Glycogenolysis and Gluconeogenesis

Glycogenolysis occurs primarily in the..

cytosol; in liver and skeletal muscle

glycogenolysis produces

G6P and glucose

When does glycogenolysis occur?

short-term fasting and quick energy during muscle contraction

What is the first step of glycogenolysis

glycogen phosphorylase → phosphorylation of glycogen, which is the fastest step and doesn’t need ATP

What is the issue with glycogen phosphorylase

only cleaves a-1,4 linkages and cannot remove glucose residues near branch points (a-1,6 linkages)

What is the second step of glycogenolysis

debranching of glycogen with glycogen debranching enzyme 

Glycogen debranching enzyme (GDE) transferase activity

transfers 3 of 4 glucose resides from a branch point to a nearby linear chain, exposing single remaining residue attached via a-1,6 bond

Glycogen debranching enzyme (GDE) a-1,6 glucosidase activity

after transferase activity, hydrolyze a-1,6 bond, releasing free glucose molecule → creates LINEAR glycogen molecule so glycogen phosphorylase can continue break down a-1,4 linkages

What is the third step of glycogenolysis

conversion of G1P → G6P by phosphoglucomutase

Fate of G6P from glycogenolysis

muscle: glycolysis (bypasses ATP consuming step)

hepatocytes: free glucose

What is true about the fate of G6P in muscles

it yields one extra ATP compared to glucose derived from bloodstream because it bypasses the first ATP-consuming step of glycolysis 

Where does the conversion of G6P to free glucose occur?

Liver, ER of hepatocytes

Why is the liver’s ability to produce free glucose from G6P important?

maintaing blood glucose homeostasis especially during short fasting, prolonged exercise, or btw meals

What is true about G6P

it is an allosteric modulator of many catabolic enzymes

What is the compartmentalization of G6P in the ER important for?

regulating flux btw glucose storage and release

preventing futile re-phosphorylation/de phosphorylation cycle that would waste energy

regulate glucose release

Between amylopectin and glycogen, which is more highly branched?

glycogen (branches every 8-12 residues, compared to 20-30)

What is the purpose of glycogen being highly branched?

allows for rapid mobilization of glucose (lots of enzymatic sites)

more soluble (enzymatic access)

compactness

Glycogenin

primer that catalyzes attachment of first few glucose molecules in glycogen synthesis

Main regulatory steps of glycogenolysis and glycogenesis

glycogen phosphorylase and glycogen synthase

what would occur if glycogenolysis and glycogenesis ran simeultaneously?

unnecessary hydrolysis of UTP and waste of ATP

How is glycogen phosphorylase regulated hormonally? (glycogenolysis)

directly via adrenaline (muscle) and glucagon (liver); to a lesser extent, insulin (indirect and direct)

works through protein Kinase A pathway

How does the hormonal regulation of glycogen phosphorylase help ensure glycogen breakdown and synthesis do not occur simultaneously?

PKA pathway also phosphorylates glycogen synthase, rendering it inactive

Allosteric regulation of glycogen phosphorylase

well fed state [G6P] [ATP] [glucose] → high → inhibits glycogen phosphorylase

High energy demand → AMP and Ca2+-CaM activates glycogen phosphorylation

How is glycogen phosphorylase allosterically regulated by Ca2+

myocyte depolarizes due to synaptic signaling causing inc in Ca2+ release from ER

Ca2+ binds to CaM, bypassing cAMP-PKA step

What is responsible for the inc in blood glucose during stress

increase in Ca2+ release activating glycogen phosphorylase kinase, bypassing cAMP-PKA step

What is true about allosteric regulation of glycogen phosphorylase in muscles?

AMP and Ca2+ activate glycogen phosphorylase B even when unphosphorylated

Allosteric regulation of glycogenolysis is ATP _____ while hormonal regulation is _____

independent, dependent

Allosteric regulation of glycogen phosphorylase is capable of..

overriding the effects of hormone regulation

Vione Gierke disease

mutation of G6P → overaccumulation of glycogen in iver → hepatomegaly combined w/chronic hypoglycemia and impaired growth

McArdle disease

skeletal muscle phosphorylase defiency

temporary weakness + severe cramping after exercise but normal glycemia

benign

How much ATP does glycogenolysis ultimately yield after anaerobic glycolysis?

3 ATP

What enzyme in glycogenolysis is involved in the liver but not in the muscle?

glucose 6 phosphatase 

Gluconeogenesis is critical for maintaing a constant source of glucose for our body during..

prolonged fasting or insufficient carbohydrate intake

Gluconeogenesis synthesizes glucose from..

non-carb precursors: lactate, glycerol, and glucogenic amino acids

Following short fasting, 90% of gluconeogenesis occurs in the _____ while during prolonged fasting 40% occurs in the ____

liver; kidneys

Step 1 of gluconeogenesis: Pyruvate carboxylase

pyruvate → oxaloacetate; uses ATP, CO2, and biotin

Step 2: PEPCK

OAA → PEP (uses GTP, releases CO2)

The steps from _________ (steps 3-8) use the same enzymes as glycolysis but in reverse, consuming ATP and NADH rather than producing them

PEP to F16BP 

Step 9 of gluconeogenesis: FBPase-1

F16P → F6P

Which step in gluconeogenesis is the key regulatory step and what is it activated and inhibited by?

FBPase-1; Activated by ATP, inhibited by AMP and F26BP

FBPase-1 is indirectly regulated by this hormone

glucagon signlaing phorphorylate PFK-2, thus inhibiting its production of F26P

What prevents gluconeogenesis and glycolysis from running at the same time

the regulatory steps in both pathways in the conversion of F16P → F6P and vise versa (know which enzymes and what they are inhibited by and their relationship)

step 10 of gluconeogenesis: Phosphoglucose Isomerase (PGI)

F6P → G6P (same as glycolysis)

Step 11 of gluconeogenesis: Glucose-6 phosphatase

G6P → Glucose

This enzyme is located in the ER of hepatocytes and renal cortical cells and requires a..

Glucose-6 phosphatase; G6P transporter

Conversion of lactate into glucose uses the…

cori cycle in the liver; does not require energy and produces NADH

Conversion of glycerol into glucose

TGs → DHAP → glycolysis (shortest and most efficient way)

Conversion of AAs into glucose

ex. Alanine → pyruvate → oxaloacetate → gluconeogenesis

Where is the energy and reducing power derived from for gluconeogenesis

fatty acid oxidation, especially during fasting

Energy cost of glucose synthesized from pyruvate

4 ATP, 2 GTP, 2 NADH (-11)

Energy cost of glycerol to glucose

2 ATP needed; 2 NADH generated (+3)

Energy cost from lactate to glucose

4 ATP, 2 GTP (-6)

Energy cost from AA to glucose

depends on AA:

no cost for alanine

glutamate generates NADH

other AAs require ATP

What is the primary hormone that promotes gluconeogenesis

glucagon

How does glucagon regulate gluconeogenesis

inc cAMP signaling → PFK A → PFK2 phosphorylated → Inhibits F26P, which in turn is an inhibitor of FBPase-1, so activates the pathway

Glucagon increases the expression of these two gluconeogenic enzymes

PEPCK and FPBase-1

How is gluconeogenesis allosterically inhibited?

acetyl coA → activates pyruvate carboxylase

AMP → inhibits FBPase

Which is true of gluconeogensis?

It acts as a long-term solution when glycogen stores are depleted

why fructose does not stimulate insulin release the way glucose does.

β-cells cannot metabolize fructose into glucose so no ATP is generated to help trigger insulin release