Regulation of Glucose Metabolism & Polysaccharides as Storage Mechanisms (lec 12)

Regulatory steps of Glycolysis regulate around what 3 irreversible steps?

Hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK)

Feedback Inhibition

enough products —> lets stop (starts to go back to remain balanced)

Feed- Forward activation

have enough substrates (reactants) —> proceed forward

Hexokinase regulation: Is inhibited (blocked) by its product…?

classic feedback inhibition

What goes on in hexokinase regulation

• 2-Deoxyglucose (2-DG) can be phosphorylated (add a phosphate) by hexokinase to make 2-DG-phosphate (2-DGp)

• 2-GDp cannot be converted by phosphoglucose isomerase b/c its an competitive inhibitor

• extra 2-DG blocks more glucose from being phosphorylated, starving the cells

What is mechanisms of PFK Regulation

• AMP= adenosine monophosphate

  • cells are low on ATP, need more energy, so more glycolysis

  • AMP is more of an indirect effect

• super high levels of ATP

  • don’t need more energy —> block glycolysis

• H+ build up = too much lactate

  • build of product —> shut down

• citrate- part of aerobic metabolism, also a product

• most PFK regulators work allosterically

what is allosteric activator

allow effectors to bind to the protein, often resulting in a conformational change and/or a change in protein dynamics. Effectors that enhance the protein's activity

Fructose-2, 6-bisphosphate (F-2, 6-BP)

• strong PFK allosteric activator

• produced by another isoform of PFK called PFK-2

• phosphorylates at the 2 position instead of he 1 position

• lots of F-6-P leads to the production of F-2, 6-BP, which activates PFK to increase rate

• Feed-forward activation

what is PFK-2 regulation

• AMP-activated protein kinase (AMPK) senses high levels of AMP, turns on the kinase activity of PFK-2

• PFK-2 then makes F-2, 6-BP from F-6-P

  • ramps up glycolysis

• protein kinase A (PKA) inactivates PFK-2 kinase and activates PFK-2 phosphate function

  • F-2, 6-BP → F-1, 6-P

  • loss of F-2, 6-BP slows glycolysis

what is Pyruvate Kinase (PK) Regulation

• F-1, 6-BP

  • there are more reagents, ready to go, feed forward

• ATP= high energy state

  • shut down energy production

• Acetyl- CoA and alanine are downstream products, if they build up, we don’t wanna make more

Why do we regulate multiple enzymes?

• glucose is a primary point of entry for carbon at most cells

• carbon is used in almost everything

• glycolysis is common to practically all life on Earth

Why these processes (glycolysis) is highly regulated…

B/c they are happening in different cells, under different conditions, like glycolysis, gluconeogensis.. a futile cycle

What is glucose

a simple sugar that is easily broken down

how do plants and animals store glucose

polymers

what type of polysaccharides do plants make

starch and cellulose

what type of polysaccharides do animals make

glycogen

What is glycogen

• a branching polymer

• 75% found in muscle tissues

• 25% in the liver

• cannot be transported, must be metabolized where it’s made cuase its so big

• muscles never share their glucose, liver does

Glycogen synthesis Pathway

• glucose-6-P (G6P) is converted to glucose-1-P (G1P) by phosphoglucomutase (not phosphoglucose isomerase from glycolysis)

• G1P is attached to UDP to facilitate addition to growing chain

• UDP is lost during chain addition