For each enzyme, indicate the pathway it is a part of, and indicate whether, in

Question

For each enzyme, indicate the pathway it is a part of, and indicate whether, in the liver, it is activated by the actions of insulin or glucagon. The phrase "by the actions of", means that it does not have to be a direct activation, but can be caused by a cascade effect initiated by the hormone.

Do not be deceived by the width of the text box. Moodle does this weird thing where they set the spaces of the text box with a random number of spaces. For each enzyme, indicate the pathway it is a part of, and indicate whether, in the liver, it is activated by the actions of insulin or glucagon. The phrase "by the actions of', means that it does not have to be a direct activation, but can be caused by a cascade effect initiated by the hormone. Each of the enzymes below is involved in a hormone sensitive cascade that impacts glycogen metabolism. For each enzyme, select the direct method of activation of the enzyme.

Explanation / Answer

Dear Student,

1. Pyruvate Kinase

Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP yielding one molecule of pyruvate and one molecule of ATP.

Pyruvate Kinase lies within the glycolytic pathway, which produces pyruvate molecules, the final product of aerobic glycolysis.

However, in anaerobic glycolysis, lactate dehydrogenase will utilize the NADH produced by glyceraldehyde phosphate dehydrogenase to reduce pyruvate to lactate.

Liver pyruvate kinase is regulated indirectly by epinephrine and glucogan.

An increase in blood sugar leads to secretion of insulin, which activates phosphoprotein phosphatase I, leading to dephosphorylation and activation of pyruvate kinase.

These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction (pyruvate carboxylase and phosphoenolpyruvate carboxykinase), preventing a futile cycle.

Here the enzyme pyruvate kinase is activated by insulin.

2. Frutose 1,6-biphosphatase

Fructose 1,6- bisphosphatase is an enzyme that converts fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle which are both anabolic pathways.

Fructose bisphosphatase catalyses the reverse of the reaction which is catalysed by phosphofructokinase in glycolysis.

These enzymes only catalyse the reaction in one direction each, and are regulated by metabolites such as fructose 2,6-bisphosphate so that high activity of one of the two enzymes is accompanied by low activity of the other.

More specifically, fructose 2,6-bisphosphate allosterically inhibits fructose 1,6-bisphosphatase, but activates phosphofructokinase-I.

Fructose 1,6-bisphosphatase is involved in many different metabolic pathways and found in most organisms.

The enzyme fructose 1,6-biphosphatase is activated by glucogon.

3. Glycogen Phosphorylase

Glycogen phosphorylase is one of the phosphorylase enzymes.

Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond.

Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

Glycogen phosphorylase undergoes glycolysis pathway where it breaks up glycogen into glucose subunits (see also figure below):

(-1,4 glycogen chain)n + Pi (-1,4 glycogen chain)n-1 + -D-glucose-1-phosphate.[2]

Glycogen is left with one fewer glucose molecule and the free glucose molecule is in the form of glucose-1-phosphate.

In order to be used for metabolism, it must be converted to glucose-6-phosphate by the enzyme phosphoglucomutase.

Hormones such as epinephrine, insulin and glucagon regulate glycogen phosphorylase using second messenger amplification systems that are linked to G proteins.

But in the liver, glucagon activates another G-protein-linked receptor that triggers a different cascade, resulting in the activation of Phospholipase C (PLC).

PLC indirectly causes the release of calcium from the hepatocytes' endoplasmic reticulum into the cytosol.

The increased calcium availability binds to the calmodulin subunit and activates glycogen phosphorylase kinase.

Glycogen phosphorylase kinase activates glycogen phosphorylase in the same manner mentioned previously.

Here the enzyme is regulated by insulin as well as glucogon.

4. Glycogen Synthase

Glycogen synthase is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers of glycogen.

It is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and (1,4--D-glucosyl)n to yield UDP and (1,4--D-glucosyl)n+1.

In other words, this enzyme converts excess glucose residues one by one into a polymeric chain for storage as glycogen.

Glycogen synthase concentration is highest in the bloodstream 30 to 60 minutes[2] following intense exercise.

It is a key enzyme in glycogenesis.

Glycogen synthase undergoes glycolysis pathway.

The mechanism for synthesis is similar in glycogen synthase and glycogen phosphorylase.

These regulatory enzymes are regulated by insulin and glucagon signaling pathways.

5. Phosphate fructokinase 1

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes (EC 2.7.1.11) of glycolysis.

It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors.

PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP.

Glycolysis is the foundation for respiration, both anaerobic and aerobic.

Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory and rate limiting steps of glycolysis.

PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell’s energy requirements.

Phosphofructose kinase 1 is inhibited by glucagon through repression of synthesis.

Glucagon activates protein kinase A which, in turn, shuts off the kinase activity of phosphofructose kinase 2.

This reverses any synthesis of Fructose 2,6 -biphosphate from Fructose 6-phosphate and thus inhibits Phosphofructose kinase 1 activity.

Here the enzyme is regulated by glucogon.

6. Pyruvate Carboxylase

Pyruvate carboxylase (PC) is an enzyme of the ligase class that catalyzes the irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

During gluconeogenesis, pyruvate carboxylase is involved in the synthesis of phosphoenolpyruvate (PEP) from pyruvate.

Pyruvate is first converted by pyruvate carboxylase to oxaloacetate (OAA) in the mitochondrion requiring hydrolysis of one molecule of ATP.

The OAA is then decarboxylated and simultaneously phosphorylated, which is catalyzed by one of two isoforms of phosphoenolpyruvate carboxykinase (PEPCK) either in the cytosol or in the mitochondria to produce PEP.

Under ordinary gluconeogenic conditions, OAA is converted into PEP by mitochondrial PEPCK; the resultant PEP is then transported out of the mitochondrial matrix by an anion transporter carrier system and converted into glucose by cytosolic gluconeogenic enzymes.

Similarly to other gluconeogenic enzymes, PC is positively regulated by glucagon and glucocorticoids while negatively regulated by insulin.

Here the enzyme is regulated by glucogon.

7. Pyruvate Dehydrogenase

Pyruvate dehydrogenase is the first component enzyme of pyruvate dehydrogenase complex (PDC).

The pyruvate dehydrogenase complex contributes to transforming pyruvate into acetyl-CoA by a process called pyruvate decarboxylation.

Pyruvate dehydrogenase undergoes phosphorylation pathway.

PDK is inhibited by dichloroacetic acid and pyruvate resulting in a higher quantity of active unphosphorylated PDH.

Phosphorylaton is reversed by pyruvate dehydrogenase phosphatase, which is stimulated by insulin, PEP, and AMP, but competitively inhibited by ATP, NADH, and Acetyl-CoA.

Here the enzyme is regulated by insulin.

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