Amino Acid Structure and Properties

Response to Organisms Physiology

Hormonal Response to Changes at the Organism Level

These same pathways not only respond the cells energy state but also to the organism's energy state. While the END result is similar.... some change that alters the equilibrium between GOOD and POOR catalytic structures, the mechanism must be (and is) entirely different. The organism measures its energy state not in terms of [ATP] but in blood glucose concentration. When blood glucose is high, the organism should take up glucose into the liver and store it as Glycogen. On the other hand as blood glucose decreases, the organism should break down Glycogen AND increase the rates of gluconeogenesis in the liver to for highest rates of glucose synthesis and ship it out to the blood. In this way the blood glucose levels remain fairly constant throughout the day so long as there is Glycogen to break down.

The pancreas reacts to blood glucose as follows:

Let's take a closer look at the Glucagon response in the liver.

In short many enzymes in liver cells are covalently modified with a phosphate group as [Glucagon] increases in the blood. It occurs via a cascade type system that is somewhat reminiscent of the blood coagulation cascade that we have looked at on occasion.

Enzymes that are covalently modified with a phosphate group:

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glucagon effect animation
Color Code: Abbreviations:
Active Enzyme: YellowG protein: GDP binding protein
Inactive enzyme: RedF26BPase: Fructose 2,6 Bisphosphatase
Phosphorylated protein (label color):MagentaSPK: Synthase/Phosphorylase Kinase (ATP dependent phosphorylation of Glycogen synthase and Glycogen Phosphorylase)
Protein Not Phosphorylated (label color):BlackGS:Glycogen synthase
Non Proteins: Black GP: Glycogen Phosphorylase
Protein never modified (label color):GreenR: regulatory subunit of cAMP dependent protein kinase
C: catalytic subunit of cAMP dependent protein kinase

Short description of the Glucagon "activation" process:

  1. Glucagon in the blood is secreted by the pancreas in response to LOW blood sugar
  2. Glucagon binds to the Glucagon receptor. The receptor uses ATP to phosphorylate itself (autophosphorylation)
  3. G protein, in contact with phosphorylated receptor exchanges GTP for GDP
  4. It's subunits separate into one containing the GTPase activity and two others
  5. The GTP containing subunit of the G protein contacts Adenylate cyclase. Adenylate cylase starts to produce cAMP.
  6. As the [cAMP] in the cell rises it binds to cAMP dependent protein kinase ( a tetrameric protein containing two catalytic subunits and two regulatory subunits) as a tetramer it is inactive.
  7. cAMP binding to cAMP dependent protein kinase causes the regulatory subunits to dissociate from the catalytic subunits. The catalytic subunits are now active for ATP dependent phosphorylation.
  8. The active cAMP dependent protein kinase phosphorylates (among others) two proteins: 1 synthase/Phosphorylase kinase, 2 the peptide that contains phosphofructokinase-2 and fructose-2,6-bisphosphatase activities.
  9. The protein # 2 in the previous step is most active in the fructose 2,6-Bisphosphatase activity it starts to hydrolyze fructose-2,6-Bisphosphate to fructose-6-phosphate. The synthase/Phosphorylase kinase is now active to phosphorylate Glycogen synthase (least active form) and Glycogen Phosphorylase (most active form)
  10. The activities of Glycogen synthase and Glycogen Phosphorylase ensure that Glycogen is mostly broken down under these circumstances

Short description of the "relaxation" back to "normal" process:

  1. Glucagon concentration decreases in blood (It is a small peptide with a short half life in the blood)
  2. Glucagon dissociates from the receptor. The receptor become conformation is such that it stop autophosphorylation.
  3. The GTP bound protein has a SLOW inherent GTP hydrolysis activity so with some time it hydrolyzes GTP to GDP + PO4=
  4. The G protein reassociates and this inactivates the adenylate cyclase activity
  5. The enzyme phosphodiesterase hydrolyzes cAMP to AMP
  6. The GENERAL enzyme, protein phosphatase, hydrolyzes the phosphate groups off of most phosphorylated proteins.