Hexose Metabolism. An overview of sugar metabolism and how these sugars enter glycolysis.

Transcription

1 Hexose Metabolism An overview of sugar metabolism and how these sugars enter glycolysis. See chapter 15 of Fundamentals of Biochemisty: Life at the Molecular Level, 4 th Ed by Voet, Voet, and Pratt.

2 Overview Common Hexoses Fate of Fructose Fate of Galactose Fate of Mannose

3 Common Hexoses The most common hexoses processed in metabolic pathways are Glucose Fructose Galactose Mannose Glucose is simply shuttled through glycolysis, as discussed previously. Fructose can either enter glycolysis directly or be turned into GAP and then shuttled into glycolysis. Galactose is converted into glucose-6-phosphate via a series of oxidation reductions using a UDP-sugar intermediate Mannose is converted into F6P and then shuttled into glycolysis.

4 Fate of Fructose In muscles, hexokinase is a non-specific enzyme and so fructose can be converted into F6P directly and enters glycolysis that way. In the liver, hexokinase is not present. Instead the enzyme that initiates glycolysis is glucokinase (a specific enzyme that functions like hexokinase) which is specific for glucose. So in the liver, fructose in converted to glycolytic intermediates in a pathway that involves seven enzymes. The pathway in the liver has a two separate routes, with the same cost of ATP. One route is more direct whereas the other produces glycerol, which can be used to produce the backbone for glycerophospholipids and triacyclglycerols.

5 Fate of Fructose: Short path Fructose is phosphorylated to form fructose-1-phosphate (F1P) by action of the enzyme fructokinase. Neither hexokinase or PFK can phosphorylate F1P at C6 to form FBP. F1P is the cleaved by an aldolase isozyme, Aldolase B. Aldolase A is found in muscle and is specific for FBP. Liver cells however have Aldolase B, which can cleave F1P into glyceraldehyde and DHAP. Aldolase B is also commonly called F1P aldolase. DHAP can then be converted to GAP by TIM. Glyceraldehyde can be phosphorylated to make GAP using ATP and glyceraldehyde kinase. GAP then enters glycolysis like normal.

6 Fate of Fructose: Long path Like in the short path, fructose is first phosphorylated by fructokinase to make F1P, which is then subsequently cleaved by Aldolase B into DHAP and glyceraldehyde. From here DHAP will continue like normal but glyceraldehyde has a different potential fate. Glyceraldehyde can be reduced by NADH and alcohol dehydrogenase to produce NAD + and glycerol. The glycerol molecule can the be phosphorylated by ATP through the action of the enzyme glycerol kinase. The resulting product is glycerol-3-phosphate. Glycerol-3-phosphate is then oxidized to DHAP using NAD + by action of the enzyme glycerol phosphate dehydrogenase. DHAP can then enter glycolysis like normal.

7 Q: In the conversion of fructose into glycolytic intermediates which pathway requires more ATP? Q: Suggest a possible mechanism for Aldolase B. (How and why would it differ from Aldolase A?) Q: Write a net balanced chemical equation for the conversion of fructose into GAP. Do this for both routes and compare them.

8 Fate of Galactose Galactose is typically obtained from dairy products in the form of the disaccharide lactose and is converted to G6P for metabolism. The first step is the conversion of galactose to galactose-1- phosphate by the action of ATP dependent galactokinase. UDP-glucose has its glucose residue replaced with galactose to yield UDP-galactose and G1P. G1P can then be isomerized into G6P via the enzyme phosphoglucomutase. The transfer of glucose and galactose on UDP is performed by the enzyme galactose-1-phosphate uridylyl transferase. UDP-galactose can then be turned into UDP-glucose by action of the enzyme UDP-galactose-4-epimerase. UDP-galactose-4-epimerase has an associated NAD + which suggests that the mechanism involves a subsequent oxidation then reduction reaction.

9 Q: Draw the structure of galactose and indicate how it differs from glucose. Q: How does the ATP cost differ in galactose metabolism versus glucose metabolism? How does the net yield differ? Q: If you were trying to verify that the mechanism of UDPgalactose-4-epimerase, what intermediate compound would indicate that it likely used a subsequent oxidation reduction?

10 Fate of Mannose Mannose is typically eaten in the form of polysaccharides and glycoproteins and is the C2 epimer of glucose. Mannose is converted to F6P and then enters into glycolysis and this process is a two step pathway. The first step is catalyzed by hexokinase and converts mannose to mannose-6-phosphate. Phosphomannose isomerase converts mannose-6-phosphate to F6P in a reaction similar to phosphoglucose isomerase.

11 Q: Draw the Haworth structures of glucose, mannose, and galactose. Q: Why are is the entrance of mannose into glycolysis likely so much simpler than galactose? Explain. Q: How does the net ATP yield of glucose, mannose, and galactose passage through glycolysis differ?