Loading presentation...

Present Remotely

Send the link below via email or IM

Copy

Present to your audience

Start remote presentation

  • Invited audience members will follow you as you navigate and present
  • People invited to a presentation do not need a Prezi account
  • This link expires 10 minutes after you close the presentation
  • A maximum of 30 users can follow your presentation
  • Learn more about this feature in our knowledge base article

Do you really want to delete this prezi?

Neither you, nor the coeditors you shared it with will be able to recover it again.

DeleteCancel

Make your likes visible on Facebook?

Connect your Facebook account to Prezi and let your likes appear on your timeline.
You can change this under Settings & Account at any time.

No, thanks

Glucose Supplies: Glycogen, Gluconeogenesis, & Disease

Presentation covering glycogen metabolism, gluconeogenesis, and associated diseases
by

Jay Silveira

on 13 September 2013

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of Glucose Supplies: Glycogen, Gluconeogenesis, & Disease

Fructose 1,6-Bisphosphate
Glucose
Glucose 6-Phosphate
Fructose 6-Phosphate
Dihydroxyacetone Phosphate
Glyceraldehyde
3-Phosphate
1,3-Bisphosphoglycerate
3-Phosphoglycerate
2-Phosphoglycerate
Phosphoenolpyruvate
Pyruvate
Lactate
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
Hexokinase
Phosphoglucose Isomerase
Phosphofructokinase
Aldolase
Triose Phosphate Isomerase
Glyceraldehyde 3-Phosphate Dehydrogenase
Phosphogylcerate Kinase
Phosphogylcerate Mutase
Enolase
Pyruvate Kinase
Lactate Dehydrogenase
C5
C6
Glycogen Metabolism, Gluconeogenesis, & Disease - Objectives
Describe the structure of glycogen.
Know 10 key enzymes involved in glycogen synthesis and degradation and understand their function.
Learn the common names and the biochemistry behind glycogen storage diseases I through VI.
Know the three key sources of carbon for creating glucose via gluconeogenesis.
Explain the implications of fructose 1,6-bisphosphatase deficiency

Phosphoglucose Isomerase
Aldolase
Triose Phosphate Isomerase
Glyceraldehyde 3-Phosphate Dehydrogenase
Phosphogylcerate Kinase
Phosphogylcerate Mutase
Enolase
Lactate Dehydrogenase
Glycolysis is such a central and critical metabolic pathway that you can’t exist without it!
Phosphofructokinase
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
C5
C6
Structure learning tip…
G-6P is easy to draw if you’ve learned glucose, simply exchange the hydroxyl at position 6 for a phosphate group.
C5
C6
Glycogen
Gluconeogenesis
When the glycogen in the liver is depleted, blood glucose is maintained by gluconeogenesis. The glucose is derived from three primary sources:
Lactate from anaerobic glycolysis is converted to pyruvate, then oxaloacetate, then malate for mitochondrial export, back to oxaloacetate, then PEP and onward to glucose.
Amino acids at the level of pyruvate from alanine or TCA cycle intermediates from other amino acids.
Glycerol enters the pathway at the level of triose phosphates.
Gluconeogenesis is much like glycolysis in reverse, except that certain steps in glycolysis must be bypassed with new enzymes. Which steps are likely to require new enzymes?
The irreversible steps
BIOC 212
14
Where does the glycerol come from?

