough examples though, it becomes clearer (relative to learning metabolism, that is) that protein structure determines function. That is, the unique structure of an enzyme is highly specific for its given task. Moreover, seeing how different molecules can be fed into the same pathway provides us with potential points of regulation (or dysregulation) – a topic coming up next.
Thoughts?