ESSENTIALS OF GLYCOBIOLOGY LECTURE 4 MONOSACCHARIDE METABOLISM AND SUGAR NUCLEOTIDE TRANSPORTERS Hud...
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Transcript of ESSENTIALS OF GLYCOBIOLOGY LECTURE 4 MONOSACCHARIDE METABOLISM AND SUGAR NUCLEOTIDE TRANSPORTERS Hud...
ESSENTIALS OF GLYCOBIOLOGY
LECTURE 4MONOSACCHARIDE METABOLISM
AND SUGAR NUCLEOTIDE TRANSPORTERS
Hud Freeze
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
GlcGlc
Man
Gal
GalNAcGlcNAc
Fuc
GlcA
Xyl
Sia
THE SUGAR LEAGUE
Fru-6-P
THREE WAYS TO ACTIVATE A SUGAR
Activated Sugar Donors
MONOSACCHARIDE TRANSPORTERS
GP
NH2
N
GRK
GR
E RG
w
PESPRYL ERVGRRPETKG
E
Y
Y
COOH
G G
Facilitated Diffusion Transporter Topology and Signature Motifs
GLUT1
GLUT2
GLUT4
GLUT3
GLUT14
GLUT8
GLUT6
GLUT10
GLUT12
GLUT5
GLUT9
GLUT11
HMIT
fructose
glucose/fructose
H+-myo-inositol
erythrocytes, brain
liver, islets
brain, testis, ovary muscle, fat, heart
Intestine, testis, kidney
spleen, leukocytes, brain
blastocysts, brain, testis
liver, kidney
Liver, pancreas
Heart, muscle
Heart, prostate
brain
testis
Human Hexose Facilitated Diffusion Transporters
SPECIFICITY NAME LOCALIZATION
OVERVIEW OF SUGAR METABOLISM IN CELLS
Remember:1. Glucose is central2. Pathways not robust in all cells3. Map is 2-D, not 3-D
Galactosemia is caused by aFailure in Gal-1-P:UDP-GlcUridyl transferase
GALACTOSE ACTIVATION USES ALL THE OPTIONS
GALACTOSE METABOLISM
UDP-Glc + Gal-1-P Glc-1-P + UDP-GalX
Galactosemia
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
Mannose supplements can treat a human disorder: Fru-6-P-->Man-6-P
Oral fucose supplements wereused to treat a human genetic disorder
UDP-GlcNAc epimerase/kinase Defective in two different humandiseases
Fru-6-P is the only freely soluble glycolytic intermediate
Are the enzymes and substrates in the cytosol really “soluble”?
If all the sugars can be inter-converted, how can you follow just one?
Remains as [3H]Mannose
Remains as [4-3H]Galactose
TRICKS OF THE TRADE
?’s
All of the precursors are made in the cytoplasm or nucleus--BUT, most glycoconjugates are made in the Golgi or ER
TRANSPORTERS IN THE GOLGI
TRANSPORTERS IN THE ENDOPLASMIC RETICULUM
HOW IT WORKS
TRANSPORTERS: A FAMILY IN LOVE WITH ITS MEMBRANES
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