The Essentials of Nucleotide Sugars !

!Lance Wells

X 11

Sugar Activated form Glc

] UDP-sugar

Gal GlcNAc GalNAc GlcA Xyl Man ] GDP-sugar Fuc Sia ] CMP-Sia !

Sugar Nucleotides (high energy donors) in Mammals

What mammalian sugars are missing? IdoA (epimerized in glycan chains, not added)

Ribitol (CDP-ribitol, new sugar nucleotide/O-Man structures)

Glucose is only Sugar Needed for Synthesis of All Sugar Nucleotides

Note: No salvage Pathway for GlcA!

Key  Control  Points:  Early  step  enzymes  that  are    inhibited  by  end-­‐product  Sugar  nucleo<de  

Salvage PathwaysExample: Glc à Glc-6-P à Glc-1-P à UDP-Glc

Example: Fuc à Fuc-1-P à UDP-Fuc

Example: Neu5Ac à CMP-Neu5Ac

None or Unknown:

General Principles for Synthesis

1:  ini&ated  by  kinase  reac&on,  consumes  2  NTP    example:  Glc  à  Glc-­‐6-­‐PàGlc-­‐1-­‐PàUDP-­‐Glc  

 2:  mul&ple  ways  (epimeriza&on,  decarboxyla&on,  etc.)  

 example:  UDP-­‐GlcNAcàUDP-­‐GalNAc  ;  UDP-­‐GlcA  àUDP-­‐Xyl    3:    nucleo&de-­‐exchange  reac&on  

 example  Gal-­‐1-­‐P  +UDP-­‐Glc  à  Glc-­‐1-­‐P  +  UDP-­‐Gal  

Leloir PathwayUDP-Gal/UDP-Glc

AndUDP-GalNAc/UDP-GlcNAc

Interconversion

Galactosemia and potentially CDGs?? (for ‘19 lecture)

Conversion of activated sugar donors

Chapter 4 Figure 2 Essentials of Glycobiology

Second Edition

Generation of UDP-GlcNAc

UDP-GlcNAc as a Nutrient Sensor

GDP-Fuc from GDP-Man UDP-GlcA from UDP-Glc

UDP-Xyl from UDP-GlcA

Reminder: No salvage pathway for GlcA (not clear for Xyl)

CMP-Sialic AcidSynthesis

Glucose is only Sugar Needed for Synthesis of All Sugar Nucleotides

Note: No salvage Pathway for GlcA!

Key  Control  Points:  Early  step  enzymes  that  are    inhibited  by  end-­‐product  Sugar  nucleo<de  

Transporters for nucleotide sugars

Chapter 4, Figure 4 Essentials of Glycobiology

Second Edition

Getting sugars in cells

Dolichol phosphate: The “other” high energy sugar donor

Chapter 8, Figure 2Essentials of Glycobiology

Second Edition

Dol-P-Man N-link, O-Man, C-Man, GPI anchors

Dol-P-Glc N-linked biosynthesis

Dol-P-GlcNAc N-linked biosynthesis

Generated enzymatically using corresponding sugar

nucleotides (GDP-Man, UDP-Glc, UDP-GlcNAc)…must be “flipped” into lumen of ER

Chapter 4, Figure 1

Biosynthesis and interconversion of monosaccharides

Essentials of Glycobiology Second Edition