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ESSENTIALS OF GLYCOBIOLOGY LECTURE 4 MONOSACCHARIDE METABOLISM AND SUGAR NUCLEOTIDE TRANSPORTERS

ESSENTIALS OF GLYCOBIOLOGY LECTURE 4 MONOSACCHARIDE METABOLISM AND SUGAR NUCLEOTIDE TRANSPORTERS Hud Freeze. INTRODUCTION. Traditional Approach--Study the enzymes and substrates in cells Holistic Approach--Add homeostasis and disease considerations

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ESSENTIALS OF GLYCOBIOLOGY LECTURE 4 MONOSACCHARIDE METABOLISM AND SUGAR NUCLEOTIDE TRANSPORTERS

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  1. ESSENTIALS OF GLYCOBIOLOGY LECTURE 4 MONOSACCHARIDE METABOLISM AND SUGAR NUCLEOTIDE TRANSPORTERS Hud Freeze

  2. INTRODUCTION • Traditional Approach--Study the enzymes and substrates in cells • Holistic Approach--Add homeostasis and disease considerations • Glucose is the central player, but not the only player • Monosaccharides = sugars • First Principles • Meet the players • Source of sugars: • Transport into cells • salvage them • make them in cells • Activate the sugars • Deliver activated sugars to the proper location

  3. Xyl GlcA Sia GlcNAc GalNAc THE SUGAR LEAGUE Fuc Gal Glc Glc Man Fru-6-P

  4. THREE WAYS TO ACTIVATE A SUGAR

  5. Activated Sugar Donors

  6. MONOSACCHARIDE TRANSPORTERS

  7. Facilitated Diffusion Transporter Topology and Signature Motifs N GR Y w G G G P Y PETKG PESPRYL E RG GRK ERVGRR E NH2 COOH

  8. Human Hexose Facilitated Diffusion Transporters SPECIFICITY NAMELOCALIZATION erythrocytes, brain GLUT1 muscle, fat, heart GLUT4 brain, testis, ovary GLUT3 testis GLUT14 glucose/fructose liver, islets GLUT2 blastocysts, brain, testis GLUT8 spleen, leukocytes, brain GLUT6 Liver, pancreas GLUT10 Heart, prostate GLUT12 H+-myo-inositol HMIT brain fructose GLUT5 Intestine, testis, kidney liver, kidney GLUT9 GLUT11 Heart, muscle

  9. OVERVIEW OF SUGAR METABOLISM IN CELLS Remember: 1. Glucose is central 2. Pathways not robust in all cells 3. Map is 2-D, not 3-D

  10. Galactosemia is caused by a Failure in Gal-1-P:UDP-Glc Uridyl transferase

  11. GALACTOSE ACTIVATION USES ALL THE OPTIONS

  12. GALACTOSE METABOLISM

  13. Galactosemia UDP-Glc + Gal-1-PGlc-1-P + UDP-Gal X Inability to metabolize Galactose--potentially lethal Treatment: Galactose restricted diet Even with proper diet: patients have dyspraxic speech, ovarian failure, poor growth, neurological impairment Knockout mouse does not have disease phenotype! Other genes important

  14. Mannose supplements can treat a human disorder: Fru-6-P-->Man-6-P

  15. Oral fucose supplements were used to treat a human genetic disorder

  16. UDP-GlcNAc epimerase/kinase Defective in two different human diseases

  17. Are the enzymes and substrates in the cytosol really “soluble”? Fru-6-P is the only freely soluble glycolytic intermediate

  18. If all the sugars can be inter-converted, how can you follow just one?

  19. Remains as [3H]Mannose TRICKS OF THE TRADE Remains as [4-3H]Galactose

  20. ?’s

  21. All of the precursors are made in the cytoplasm or nucleus-- BUT, most glycoconjugates are made in the Golgi or ER

  22. TRANSPORTERS IN THE GOLGI

  23. TRANSPORTERS IN THE ENDOPLASMIC RETICULUM

  24. HOW IT WORKS

  25. TRANSPORTERS: A FAMILY IN LOVE WITH ITS MEMBRANES

  26. SUMMARY AND TAKE HOME MESSAGES Glucose can be made into all sugars (monosaccharides) All sugars require activation and most require transport of the activated forms Transporters deliver the sugars to cells Salvaged and imported sugars can contribute to glycoconjugate synthesis The relative contributions of each source may be cell/tissue specific Some disorders in sugar metabolism can be treated with dietary modifications Specificity of sugar nucleotide and monosaccharide transporters is hard to predict Sugar is good for you---mostly

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