The breakdown of fats (a.k.a. triglycerides)
Gluconeogenesis
When the glycogen in the liver is depleted, blood glucose is maintained by gluconeogenesis. The glucose is derived from three primary sources:
Lactate from anaerobic glycolysis is converted to pyruvate, then oxaloacetate, then malate for mitochondrial export, back to oxaloacetate, then PEP and onward to glucose.
Amino acids at the level of pyruvate from alanine or TCA cycle intermediates from other amino acids.
Glycerol enters the pathway at the level of triose phosphates.
BIOC 212
13
The liver cannot respond to the need for glucose, and hypoglycemia results.
BIOC 212
11
In individuals afflicted with this disease, muscle cramps occur at the onset of exertion because muscle glycogen cannot be broken down to supply needed glucose for energy. The cramps can subside as exertion is continued and blood flow increases – supplying sufficient glucose.
BIOC 212
10
Glycogen has very short outer chains because it cannot be degraded further, and accumulates in liver and muscle
BIOC 212
8
Pompe’s was the first glycogen storage disease to be identified (1932)
The most devastating glycogen storage disease of a special lysozyme enzyme that degrades maltose (glucose dimer). Lysosomes accumulate glycogen in all cells, and death occurs by cardiorespiratory failure before the age of 1.
On April 28, 2006 the US FDA approved the use of Myozyme (alglucosidase alfa, rhGAA), the first treatment for patients with Pompe disease, by intravenous infusion of solution into a vein.. This was based on enzyme replacement therapy work pioneered by Drs Arnold Reuser and Ans van der Ploeg at Erasmus University, Rotterdam. This eventually led to successful clinical trials.
Myozyme is manufactured by Genzyme Corp. in Cambridge, Massachusetts, USA., and costs an average of $300,000 a year, and must be taken for the patients' entire life. Some insurers have refused to pay for it.
BIOC 212
7
Glc-6-P buildup inhibits glycogen phosphorylase – can’t increase blood glucose in response to glucagon or epinephrine. Massive liver enlargement
BIOC 212
6
Debranching
Enzyme
The outer 3 glucose residues are added to the main branch
Glycogenolysis (Glycogen Breakdown)
After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis stops. The hormone glucagon is secreted in increasing amounts. Glycogenolysis has some similarities to glycogenesis in reverse, the glucose residues are:
Removed from external a14 linkages and phosphorylated to Glc-1-P by glycogen phosphorylase, the rate-limiting regulatory step of the process.
Converted to Glc-6-P, then glucose, and released into the blood.
Branch points are removed through the combined work of a pair of enzymes.
Transglycosylase
Glucosidase
BIOC 212
4
Glycogenesis (Glycogen Synthesis)
As a carbohydrate meal is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin, which stimulates the action of several enzymes. Glucose from the portal vein enters the liver cells (hepatocytes). The glucose is:
Converted into Glc-6-P then Glc-1-P
Activated to UDP-Glc
Transferred to glycogen in an a14 linkage by glycogen synthase – the regulatory enzyme for the process.
Branched with a16 linkages when the chains exceed eight residues in length.
Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases.
BIOC 212
3
Glycogen structure: α1→4 chains and an α1→6 branch point. Glycogen is stored as granules in liver and muscle cytoplasm.
Glycogen
Glycogen is a highly-branched polysaccharide of glucose that represents the sugar’s principal storage form in animal cells. Most of the glucose units are linked by α-1,4 glycosidic bonds, but every 4 to 6 residues there is an α-1,6 glycosidic bond with a second residue, which results in the creation of a branch.
BIOC 212
1
What cells are constantly making lactate because they run glycolysis anaerobically?

Red
Blood
Cells!
Gluconeogenesis
When the glycogen in the liver is depleted, blood glucose is maintained by gluconeogenesis. The glucose is derived from three primary sources:
Lactate from anaerobic glycolysis is converted to pyruvate, then oxaloacetate, then malate for mitochondrial export, back to oxaloacetate, then PEP and onward to glucose.
BIOC 212
12
One of the most severe glycogen storage diseases – glycogen is found in very long chains, and has reduced solubility. Victims rarely survive past 4 years of age due to liver dysfunction.
BIOC 212
9
*
* http://en.wikipedia.org/wiki/Glycogen_debranching_enzyme --> see second paragraph
Debranching
Enzyme

Synthesis
Glucokinase/Hexokinase – adds phosphate to glucose
Phosphoglucomutase – Converts G-6P to G-1P
UDP-glucose pyrophosphorylase – Converts G-1P to UDP-Glc
Glycogenin – creates glycogen primers of 8 glucose units
Glycogen synthase – adds glucose units to glycogen
Branching enzyme – creates branch points
Degradation
Glycogen phosphorylase – cleaves glucose units from glycogen
Transferase – transfers blocks of 3 glucose units (debranching enzyme)
Glucosidase – cleaves branch points (debranching enzyme)
Phosphoglucomutase – Converts G-1P to G-6P
Glucose 6-phosphatase – removes phosphate from G-6P
BIOC 212
5
Glycogen structure
Glycogen
Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for glucose, but one that is less compact than the energy reserves of triglycerides. Only the glycogen stored in the liver can be made accessible to other organs, and these hepatocytes have the highest concentration of it – roughly 3-5%, but up to 8% of the fresh weight in well fed state, or 100–120 g in an adult. In the muscles, glycogen is found in a much lower concentration (0.5-1% of the muscle mass), but the total amount exceeds that in liver because of the relatively large mass of muscle present in the body.
BIOC 212
2
Apnea = suspension of external breathing
F-1,6-BPase deficiency:
Hypoglycemia
Elevated lactate
X
Gluconeogenesis
BIOC 212
15
Glycogen is a highly-branched polysaccharide of glucose that represents the sugar’s principal storage form in animal cells. Most of the glucose units are linked by α-1,4 glycosidic bonds, but every 10 to 14 residues there is an α-1,6 glycosidic bond with a second residue, which results in the creation of a branch (note that the structure above is condensed with only 2 glucose residues between branch points for illustration purposes).
1
4
1
4
1
6
1
6
As a carbohydrate meal is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin, which stimulates the action of several enzymes. Glucose from the portal vein enters the liver cells (hepatocytes).

