|Lecture Notes: 4 April||
Start with G-6-P, again note that this molecule is at a metabolic crossroads. First convert to G-1-P using Phosphoglucomutase:
This reaction is very much like PGA Mutase, requiring the bis phosphorylated intermediate to form and to regenerate the phosphorylated enzyme intermediate. Note that this reaction is easily reversible, though it favors G-6-P.
Again a separate "support" enzyme, Phosphoglucokinase, is required to form the intermediate, this time using ATP as the energy source:
UDP-glucose pyrophosphorylase, which catalyzes the next reaction, has a near zero G° ':
It is driven to completion by the hydrolysis of the PPi to 2 Pi by Pyrophosphatase with a G° ' of about -32 kJ (approx. one ATP's worth of energy).
Finally glycogen is synthesized with Glycogen Synthase:
This reaction is favored by a G° ' of about 12 kJ, thus the overall synthesis of glycogen from G-1-P is favored by a standard free energy of about 40 kJ. Note that the glucose is added to the non-reducing end of a glycogen strand, and that there is a net investment of 2 ATP equivalents per glucose (ATP to ADP and UTP to UDP, regenerated with ATP to ADP). Note also that glycogen synthase requires a 'primer.' That is it needs to have a glycogen chain to add on to. What happens then in new cells to make new glycogen granules? Can use a special primer protein (glycogenin). Thus glycogen granules have a protein core.
These reactions will give linear glycogen strands, additional reactions are required to produce branching. Branching enzyme [amylo-alpha-(1,4) to alpha-(1,6)-transglycosylase] transfers a block of residues from the end of one chain to another chain making a 1,6-linkage (cannot be closer than 4 residues to a previous branch). [FYI: For efficient release of glucose residues it has been determined that the optimum branching pattern is a new branch every 13 residues, with two branchs per strand.]
Glycogen is broken down using Phosphorylase to phosphorylize off glucose residues:
Note that no ATP is required to recover Glucose phosphate from glycogen. This is a major advantage in anaerobic tissues, get one more ATP/glucose (3 instead of 2!). [FYI: Phosphorylase was originally thought to be the synthetic as well as breakdown enzyme since the reaction is readily reversible in vitro. However it was found that folks lacking this enzyme - McArdle's disease - can still make glycogen, though they can't break it down.]
Phosphorylase can only cleave 1,4-linkages, so now need Debranching enzyme. Debranching enzyme has two activities: a) amylo-alpha-1,4-transferase moves the terminal three residues of a chain onto another branch; whereas alpha-1,6-glucosidase hydrolyzes the 1,6-linkage to give free glucose. Thus muscle can release a small quantity of glucose into the blood without actually doing gluconeogenesis.
Since the Glycogen synthase and phosphorylase reactions are in opposition we need a control system. Glycogen storage/release strategies vary widely with different tissues. In liver, glycogen is used to provide glucose to the serum between meals - it serves a homeostatic function. Glycogen control in liver is thus designed to breakdown and release glycogen when serum [glucose] is low and synthesize glycogen when serum [glucose] is high.
In the liver glycogen metabolism is largely regulated by glucose concentrations, which in turn reflect serum glucose concentrations.
FYI - Glycogen Control in Liver
The net result is that glycogen is synthesized when [glucose] is hi, and it is broken down when [glucose] is low.
In muscle it turns out that glycogen synthesis/breakdown is controlled by a very complex system enabling both rapid response to emergencies and exquisite overall control of the opposing activities to respond to a variety of situations. This is accomplished through the Glycogen Cascade Control system. (The diagram shown is actually a simplified representation, especially of the synthase enzyme, which turns out to have 9 phosphorylatable sites which are phosphorylated by a number of different kinases responding to different complex physiological situations and with varying responses by the enzyme.)
Response begins with a hormonal signal, such as adrenalin, binding to the receptor on the cell surface. This results in the phosphorylation of GDP to GTP on an intracellular G-protein. The G-protein can now interact with Adenylate cyclase to produce the "second messenger" 3', 5'- cyclic AMP (cAMP). Cyclic AMP then binds to the regulatory subunit of cAMP-dependent protein kinase, releasing the active catalytic subunits (C), which can now phosphorylate inactive o-phosphorylase kinase b to the active m-phosphorylase kinase a (o= original, m= modified, b= inactive, a= active). Phosphorylase kinase a then phosphorylates o-Glycogen phosphorylase b to the active m-Glycogen phosphorylase a, resulting in the breakdown of glycogen with the release of G-1-P.
Note the parallel kinase cascade which simultaneously shuts down Glycogen synthase.
Finally, one does not always have a warning, that is time to get the endocrine system going to produce adrenalin, thus the release of Calcium in the muscle cells bypasses much of the cascade, activating the normally inactive o-Phosphorylase kinase b , which then acts on both the phosphorylase and the synthase.
In the non-oxidative portion of the Pentose Phosphate Pathway a series of sugar interconversions takes the RU-5-P to intermediates of other pathways: Ribose-5-P for nucleotide biosynthesis, and F-6-P and Ga-3-P for glycolysis/gluconeogenesis. All of these reactions are near equilibrium, with fluxes driven by supply and use of the three intermediates listed above.
Last modified 4 April 2007