What is the 1st step of glycogen synthesis?
Phosphorylation of glucose to glucose-6-phosphate via hexokinase (muscle) or glucokinase (liver)
What is the 2nd step in glycogenesis, after phosphorylation of its monomers?
Isomerization of g-6-p...
Intermediate: Glucose 1,6-Bisphosphate
What is the enzyme catalyzing the isomerization of glucose-6-phosphate and how does it do this?
- is phosphorylated on a serine residue and gives up this phosphoryl group to G-6-P to make G-1,6-BP
- then takes it back to leave G-1-P
What inhibits phosphoglucomutase?
What is the third step in glycogenesis (after isomerization of G6P)?
Combination of G-1-P and UTP...
Reactants: Glucose-1-phosphate + Uridine Triphosphate
Enzyme: UDP-Glucose Pyrophosphorylase
Products: UDP-Glucose + Pyrophosphate (PPi)
Why must an "active" form of glucose be made by addition of a nucleoside?
To overcome energetic unfavorability of polymerization by creating high group transfer potential
What drives the reaction catalyzed by UDP-Glucose Pyrophosphorylase?
Pyrophosphatase hydrolyzes the pyrophosphate cleaved off of uracil-triphosphate creating two Pi
- this pulls the reaction forward by getting rid of one of its products
What characteristics of UDP-Glucose Pyrophosphorylase make its reaction not a regulatory step of glycogenesis?
- low Km for G-1-P
- high concentration
What kind of bonds exist between glucose monomers in glycogen?
And at branching points?
between monomers: alpha 1-4 glycosidic bonds
at branching points: alpha 1-6 glycosidic bonds
What are the two "ends" of glycogen chains + what characterizes them?
Non-reducing End - no free glycosidic -OH
Reducing End - theoretically a free glycosidic -OH but in reality it is bound to glycogenin (which would be the "R" group in the image below)
Once UDP-glucose is formed, glycogen chain synthesis can begin.
Via what central molecule + how?
- autocatalyzes glucosylation via UDPGlc
- adds 7 glucose residues to itself to form glycogen primer
Once a glycogen primer is formed, how is it elongated?
- creates further alpha 1-4 bonds at the non-reducing end of the glycogen primer
How are glycogen branches made?
Glycogen Branching Enzyme
(Glycosyl 4,6 Transferase)
- when a glycogen branch is at least 11 glucoses long, this enzyme transfers a part of the chain to the middle of a neighboring chain via alpha 1-6 bond
What are 2 advantages of glycogen's branched structure?
- higher solubility
faster metabolism - via more non-reducing terminals
How are glycogen chains (not branches) broken down?
- cleaves 1-4 linkages via phosphorolysis to create glucose-1-phosphate
What does glycogen phosphorylase require in order to function?
How is it connected to this required co-factor?
Pyridoxal Phosphate (PLP)
- a coenzyme connected via Schiff-base linkage at the enzymes active site
How are glycogen branches broken down?
The enzyme has two activities. What are they?
Once the chains have been shortened to about 4 glucoses on either side of the branch point...
Debranching Enzyme uses...
Glucan transferase activity to move a trisaccharide from one side of the branch to the other, and...
1-6-Glycosidase activity to remove the one glucose at the branch point.
Once glycogen has been broken into monomers, how is it used?
Phosphoglucomutase changes G1P to G6P
Glucose-6-Phosphatase removes phosphate to make glucose
In what other way can glycogen granules be broken down, especially in neonates?
What genetic disorder relates to this?
- lysosomes engulf granules and maltase hydrolyzes glycogen
- lack of lysosomal maltase
- causes lysosomal glycogen buildup + muscle hypotonia/dystrophy
What genetic disorder of glycogen metabolism results from lack of a dephosphorylating enzyme in the liver?
What are its two subtypes?
Von Gierke Disease (Type I Glycogenosis)
- lack of glucose-6-phosphatase
- glycogen accumulates in liver + kidneys
- hypoglycemia; lactic acidemia; ketosis; hyperlipemia
- lack of ER G-6-P Transporter
- same effects + impaired neutrophil function
What genetic disorder effects muscle glycogen metabolism?
McArdle Disease (Type V Glycogenosis)
- lack of muscle-type glycogen phosphorylase
- muscle glycogen buildup + painful cramps