Glycogen synthesis can't start without a primer - so the enzyme
glycogenin
serves as this primer, as well as the core of the glycogen granule. Several molecules of glucose are added to a tyrosine residue of the
glycogenin
enzyme, which permits
glycogen synthase
to begin building the rest of the glycogen chain.
Glycogenin
There are multiple steps involved to get glucose into glycogen

1) The glucose is converted into Glucose-6-Phosphate as usual in glycolysis by
hexokinase
(or glucokinase)

2) The phosphate is moved to carbon 1 on glucose by
Phosphoglucomutase

3) The Glucose 1-phosphate is activated to UDP glucose by
UDP-glucose pyrophosphorylase
The molecule of UDP-glucose is then added to the end of the glycogen chain by glycogen synthase, creating an alpha 1-4 glycosidic bond.
Glycogen synthase
is the main regulatory enzyme for the process.
When glycogen chains exceed approximately eight residues in length, they are branched by adding a glucose residue through an alpha 1-6 linkage, and a chain of several glucose are removed from the main chain of the glycogen and added on to the new branch. Both these actions are performed by
Branching Enzyme
. Branches are typically found every 10 to 14 glucose units.
After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis stops. The hormone glucagon is secreted in increasing amounts, and glycogenolysis, or glycogen breakdown, begins. Glycogenolysis has some similarities to glycogenesis in reverse, the glucose residues are first removed and simultaneously phosphorylated at carbon number 1 from external alpha 1-4 linkages by
glycogen phosphorylase
, the rate-limiting regulatory step of the process.
Branch points are removed through the combined work of a pair of enzymes, a
transferase
, which removes all but the last alpha 1-6 linked gl
u
cose residue of the branch and transfers it to the end of the main glycogen chain, and a
glucosidase
that cleaves off the alpha 1-6 linked glucose molecule. These activities are found together on the enzyme known as
debranching enzyme
.
The released glucose 1-phosphate residues are converted to Glc-6-P, by
phophoglucomutase
, and in the case of the liver, the phosphate is removed by the enzyme
glucose 6-phosphatase
, and the glucose is released into the blood.
Glucose 6-phosphate
Glycogen Enzymes Summary
Lysosomal alpha glucosidase deficiency: The most devastating glycogen storage disease of a special lysozyme enzyme that degrades maltose (glucose dimer). Lysosomes accumulate glycogen in all cells, and death occurs by cardiorespiratory failure before the age of 1.
Debranching enzyme deficiency: Glycogen has very short outer chains because it cannot be degraded further, and accumulates in liver and muscle.
Branching enzyme deficiency: One of the most severe glycogen storage diseases – glycogen is found in very long chains, and has reduced solubility. Victims rarely survive past 4 years of age due to liver dysfunction.
Muscle glycogen phosphorylase deficiency: In individuals afflicted with this disease, muscle cramps occur at the onset of exertion because muscle glycogen cannot be broken down to supply needed glucose for energy. The cramps can subside as exertion is continued and blood flow increases – supplying sufficient glucose.
Liver glycogen phosphorylase deficiency: The liver cannot respond to the need for glucose, and hypoglycemia results.
Glycerol
Amino
Acids
When the glycogen in the liver is depleted, blood glucose is maintained by gluconeogenesis. The glucose is derived from three primary sources:

1) Lactate from anaerobic glycolysis is converted to pyruvate, then oxaloacetate, then malate for mitochondrial export, back to oxaloacetate, then PEP and onward to glucose.

2) Amino acids at the level of pyruvate from alanine or TCA cycle intermediates from other amino acids.

3) Glycerol enters the pathway at the level of triose phosphates.
Gluconeogenesis is much like glycolysis in reverse, except that certain steps in glycolysis must be bypassed with new enzymes. Which steps are likely to require new enzymes?
1) Lactate from anaerobic glycolysis is converted to pyruvate, then oxaloacetate, then malate for mitochondrial export, back to oxaloacetate, then PEP and onward to glucose.
2) Amino acids at the level of pyruvate from alanine or TCA cycle intermediates from other amino acids.
3) Glycerol enters the pathway at the level of triose phosphates.
What cells are constantly making lactate because they run glycolysis anaerobically?
Glucose 6-phosphatase deficiency: Glc-6-P buildup inhibits glycogen phosphorylase – can’t increase blood glucose in response to glucagon or epinephrine. Massive liver enlargement.
Where does the glycerol come from?
Glucose
6-phosphatase
Fructose-1,6
biphosphatase
pyruvate carboxylase
&
PEP carboxykinase
F-1,6-BPase deficiency:
Hypoglycemia
Elevated lactate
Full transcript