Monosaccharides and Glycosides Flashcards
Sugars and sugar derivatives play numerous additional roles besides simply providing chemical energy for the synthesis of ATP. This includes functional and structural roles in
Glycosaminoglycans, glycolipids, and proteoglycans
The simple sugars galactose, glucose, mannose, and fructose have the same chemical formula (C6H12O6). Hence, these four sugars are
Isomers
Among isomers, a geometric difference at any single carbon other than the carbonyl carbon results in
Epimers
By virtue of intramolecular reactivities, sugars can exist in either straight chain or ring conformations. The predominant structure of aldoses such as glucose and galactose is a
Six membered hemi-acetal ring
This six-membered hemi-acetal ring is also referred to as a
Pyranose ring
Adopt either a five membered hemiketal ring structure (4 carbons, 1 oxygen), also called a furanose ring or a six-membered ring
-ex: Fructose
Ketoses
Form a six membered (5 carbons, 1 oxygen) hemiacetal ring, also referred to as a pyranose ring
-ex: Glucose and Galactose
Aldoses
In all these cases, ring formation will result in two alternative configurations at the
Anomeric carbon (Carbon #1 of aldoses and #2 of Ketoses)
Structural variants about the anomeric carbon are called
Anomers
Anomers, (expressed as a and B) equilibrate with each other via the
Open chain intermediate
Mirror image structural variants are called
-ex: D- and L-Glucose
Enantiomers
A trisaccharide of galactose, glucose, and fructose
Raffinose
A Disaccharide of glucose
Trehalose
Extensively polymerized sugars are also prevalent in our diets, including
Amylose, amylopectin, and glycogen
While simple sugars are absorbed directly, disaccharides and polysaccharides must first be
Hydrolyzed to simple sugar constituents
Digestion of start begins with
Salivary a-amylase
Continues this process once the acidic contents of the stomach have been neutralized
Pancreatic a-amylase
The bulk of CHO digestion (hydrolysis) occurs at the mucosal lining of the jejunum, with the secretion of additional digestive enzymes, such as
Glucoamylase/maltase (a-1,4), Sucrase/isomaltase (a-1,6), and lactase
The products of these normally quite efficient hydrolyzing enzymes are the three simple sugars
Glucose, fructose, and galactose
ABSORPTION of these three sugars, in the intestinal epithelium, is the responsibility of which three transporters?
SGLT1, GLUT5, and GLUT2
The principal lumenal transporters
SGLT1 and GLUT5
The principle transporter into the capillaries
GLUT2
They arise by a number of means, with their root cause being the incomplete digestion
Di- and oligosaccharides
The passage of significant quantities of osmotically active complex sugars into the large intestine results in
Bloating, dehydration, and gas (i.e. CO2 and H2 production)
Failure to fully digest CHO can stem from genetic deficiency for one of the above hydrolases, temporary loss of hydrolase activity through other intestinal pathology, and
“Adult” onset of enzyme deficiency
Perhaps the most common of these age-dependent onset phenomena
Lactase deficiency
Up to half of all adults, and up to 90% of blacks and Asians are deficient for
Lactase
Diagnosis of these enzyme deficiencies is done by
Oral tolerance tests
How do cells essentially “capture” incoming sugars?
Phosphorylation
Isn’t transported by SGLT1, GLUT2, or GLUT5, and the presence of the phosphate makes passive transit of the membrane an extremely low probability event
Glucose-6-phosphate
Glucose and galactose have the same chemical formula and are both aldoses. How does the cell convert one into the other?
Epimerization
Because glucose and fructose differ only in the location of the carbonyl carbon, how can the cell convert one to the other?
Isomerization
An additional transformation that sugars undergo is their conversion to
Nucleotide linked forms (ex: UDP glucose)
The integration of fructose into mainstream CHO metabolism requires only two steps, occurring principally in the
Liver, intestines, and kidneys
Whereas intestinal fructose absorption is relatively slow, the first step in fructose metabolism is a very
Fast step
Both recruit dietary fructose as a substrate, to produce fructose 6-phosphate and fructose 1-phosphate (F-1-P), respectively
Hexokinase and Fructokinase
Hexokinase is comparatively quite inefficient at this, hence the significant majority of fructose is converted to fructose 1-phosphate by
Fructokinase
Only makes substantial contribution to fructose metabolism at very high substrate concentrations
Hexokinase
Cleaves Fructose1-P to D-glyceraldehyde and dihydroxyacetonephosphate (DHAP)
Aldolase B
Can enter pathways for glycolysis or gluconeogenesis
DHAP
Can enter glycolysis or be transformed into glycerol, the backbone for lipids
D-glyceraldehyde
Pathologies associated with dietary fructose take which two basic forms?
