1. Sugar Catabolism and Biosynthesis Medical Biochemistry, Lecture 42

2. Lecture 42, Outline Examine how glucose metabolism relates to other sugars Fructose metabolism and related diseases Galactose metabolism and related diseases Glucuronate metabolism and functions Understand nucleotide sugar interconversions Marks, Marks and Smith Chapter 29, primary source, Harper’s Ch 22 secondary source. Review Ch. 15 for sugar structural properties

3. Figure 29.4, MMS UDP-Glucose Metabolism

4. High Energy Phosphates in UDP-Glucose Metabolism

5. UDP-Glucose Glycosyltranserase Reaction

6. Figure 29.6, MMS Glucuronic Acid Metabolism

7. Glucuronidation Reactions: (Primarily in liver, intestine) Bilirubin di-glucuronide

8. URONIC ACID PATHWAY Glucuronate derived from breakdown of UDP-glucuronate (which ultimately came from glucose via UDP-glucose) Alternative oxidative pathway for glucose Not in humans

9. Figure 29.2, MMS Fructose Metabolism

10. -Fructose is found in foods containing sucrose (fruits), high- fructose corn syrups, and honey. -Dietary fructose is converted to Fructose-1-P by fructokinase (primarily in the liver, kidney and intestine). -Normal aldolase B function generates dihydroxyacetone phosphate and glyceraldehyde from Fructose-1-P. The affinity of aldolase B for fructose-1-P is much poorer than that of fructose-1,6-biphosphate, thus fructose-1-P accumulates in fructokinase-expressing tissues. Thus, aldolase B is the rate-limiting enzyme for fructose metabolism (but not glucose).

11. Hereditary Fructose Intolerance -HFI results from a heriditary mutation in aldolase B that leads to a poorly active enzyme. With aldolase B mutations, fructose and fructose-1-P accumulate to much higher levels for even longer periods of time, leading to inhibition of glycogen phosphorylase. This interferes with normal glycogenolysis and gluconeogenesis (resulting in hypoglycemia and lactic acidosis). The F-1-P also depletes the phosphate pools, which can affect the catabolism of adenine nucleotides and depletion of ATP levels. -Seen primarily in children, symptoms include diarrhea, vomiting, failure to thrive and effects of hypoglycemia (weakness, tremulousness, sweating). The more dietary fructose ingested, the more severe the symptoms. Untreated, can result in hepatic and/or renal failure. Treated by limiting dietary intake of fructose

12. Fructose and Sorbitol Fructose can be synthesized from glucose via aldol reductase conversion to sorbitol, and a sorbitol dehydrogenase reaction to fructose. This is a normal pathway in seminal vesicles, and spermatazoa utilize fructose as a major fuel source. In the eye, sorbitol production can be a problem in the formation of cataracts, especially in patients with diabetes mellitus. In the same condition, the increased fructose and sorbitol levels create a high osmotic pressure in the lens. Non-enzymatic glycosylation of lens proteins from glucose and fructose also result. All of these cumulative effects result in the opaque cloudiness of the lens associated with cataracts.

13. Fructosuria Rare, but benign, genetic disorder caused by a deficiency in fructokinase Why is this defect benign, as opposed to HFI? Answer: no toxic fructose metabolites accumulate, most is excreted harmlessly in the urine

14. Lactose Biosynthesis Lactose is formed only in the mammary gland during lactation by a two-subunit endoplasmic reticulum enzyme, galactosyltransferase plus a modifier protein,  - lactalbumin  -lactalbumin is made in response to the hormone prolactin following parturition; it lowers the K m of glucose for galactosyltransferase from 1200 to 1 mM. In the absence of  -lactalbumin, galactosyltransferase functions in glycoprotein biosynthesis pathways

16. Figure 29.11, MMS Metabolism of Galactose

17. Galactose Metabolic Energy Equation

18. More Galactose Metabolism How do we survive without drinking milk (the major dietary source of galactose)? Can a new mother who is severely lactose intolerant lactate in the absence of dietary dairy products? Answer: UDP-Glc/Gal-4-Epimerase This enzyme facilitates galactose conversion to Glucose-1-P, and also functions to convert glucose metabolites to UDP-galactose for lactose synthesis and formation of glycoproteins.

19. Galactosemias Hereditary disorders preventing the metabolism of galactose (derived from milk/dairy lactose) into glucose metabolites. One of the most common genetic diseases, and frequently screened in newborns Result from defects in galactose 1-phosphate uridylyltransferase or galactokinase (a milder, rarer form) Leads to accumulation of galactose-1-P in tissues, blood and urine; eventually depletes liver of inorganic phosphate, and can lead to liver failure and mental retardation. Gal-1-P inhibits phosphoglucomutase, leading to disregulation of UDP-glucose and UDP- glucuronate metabolism, eventually resulting in loss of glucuronidated bilirubin (resulting in jaundice)

20. Metabolic Effects of Gal-1-P Accumulation in Galoctosemia

21. Galactosemias (cont.) In the eye lens, accumulated galactose is converted by aldol reductase to galactitol; contributes to cataract formation. In newborns, failure to thrive and vomiting/diarrhea following milk ingestion are the initial symptoms cataracts form and jaundice symptoms appear within the first 2 weeks. Diagnosed by an enzyme activity test from erythrocytes, and controlled by galactose free diet In galactokinase deficiencies, Gal-1P does not accumulate, but cataracts are still a problem

22. Figure 29.12a, MMS Sugar Nucleotide Conversions

23. Figure 29-12b, MMS Sugar Nucleotide Conversions (cont.)