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

1. Sugar + ATP Sugar-P

NTP PPi

Sugar-NDP

3. Sugar(A)-NDP + Sugar(B)-1-P Sugar(B)NDP + Sugar(A)-1-P

2. Sugar(A)-NDP Sugar(B)-NDP

THREE WAYS TO ACTIVATE A SUGAR

SugarActivated Form

Glc

Gal

GlcNAc

GalNAc

GlcA

Xyl

Man

Fuc

Sia

UDP-Sugar

GDP-Sugar

CMP-Sia

Activated Sugar Donors

Type Primary Location Km (Glucose)

(mM)

Ion Coupled

(Na+/glucose) Epithelial Cells

SGLT 1 Small intestine

Some kidney

0.1 - 0.8

SGLT 2 Kidney cortex 1.6

Facilitated -diffusion

GLUT 1 Erythrocytes, blood tissue barrier 5

GLUT 2 Liver, small intestine 6-12

GLUT 3 Neurons, placenta 1-2

GLUT 4 Adipose tissue, skeletal muscle,insulin regulated

5

GLUT 5 Small intestine 6 (Fructose)

GLUT 7 Microsomal ? Glc from ER -

Man Many cell types 30-70 µM(Mannose)

Fuc Several cell types ~250 µM (Fucose)

MONOSACCHARIDE TRANSPORTERS

IsoformIsoform Main Tissue LocalizationMain Tissue Localization Functional Characteristics Functional Characteristics (Transport)(Transport)

GLUT1GLUT1 Erythrocytes, brain, ubiquitousErythrocytes, brain, ubiquitous GlucoseGlucose

GLUT2GLUT2 Liver, pancreas, intestine, kidneyLiver, pancreas, intestine, kidney Glucose (low affinity); FructoseGlucose (low affinity); Fructose

GLUT3GLUT3 BrainBrain Glucose (high affinity)Glucose (high affinity)

GLUT4GLUT4 Heart, muscle, adipose tissue, Heart, muscle, adipose tissue, brainbrain

Glucose (high affinity)Glucose (high affinity)

GLUT5GLUT5 Intestine, testes, kidneyIntestine, testes, kidney Fructose; Glucose (very low Fructose; Glucose (very low affinity)affinity)

GLUT6GLUT6 Brain, spleen, leucocytesBrain, spleen, leucocytes GlucoseGlucose

GLUT7GLUT7 n.d.n.d. n.d.n.d.

GLUT8GLUT8 Testes, brain and other tissuesTestes, brain and other tissues GlucoseGlucose

GLUT9GLUT9 Liver, kidneyLiver, kidney n.d.n.d.

GLUT10GLUT10 Liver, pancreasLiver, pancreas GlucoseGlucose

GLUT11GLUT11**

Heart, muscleHeart, muscle Glucose (low affinity); Fructose Glucose (low affinity); Fructose (long form)(long form)

GLUT12GLUT12 Heart, prostate, muscle, small Heart, prostate, muscle, small intestine, adipose tissueintestine, adipose tissue

n.d.n.d.

GLUT13GLUT13 Testes specificTestes specific n.d.n.d.

GLUT14GLUT14 BrainBrain HH++–myo–inositol –myo–inositol

* GLUT11 occurs in two splice variants: a short from (low-affinity glucose transport and a long form (which may be a fructose transporter).

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, brainblastocysts, brain, testis

liver, kidney

liver, pancreas

heart, muscle

heart, prostate

brain

testis

Human Hexose Facilitated Diffusion Transporters

SPECIFICITY NAME LOCALIZATION

M *

M

M

M M

M

M

M

M

M

M

M

M M

MMGl

Gl

M M

M

M

M

*

*

*

M

GlM

M

*

M1P

M6P

GlM

Gl6PF6P

GDP-M

EXTRACELLULARFLUID

CELL

*

GUT

LYS

ER G

M GlF

F

F F FGl

M

Figure 6: Mannose flux in cells.