- ) Excessive intake
2. ) Hereditary deficiency for specific enzymes
In both cases, fructose toxicity is related to the formation of large amounts of
F-1-P
In both cases, fructose toxicity is related to the formation of large amounts of fructose 1-phosphate, with very slow turnover into
D-glyceraldehyde and DHAP
Because of the comparatively slow rate of catalysis by aldolase B (compared to that for fructokinase), under conditions of high dietary fructose intake there can be a significant build up of
F-1-P
A buildup of F-1-P causes a sequestration of the cell’s supply of
Pi
This, in turn, causes a decrease in available ATP levels, with concomitant increases in
ADP and AMP
Deamination of ADP and AMP results in
Hyperuricemia
Eventual action of aldolase B on this built up Fructose 1-P supply results in elevated levels of
Pyruvate and lactate
Also builds up by virtue of its competition with uric acid for filtration by the kidney
Lactate
Also increases under these high fructose conditions
Fatty acid and TAG synthesis
Because of these several adverse effects of high fructose in the diet, early theories that fructose is a ‘safe’ sugar for diabetics to use in place of glucose have largely been
Abandoned
Apart from the adverse effects of elevated uric and lactic acids, and elevated levels of fatty acids and triacylglycerols, the liver also metabolizes fructose-derived trioses via gluconeogenesis, thereby
Raising blood glucose anyway
Inborn errors in fructose metabolism fall into which two groups?
Essential fructosuria and hereditary fructose intolerance
Results from the absence of fructokinase.
-This is a rare and asymptomatic deficiency
Essential Fructosuria
Can be quite serious and has biochemical consequences very similar to that described above for excessive fructose intake in a normal individual
Hereditary Fructose Intolerance (HFI)
High levels of Fructose1-P build up (up to 10 mM) even in the absence of high fructose (or sucrose) intake with
HFI
Clinical manifestations of HFI include
Hypoglycemia, nausea, and vomiting after mild fructose exposure
Infants with HFI struggle with a failure to thrive and develop, including longer term concerns for
Liver damage and dysfunction
What is the aim of treatment for HFI?
Elimination of fructose from the diet
Prevents inhibition of glucokinase by fructose 6-phosphate
F-1-P
The principal monosaccharide in seminal fluid
Fructose
Fructose is synthesized in the seminal vesicles (along with other tissues, in both sexes) by the so-called
Polyol pathway
This two step conversion of glucose to fructose (polyol pathway) is driven forward by high concentrations of
NADPH and NAD
The intermediate compound of the polyol pathway
Sorbitol
Has a high Km for glucose
-the first enzyme in the polyol pathway
Aldose reductase
Sorbitol accumulates in the lens and in other tissues in which aldose reductase is found in
Diabetics
Increased intracellular sorbitol concentrations cause
Tissue damage
The integration of galactose into mainstream liver CHO metabolism offers a few branch points, but also includes only a few
Enzymatic Steps
Catalyzes the formation of galactose 1-phosphate (gal1-
P)
Galactokinase
Gal1-P is then converted into
UDP Galactose
Gal1-P is then converted into UDP-galactose by an exchange reaction with UDP-glucose, catalyzed by
Galactose 1-phosphate uridyl transferase
The final step is the epimerization of UDP-
galactose to
UDP-glucose
The final step is the epimerization of UDP-galactose to UDP-glucose, carried out by
UDP-galactose 4-epimerase
There are alternative fates for this product UDP-glucose. It may be converted into
Glycogen or G-1-P
UDP-glucose has yet other fates in the synthesis of
Lactose, glycolipids, glycoproteins, and proteoglycans
Formation of essential components of cell walls and membranes are the more critical fates for
Galactose
It is possible to completely eliminate dietary galactose and yet still supply cells with all that they require through the reversible action of
UDP-galactose 4-epimerase
Caused by a deficiency in Gal1-P uridyl transferase, leading to a build up of both galactose and gal1-P
Galactosemia
Classical Galactosemia is caused by a deficiency in
Gal-1-P Uridyl transferase
Partly because of the evident lack of toxicity in high galactose levels, it is believed most negative effects seen in galactosemia are attributable to
Gal-1-P
Another problem with galactosemia is buildup in the lens of
Galactitol
Can lead to cataracts by virtue of the production of galactitol in the lens, via aldose reductase
Galactokinase deficiency
Galactokinase deficiency can lead to cataracts by virtue of the production of galactitol in the lens, via
Aldose reductase
