|Lecture Notes: 9 April||
Last time I forgot to go over a pathway diagrams, aerobic catabolism of glucose and Kreb's cycle intermediate catabolism.
Regulation and Control: The concentration of citrate also affects PFK activity as a negative effector.
Interconversion of metabolic intermediates: The TCA cycle has a central place in metabolism (even in anaerobic organisms) via its use to interconvert metabolites as summarized in Figure 13.13 in your text. We will look further at these interactions as the course proceeds.
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.
Last modified 9 April 2010