*

M mannoseF fructoseGl glucoseM1P mannose-1-pM6P mannose-6-pF6P fructose-6-pGl6P glucose-6-pGDP-M GDP-mannose

proteindistal modificationtransport processenzymatic activitytransporter

Evidence Favoring Carbohydrate Salvage Pathways

Amino Sugars

∗ >50% of label reused for new glycoconjugates (GalNAc,

GlcNAc)

∗ ~70% of 3H-GlcNAc incorporated into sugar nucleotides

in rat liver

∗ ~30% of 3H-GlcN iv injected into rats is incorporated into

plasma glycoproteins

∗ 20-30% Sialic acids recycled in some cells

∗ GlcNAc/ManNAc kinase present in many tissues

∗ GalNAc-1-kinase distinct from Gal-1-kinase

Hexose and Fucose

∗ Mannose transporter, uses physiological concentrations

of Mannose

∗ Cells lacking UDP-Gal-4-epimerase can use serum

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

OVERVIEW OF SUGAR METABOLISM IN CELLS

Remember:1. Glucose is central2. Pathways not = in all cells3. Map is 2-D, not 3-D

Biosynthesis and Interconversion of Monosaccharides. The relative contributions of

each under physiological conditions are unknown. and - donors;

- monosaccharides; -control points

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Galactosemia is caused by aFailure in Gal-1-P:UDP-GlcUridyl transferase

O

H

OH

OH

H

H

HO

CH2

OH

H

H

O

O

H

OH

OH

H

O

CH2

OH

H

H

O

O

H

OH

OH

H

HO

H

CH2

OH

H

H

UDP O UDPUDP

B. UDP-Glc

UDP-Glc

UDP-Gal - Single enzyme: UDP-Gal-4-epimerase

(4-keto intermediate)UDP-Gal

NADH + H+

++ NAD + NAD

O

HOOH

HO

CH2

OH

O

HOOHO

CH3

O

O

HO

OH

O

CH3

O

O

O

HO

OH

CH3

O

NADPH

GDP-(D)-mannose

NADPH NADP

+

NADP

+

OH

GDP-4-keto, 6-deoxy-

(D)-mannose

GDP-4-keto,

6-deoxy-(L)-glucose

GDP-(L)-fucose

GDP-Man 4,6 dehydratase GDP-keto-6-deoxymannose

3,5 epimerase/4-reductase

A. GDP-Man

GDP

GDP GDP

and GDP-keto-6-deoxymannose 3,5 epimerase/4-reductase

GDP-Fuc - Three reactions, two enzymes: GDP-Man 4,6 dehydratase

GDP

1. Sugar + ATP Sugar-P

NTP PPi

Sugar-NDP

3. Sugar(A)-NDP + Sugar(B)-1-P Sugar(B)NDP + Sugar(A)-1-P

2. Sugar(A)-NDP Sugar(B)-NDP

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

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Biosynthesis and Interconversion of Monosaccharides. The relative contributions of

each under physiological conditions are unknown. and - donors;

- monosaccharides; -control points

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

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Oral fucose supplements used to treat a human genetic disorder

O

HOOH

HO

CH2OH

O

HOOHO

CH3

O

O

HO

OH

OCH3

OO

O

HO

OH

CH3

ONADPH

GDP-mannose

NADPH NADP+

NADP+

OH

GDP-4-keto,6-deoxy-mannose

GDP-4-keto,6-deoxy-glucose

GDP-fucose

GDP-Man 4,6 dehydratase GDP-keto-6-deoxymannose 3,5 epimerase/4-reductase

A. GDP-Man

GDPGDP GDP

and GDP-keto-6-deoxymannose 3,5 epimerase/4-reductase GDP-Fuc - Three reactions, two enzymes: GDP-Man 4,6 dehydratase

GDP

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

UDP-GlcNAc epimerase/kinase Defective in two human diseases

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Fru-6-P is the only freely soluble glycolytic intermediate

Are the enzymes and substrates in the cytosol really “soluble”?

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

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

O

PO4

HOHO

OH

OH3H

Glycoproteins

PMM

[2-3H]M6P

[2-3H]M1P

O

OHHOHO

PO4

OH

F6P

G6P

Glycolysis

PMI

H2O 3HOH

[2-3H]Man

O

H

OH

OH

H

H

HO

CH2OH

HH

O

O

H

OH

OH

H

O

CH2OH

HH

O

O

H

OH

OH

H

HO

H

CH2OH

HH

UDP O UDPUDP

B. UDP-Glc

UDP-Glc

UDP-Gal - Single enzyme: UDP-Gal-4-epimerase

(4-keto intermediate) UDP-Gal

NADH + H+ + + NAD + NAD

Remains as [2-3H]Mannose

Remains as [4-3H]Galactose

TRICKS OF THE TRADE

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

Some Control Points for Sugar Nucleotide Synthesis

Enzyme Inhibitor

UDP-Glc dehydrogenase UDP-Xyl

GDP-Man 4,6-dehydratase GDP-Fuc

Glutamine:fructose-6-P acetyltransferase UDP-GlcNAc

UDP-GlcNAc epimerase/kinase CMP-Sia

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

?’s

These are the Major Leaguers, how about life in the Minors?

BIOSYNTHESIS OF UNUSUAL SUGARS

KDN--2-keto-3-deoxy-D-glycero-D-galactonononic acida sialic acid analog found mostly in fish eggs

Man--->Man-6-P---> KDN---> CMP-KDN + + PEP CTP

Glycoproteins, glycolipids

Galactofuranose--Galf, found in bacteria and lower eukaryotes

UDP-Galpp---->UDP-Galff----> Glycoconjugates mutase Galactofuranosyl transferases

QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

From: Schenk et al Glycobiol 11, 61R, 2001

SYNTHESIS OF DOLICHYL PHOSPHATESYNTHESIS OF DOLICHYL PHOSPHATE

Man Fuc

GDP-Man

Man-l-P

GTP

NADP

Dol-P-Man

GDP-Fuc

Man-6-P

Dol-P

ATP

Fuc-1-P

GTP

ATP

ManNAc-6-P

PEP

Neu5AcCMP-Neu5Ac Neu5Ac-9-P

CTP

ManNAc

UDP- GlcNAcUDP-GalNAcGalNAc

ATP

GalNAc-1-P

UTP

GlcNAc-6-P

GlcNAc-l-P

UTP

Dol-P-Glc

GlcNAc

UDP-Xyl

-CO2

UDP-GlcA

UDP-Glc

Glycogen

NAD+

UDP-Gal

Gal

Gal-1-P

UTP UDP-Glc

Dol-P

ATP

Glc-1-P

Glc

Glc-6-P Fru-6-P

ATP

Glutamine

GlcN-6-P

-NH3

Pi

ATP

AcCoA

NAD

Glycolysis

CMP-Neu5Ac

NADP

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

: Nucleotide Transport in Golgi & ER

Nucleotide ER Golgi

CMP - Sia - +++

GDP - Fuc - ++++

UDP - Gal - ++++

PAPS - ++++

GDP - Man - ++++

UDP - GlcNAc ++ ++++

UDP - GalNAc ++ ++++

UDP - Xyl ++ ++++

ATP +++ ++++

UDP - GlcA ++++ ++++

UDP - Glc ++++ +

Mammals, yeastUDP-

N-Acetylglucosamine

MammalsUDP-

N-Acetylgalactosamine

Mammals, Plants

UDP-Glucose

ATPMammals

CMP-Sialic Acid

Mammals

AMP orADP

CMP

GMP

GDP-FucoseMammals

GDP-Mannose

LeishmaniaYeast

UDP-Xylose

MammalsMammals

? Pi

Pi

UMP-2

PAPSMammals

UDP-Galactose

Leishmania

YeastMammals

UDP-Glucuronic Acid

Freeze: 6.3

TRANSPORTERS IN THE GOLGI

TRANSPORTERS IN THE ENDOPLASMIC RETICULUM

?

HOW IT WORKSHOW IT WORKS

TRANSPORTERS: A FAMILY IN LOVE WITH ITS MEMBRANES

DONORS AND CARRIERS FOR GLYCAN MODIFICATIONSDONORS AND CARRIERS FOR GLYCAN MODIFICATIONS

MODIFICATION PRECURSOR TRANSPORTER Phosphate ATP YesSulfate PAPS YesMethyl AdoMet ?Acetyl Acetyl-CoA YesPyruvate PEP ?Acyl Acyl-CoA (?) ?Succinyl Succinyl-CoA (?) ?

SUMMARY AND TAKE HOME MESSAGES

Glucose can be made into all sugars (monosaccharides)Glucose can be made into all sugars (monosaccharides)

All sugars require activation and most require transport of the activated forms All sugars require activation and most require transport of the activated forms

Transporters deliver the sugars to cellsTransporters deliver the sugars to cells

Salvaged and imported sugars can contribute to glycoconjugate synthesisSalvaged and imported sugars can contribute to glycoconjugate synthesis

The relative contributions of each source may be cell/tissue specificThe relative contributions of each source may be cell/tissue specific

Some disorders in sugar metabolism can be treated with dietary modificationsSome disorders in sugar metabolism can be treated with dietary modifications

Hard to know specificity of sugar nucleotide and monosaccharide transportersHard to know specificity of sugar nucleotide and monosaccharide transporters

Sugar is good for you---mostlySugar is good for you---mostly